Micafungin antifungal prophylaxis in children undergoing HSCT: can we give higher doses, less frequently? A pharmacokinetic study

Micafungin antifungal prophylaxis in children undergoing HSCT: can we give higher doses, less... Abstract Background Micafungin has a distinct advantage for antifungal prophylaxis in HSCT owing to its better safety profile, specifically in terms of hepatic and renal toxicity. In children, prophylactic micafungin is given as either 1 mg/kg every day or 3 mg/kg every other day. Objectives We performed a prospective single-centre observational study that investigated the pharmacokinetics (PK) of a single 5 mg/kg dose of micafungin in young children undergoing HSCT, to ascertain the eventual feasibility of twice-weekly prophylactic administration. Methods Nine children, ≤10 years of age undergoing HSCT, were enrolled and received a single intravenous dose of 5 mg/kg micafungin. Blood samples were obtained for PK analysis. Micafungin plasma concentration of >0.2 mg/L was chosen for target attainment (i.e. considered adequate prophylactic concentration). In addition, a population PK model was developed based on current and our previous PK study data. We also evaluated PK model-based simulation of PK profiles and target attainment using Monte Carlo simulation, for several dosing scenarios. Results Mean clearance was 15.3 mL/h/kg (range 11.0–21.4 mL/h/kg) and the mean elimination half-life was 11.6 h (range 7.8–16.6 h). The mean concentration at 96 h was 0.11 mg/L (range 0.03–0.26 mg/L). Eleven percent (n = 1) of patients achieved target attainment at the end of 96 h. Simulation data showed that 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies achieved at least 99% and 81% target attainment, respectively, whereas a 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Conclusions Micafungin at 5 mg/kg dosing did not achieve target attainment at the end of 96 h for antifungal prophylaxis in children undergoing HSCT. Simulation data suggest that a dosing strategy of micafungin at 5 mg/kg every 72 h is more likely to achieve target attainment in children with a higher body weight in comparison with children with a lower body weight. A cautious approach is advisable when using a high, but less frequent, dosing strategy in very young children. Introduction Disseminated fungal disease causes significant morbidity and mortality in children undergoing allogeneic HSCT.1–3 Graft-versus-host disease (GVHD) after allogeneic HSCT requires significant immunosuppression and, in turn, increases the risk of invasive fungal disease.2,4 The leading causes of opportunistic fungal disease in these patients are Candida and Aspergillus species.5,6 The life-threatening nature of invasive fungal disease necessitates antifungal prophylaxis for all patients undergoing HSCT. Several options are available for antifungal prophylaxis, but each has its own limitations and none has been found to be ideal. Oral triazoles are limited by poor absorption, inter-individual variability in metabolism and hepatic toxicity,7 whereas prophylaxis with amphotericin B is limited by nephrotoxicity.8 An alternative approach to prophylaxis is the use of intravenous micafungin, an antifungal agent of the echinocandin class, which has a more favourable safety profile compared with azoles and amphotericin B with low frequencies of hepatic and renal toxicity.9 Micafungin acts by inhibiting the production of 1,3-β-D-glucan, a key component in fungal cell wall synthesis.9 A semisynthetic lipopeptide, micafungin possesses in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species, including activity against azole-resistant Candida.9–13 The pharmacokinetics (PK) of micafungin has been studied in children in different groups and, in general, micafungin was also found to have a favourable safety profile.14–18 Children who undergo HSCT receive prophylactic micafungin at 1 mg/kg once daily or 3 mg/kg/dose every other day as previously shown by our group.17,19 Micafungin can only be administered intravenously and the family is responsible for administering the medication following discharge from the hospital. Prolonged antifungal prophylaxis is often required in children undergoing HSCT and the frequent administration places an additional burden on the family. A less frequent dosing regimen would therefore be desirable. In adults, Neofytos et al.20 studied the safety and efficacy of intermittent administration of high-dose intravenous micafungin (≥300 mg micafungin 2–3 times weekly) in patients with acute leukaemia and allogeneic HSCT recipients. Although micafungin levels were not obtained in this study, micafungin was well tolerated overall with low (6.0% of patients) incidence of breakthrough fungal infection. We hypothesized that higher-dose micafungin at 5 mg/kg would generate adequate concentrations at the end of 96 h, leading to a more practical twice-weekly dosing regimen for antifungal prophylaxis. To ascertain the feasibility of eventual twice-weekly prophylactic administration, we performed a PK study of micafungin following a single dose of 5 mg/kg in young children undergoing HSCT. Population PK models greatly assist in delineating optimal dosing regimens and have been developed for micafungin in infants and children.21,22 However, a population PK model for micafungin has not been developed in children undergoing HSCT, a unique population in which several factors can influence and alter drug PK. We developed a population PK model for micafungin in children undergoing HSCT and the model was used in a simulation analysis to evaluate PK profile and target attainment (i.e. considered adequate prophylactic concentration) for several dosing scenarios. Methods Study design This was a prospective single-centre observational clinical trial to characterize the PK of 5 mg/kg micafungin every four days in young children undergoing HSCT. Patients receiving HSCT for whom antifungal prophylaxis was clinically indicated were eligible for the study. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used to evaluate adverse events. The study included children aged ≤10 years, because the goal of our study was to evaluate the PK of micafungin in young children. Dose selection was based on our previous experience with 3 mg/kg alternate-day micafungin PK,17 and exploration of different dosing regimens using Monte Carlo PK/pharmacodynamic simulation (SimLab, Monte Carlo analysis tool, Medimatics, Maastricht, The Netherlands). Based on our simulation results, it was estimated that a 5 mg/kg dose administered every 96 h would likely result in a plasma total concentration greater than the MIC for susceptible fungal pathogens. Lack of population PK data of micafungin in children undergoing HSCT made it difficult to assume that PK of micafungin is linear in this patient population and that it could simply be extrapolated from the 3 mg/kg dose studied previously. Micamine (Astellas Pharma US, Inc., Deerfield, IL, USA) is a sterile, lyophilized product for intravenous infusion that contains micafungin sodium. The drug was reconstituted per the manufacturer’s instructions to give a micafungin solution of approximately 10 mg/mL. For infusion, this was added to 100 mL of 0.9% sodium chloride and the final concentration for infusion was kept between 0.5 and 1.5 mg/mL. The diluted solution was protected from light. All participants received a single dose of 5 mg/kg micafungin intravenously over 1 h. Ethics The study design was approved by the Cincinnati Children’s Hospital Medical Center’s institutional review board (IRB) and consent was obtained from each child’s parents before the child was enrolled in the study. An investigator-initiated Investigational New Drug (IND) approval was obtained from the FDA. PK sampling Serial blood samples were drawn around the single dose of micafungin. Venous blood samples (2.0 mL) were obtained from an indwelling catheter immediately before the micafungin infusion (i.e. time 0), at 1 h (i.e. at the end of the infusion), then at 1.5, 2, 4, 6, 8, 10, 24, 36, 48, 60, 72, 84 and 96 h after the start of the micafungin infusion. All patients had a double-lumen central venous catheter and, in accordance with standard practice, all specimens were drawn from the lumen where the micafungin was not infused.23 Micafungin assay The concentration of micafungin in plasma was determined by a modified validated HPLC assay24 in the Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. The lower limit of quantification (LLoQ) for this assay was 0.05 mg/mL. The intra-day coefficients of variation (CV) ranged from 1.28% to 9.87%. Inter-day CV for 0.5, 7.5 and 18.75 mg/L controls were 8.10%, 5.44% and 5.58%, respectively. Target attainment evaluation The MIC is a value that has been used to predict the probability of clinical success, detect resistant populations or both. CLSI and EUCAST data show that susceptibility to micafungin among Candida species can be variable.25 Micafungin is highly potent against the most common clinically relevant Candida species including Candida albicans, Candida glabrata and Candida tropicalis, all with MIC values of ≤0.06 mg/L. Higher MIC values have been observed for Candida parapsilosis (0.25–2 mg/L) and Candida guilliermondii (0.5–2 mg/L) although both species can respond clinically to micafungin therapy despite the elevated MICs.25 Susceptibility data for micafungin at our institution (Table 1) were similar and an MIC of ≤0.2 mg/L was adequate for C. albicans, C. glabrata, C. tropicalis and Candida krusei. Our observed MIC was 0.5 mg/L for C.guilliermondii and 1–2 mg/L for C. parapsilosis. It should be noted that free (not bound to protein) micafungin concentrations are considered in these estimates. Unlike with Candida species, MICs are difficult to determine for Aspergillus species and the minimum effective concentration (MEC), which leads to swollen, stubby hyphae and clumping when visualized on microscopy, is a better measure of susceptibility.26 Micafungin also has in vitro activity against Aspergillus species and an MEC of ≤0.015 mg/L is effective against common Aspergillus species.25 Similar MEC values (≤0.015 mg/L) for Aspergillus species were also observed at our institution. Based on the above MIC and MEC data, a plasma total micafungin concentration of >0.2 mg/L was chosen for target attainment, as it would cover most common clinically relevant and susceptible Aspergillus and Candida species. We considered total concentrations for target attainment and not free concentrations as it is not clear whether the free drug hypothesis can be applicable to micafungin. Ishikawa et al.27 suggest that the observed antifungal activity of micafungin is mostly superior to that predicted based on protein binding. These authors evaluated the relationship between micafungin concentration and its in vitro antifungal activity in serum. Serum samples were obtained from adults undergoing HSCT and receiving micafungin for either prophylaxis or treatment for probable fungal disease. Antifungal activity was proportional to the actual total concentration of micafungin measured by HPLC (protein bound and unbound), with the suggestion that, although micafungin is highly protein bound, binding to serum proteins is weak and, if fungi susceptible to micafungin are present, micafungin is easily released from the protein-bound form in a rapid equilibrium, to bind to target pathogens, thus exerting its antifungal activity. Table 1. Institutionala micafungin susceptibility data for Candida and Aspergillus species during the study period Organism Total number of isolates MIC (mg/L) Number of isolates C. albicans 19 ≤0.008 9 0.015 9 0.06 1 C. tropicalis 7 0.015 2 0.03 5 C. glabrata 6 ≤0.008 2 0.015 3 0.03 1 C. krusei 6 0.12 5 0.25 1 C. parapsilosis 4 1 2 2 2 Candida lusitaniae 3 0.06 2 0.12 1 C. guilliermondii 1 0.5 1 Aspergillus species 2 ≤0.015b 2 Organism Total number of isolates MIC (mg/L) Number of isolates C. albicans 19 ≤0.008 9 0.015 9 0.06 1 C. tropicalis 7 0.015 2 0.03 5 C. glabrata 6 ≤0.008 2 0.015 3 0.03 1 C. krusei 6 0.12 5 0.25 1 C. parapsilosis 4 1 2 2 2 Candida lusitaniae 3 0.06 2 0.12 1 C. guilliermondii 1 0.5 1 Aspergillus species 2 ≤0.015b 2 a Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. b Minimum effective concentration (MEC). Table 1. Institutionala micafungin susceptibility data for Candida and Aspergillus species during the study period Organism Total number of isolates MIC (mg/L) Number of isolates C. albicans 19 ≤0.008 9 0.015 9 0.06 1 C. tropicalis 7 0.015 2 0.03 5 C. glabrata 6 ≤0.008 2 0.015 3 0.03 1 C. krusei 6 0.12 5 0.25 1 C. parapsilosis 4 1 2 2 2 Candida lusitaniae 3 0.06 2 0.12 1 C. guilliermondii 1 0.5 1 Aspergillus species 2 ≤0.015b 2 Organism Total number of isolates MIC (mg/L) Number of isolates C. albicans 19 ≤0.008 9 0.015 9 0.06 1 C. tropicalis 7 0.015 2 0.03 5 C. glabrata 6 ≤0.008 2 0.015 3 0.03 1 C. krusei 6 0.12 5 0.25 1 C. parapsilosis 4 1 2 2 2 Candida lusitaniae 3 0.06 2 0.12 1 C. guilliermondii 1 0.5 1 Aspergillus species 2 ≤0.015b 2 a Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. b Minimum effective concentration (MEC). PK analysis Individual plasma concentrations were obtained before the micafungin infusion (i.e. at time 0), at 1 h (i.e. at the end of the infusion), then at 1.5, 2, 4, 6, 8, 10, 24, 36, 48, 60, 72, 84 and 96 h after the start of the micafungin infusion. Descriptive individual PK parameters AUC (AUC0–24, AUC0–48, AUC0–72 and AUC0–96), plasma Cmax, plasma Cmin (at 96 h), t½, Vss and CL were calculated using non-compartmental analysis (WinNonlin, version 6.4). The apparent terminal kel was estimated for each subject by non-linear regression analysis. The AUC was determined when possible using the linear trapezoidal method with the ‘partial area’ option of 0 to 24, 48, 72 or 96 h, using each patient’s kel estimate, which was based on at least six to eight observations. In instances when the micafungin concentration reached the LLoQ before the 96 h timepoint, the 96 h concentration was calculated by extrapolating the terminal slope on a log scale. Data are presented as mean ± SD or median and range. Statistical power was calculated to achieve a target of 95% CI within 60% and 140% of the geometric mean estimates of micafungin clearance. Per FDA guidelines, statistical power for paediatric PK studies is generally set at 80% or higher.28 Micafungin PK parameters following the administrations of 5 mg/kg and 3 mg/kg (our previous study17) were compared in order to evaluate the dose–concentration relationship. Micafungin CL, normalized by allometrically scaled body weight (L/h/70 kg), and V, normalized by body weight (L/70 kg), at 3 mg/kg and 5 mg/kg were compared using an unpaired t-test (GraphPad Prism ver 7.02, La Jolla, CA, USA). Population PK analysis and Monte Carlo simulation A population PK model was developed using 267 observations collected from 24 patients who received either a 3 mg/kg dose (published data, n = 15) or a 5 mg/kg dose (current study, n = 9) with the non-linear mixed-effect modelling software NONMEM version 7.2 (ICON Development Solutions, Ellicott City, MD, USA29) interfaced with Perl-speaks-NONMEM (PsN) version 3.5.3 and Pirana version 2.8.0. The first-order conditional estimation (FOCE) approach with η-ɛ interaction was used for all analyses. An exponential model was used to describe between-subject variability (BSV).29,30 PK parameters were assumed to log-normal distribution. For residual unexplained variability, an additive, proportional or combined model was considered. As for covariate analysis, only body weight was evaluated because of the data availability and an allometric function with a fixed coefficient of 0.75 and 1.0 was used to evaluate as a covariate for CL and V, respectively.31 Stepwise forward inclusion (P < 0.05) and backward elimination (P < 0.01) were applied for the covariate analysis. The final model was evaluated based on goodness-of-fit plots, bootstrap analysis and prediction-corrected visual predictive check using Xpose 4.4.0.32 Micafungin PK profiles for 10, 20 and 30 kg patients receiving the following three dosing scenarios were simulated based on the developed population PK model: 5 mg/kg with 3 day-interval dosing, 3 mg/kg alternate-day dosing or 1 mg/kg daily dosing. In the simulations, the distributions of CL (2.5th to 97.5th percentiles) were taken into account. Monte Carlo simulations of these dosing regimens were performed to evaluate the percentage of target attainment for the time above MIC in 500 subjects using MicLab software (Version 2.62, Medimatics). Results Nine patients were enrolled and their demographics are shown in Table 2. The median age of patients was 4.2 years (range 1.3–9.9 years). Seven patients were male and two were female. All patients had normal renal and liver function at baseline. All patients received a 5 mg/kg dose of micafungin intravenously. PK parameter estimates of micafungin for all nine patients are summarized in Table 3. The mean Cmax observed at the end of the micafungin infusion was 23.4 mg/L (range 15.4–28 mg/L). The mean t½ was 11.6 h (range 7.8–16.6 h). Micafungin at 5 mg/kg exhibited linear PK. We also compared micafungin PK parameters from this study with micafungin PK parameters at 3 mg/kg from our previous study. Mean values of individual predicted PK parameter estimates at 5 mg/kg and 3 mg/kg were not significantly different [CL = 0.85 ± 0.21 (L/h/70 kg) versus 0.73 ± 0.13 (L/h/70 kg), P = 0.15; V = 21.4 ± 4.2 (L/70 kg) versus 18.2 ± 6.3 (L/70 kg), P = 0.16]. Seibel et al.18 studied multiple dosing regimens of micafungin in children 2–17 years of age with leukaemia who received micafungin for febrile neutropenia. CL in the group that received a micafungin dose of 4 mg/kg was also similar (mean 17.2 ± 2.5 mL/h/kg) to that seen in our study. Vss at 5 mg/kg was also comparable with previous paediatric PK data.17,18,22 A comparison of AUC showed that AUC0–24 increased in a dose-proportional linear fashion. The mean AUC0–24 in this study was 242 ± 50.5 h·mg/L compared with the previously reported 191.4 ± 21.2 h·mg/L for a 4 mg/kg dose of micafungin18 and 128.5 ± 35.9 h·mg/L for a 3 mg/kg dose of micafungin.17 CL when adjusted for body weight was higher in children with lower body weight compared with children with higher body weight, across a body weight range of 7–32 kg (Figure S1a, available as Supplementary data at JAC Online). In contrast, allometrically scaled body weight-adjusted CL was comparable in children with lower and higher body weight (Figure S1b). Table 2. Patient demographics Patient Age (years) Gender Diagnosis Weight (kg) Height (cm) Body surface area (m2) Creatinine (mg/dL) AST (IU/mL) ALT (IU/mL) Bilirubin (mg/dL) 1 4.2 male thalassaemia 16.9 104 0.7 0.28 20 15 0.3 2 1.3 male juvenile myelomonocytic leukaemia 10.3 77 0.47 0.23 25 15 0.3 3 9.9 male adrenoleucodystrophy 26.9 136.5 1.01 0.45 22 18 0.2 4 6.3 male neuroblastoma 22.2 118.5 0.85 0.27 33 37 0.2 5 1.9 female sickle cell anaemia 11.6 82 0.51 0.24 18 25 0.6 6 3.9 male Diamond–Blackfan anaemia 11.6 87.5 0.53 0.26 17 48 0.3 7 5.5 male Fanconi anaemia 14.9 103.5 0.65 0.46 74 41 0.4 8 3.0 male neuroblastoma 13.4 91 0.58 0.35 38 47 0.1 9 5.7 female Fanconi anaemia 20.9 106.4 0.79 0.36 21 20 0.5 Median 4.2 14.9 103.5 0.65 0.28 22 25 0.3 Min 1.3 10.3 77 0.47 0.23 18 15 0.1 Max 9.9 26.9 137 1.01 0.46 74 48 0.6 Patient Age (years) Gender Diagnosis Weight (kg) Height (cm) Body surface area (m2) Creatinine (mg/dL) AST (IU/mL) ALT (IU/mL) Bilirubin (mg/dL) 1 4.2 male thalassaemia 16.9 104 0.7 0.28 20 15 0.3 2 1.3 male juvenile myelomonocytic leukaemia 10.3 77 0.47 0.23 25 15 0.3 3 9.9 male adrenoleucodystrophy 26.9 136.5 1.01 0.45 22 18 0.2 4 6.3 male neuroblastoma 22.2 118.5 0.85 0.27 33 37 0.2 5 1.9 female sickle cell anaemia 11.6 82 0.51 0.24 18 25 0.6 6 3.9 male Diamond–Blackfan anaemia 11.6 87.5 0.53 0.26 17 48 0.3 7 5.5 male Fanconi anaemia 14.9 103.5 0.65 0.46 74 41 0.4 8 3.0 male neuroblastoma 13.4 91 0.58 0.35 38 47 0.1 9 5.7 female Fanconi anaemia 20.9 106.4 0.79 0.36 21 20 0.5 Median 4.2 14.9 103.5 0.65 0.28 22 25 0.3 Min 1.3 10.3 77 0.47 0.23 18 15 0.1 Max 9.9 26.9 137 1.01 0.46 74 48 0.6 Table 2. Patient demographics Patient Age (years) Gender Diagnosis Weight (kg) Height (cm) Body surface area (m2) Creatinine (mg/dL) AST (IU/mL) ALT (IU/mL) Bilirubin (mg/dL) 1 4.2 male thalassaemia 16.9 104 0.7 0.28 20 15 0.3 2 1.3 male juvenile myelomonocytic leukaemia 10.3 77 0.47 0.23 25 15 0.3 3 9.9 male adrenoleucodystrophy 26.9 136.5 1.01 0.45 22 18 0.2 4 6.3 male neuroblastoma 22.2 118.5 0.85 0.27 33 37 0.2 5 1.9 female sickle cell anaemia 11.6 82 0.51 0.24 18 25 0.6 6 3.9 male Diamond–Blackfan anaemia 11.6 87.5 0.53 0.26 17 48 0.3 7 5.5 male Fanconi anaemia 14.9 103.5 0.65 0.46 74 41 0.4 8 3.0 male neuroblastoma 13.4 91 0.58 0.35 38 47 0.1 9 5.7 female Fanconi anaemia 20.9 106.4 0.79 0.36 21 20 0.5 Median 4.2 14.9 103.5 0.65 0.28 22 25 0.3 Min 1.3 10.3 77 0.47 0.23 18 15 0.1 Max 9.9 26.9 137 1.01 0.46 74 48 0.6 Patient Age (years) Gender Diagnosis Weight (kg) Height (cm) Body surface area (m2) Creatinine (mg/dL) AST (IU/mL) ALT (IU/mL) Bilirubin (mg/dL) 1 4.2 male thalassaemia 16.9 104 0.7 0.28 20 15 0.3 2 1.3 male juvenile myelomonocytic leukaemia 10.3 77 0.47 0.23 25 15 0.3 3 9.9 male adrenoleucodystrophy 26.9 136.5 1.01 0.45 22 18 0.2 4 6.3 male neuroblastoma 22.2 118.5 0.85 0.27 33 37 0.2 5 1.9 female sickle cell anaemia 11.6 82 0.51 0.24 18 25 0.6 6 3.9 male Diamond–Blackfan anaemia 11.6 87.5 0.53 0.26 17 48 0.3 7 5.5 male Fanconi anaemia 14.9 103.5 0.65 0.46 74 41 0.4 8 3.0 male neuroblastoma 13.4 91 0.58 0.35 38 47 0.1 9 5.7 female Fanconi anaemia 20.9 106.4 0.79 0.36 21 20 0.5 Median 4.2 14.9 103.5 0.65 0.28 22 25 0.3 Min 1.3 10.3 77 0.47 0.23 18 15 0.1 Max 9.9 26.9 137 1.01 0.46 74 48 0.6 Table 3. Mean (SD) PK parameter estimates after single-dose 5 mg/kg micafungin in nine patients Parameter Units Mean SD Min Max Cmax mg/L 23.4 4.3 15.4 28.5 Cmin (at 96 h) mg/L 0.12 0.07 0.05 0.26 Vss L/kg 0.26 0.09 0.12 0.39 CL mL/h/kg 15.3 2.8 11.0 21.4 t½ h 11.6 2.7 7.8 16.6 AUC0–24 h·mg/L 242 50.5 169 328 AUC0–48 h·mg/L 307 63.7 217 429 AUC0–72 h·mg/L 323 64.5 229 450 AUC0–96 h·mg/L 328 64.1 233 455 Parameter Units Mean SD Min Max Cmax mg/L 23.4 4.3 15.4 28.5 Cmin (at 96 h) mg/L 0.12 0.07 0.05 0.26 Vss L/kg 0.26 0.09 0.12 0.39 CL mL/h/kg 15.3 2.8 11.0 21.4 t½ h 11.6 2.7 7.8 16.6 AUC0–24 h·mg/L 242 50.5 169 328 AUC0–48 h·mg/L 307 63.7 217 429 AUC0–72 h·mg/L 323 64.5 229 450 AUC0–96 h·mg/L 328 64.1 233 455 Cmax, peak plasma concentration; Cmin, trough plasma concentration; Vss, volume of distribution at steady-state; CL, total body clearance; t½,elimination half-life; AUC0–24, AUC0–48, AUC0–72 and AUC0–96, area under the plasma concentration–time curve extrapolated from 0 to 24 h, 0 to 48 h, 0 to 72 h and 0 to 96 h, respectively. Table 3. Mean (SD) PK parameter estimates after single-dose 5 mg/kg micafungin in nine patients Parameter Units Mean SD Min Max Cmax mg/L 23.4 4.3 15.4 28.5 Cmin (at 96 h) mg/L 0.12 0.07 0.05 0.26 Vss L/kg 0.26 0.09 0.12 0.39 CL mL/h/kg 15.3 2.8 11.0 21.4 t½ h 11.6 2.7 7.8 16.6 AUC0–24 h·mg/L 242 50.5 169 328 AUC0–48 h·mg/L 307 63.7 217 429 AUC0–72 h·mg/L 323 64.5 229 450 AUC0–96 h·mg/L 328 64.1 233 455 Parameter Units Mean SD Min Max Cmax mg/L 23.4 4.3 15.4 28.5 Cmin (at 96 h) mg/L 0.12 0.07 0.05 0.26 Vss L/kg 0.26 0.09 0.12 0.39 CL mL/h/kg 15.3 2.8 11.0 21.4 t½ h 11.6 2.7 7.8 16.6 AUC0–24 h·mg/L 242 50.5 169 328 AUC0–48 h·mg/L 307 63.7 217 429 AUC0–72 h·mg/L 323 64.5 229 450 AUC0–96 h·mg/L 328 64.1 233 455 Cmax, peak plasma concentration; Cmin, trough plasma concentration; Vss, volume of distribution at steady-state; CL, total body clearance; t½,elimination half-life; AUC0–24, AUC0–48, AUC0–72 and AUC0–96, area under the plasma concentration–time curve extrapolated from 0 to 24 h, 0 to 48 h, 0 to 72 h and 0 to 96 h, respectively. Micafungin plasma concentrations at different timepoints and target attainment evaluation are shown in Table 4. Six patients had measurable plasma concentrations of micafungin at 96 h with a range of 0.05–0.26 mg/L, whereas concentrations were extrapolated in the three patients whose concentrations were below the LLoQ (range 0.03–0.09 mg/L). The mean concentration at the end of 96 h was 0.11 mg/L. At the end of 96 h, only one patient had concentration >0.2 mg/L. The plasma concentration of micafungin at 72 h, however, ranged between 0.13 and 0.59 mg/L and seven patients (78%) achieved a concentration >0.2 mg/L at the end of 72 h. Micafungin was well tolerated without infusional side effects in all patients. There was no significant change in renal function or liver function tests at the end of 96 h compared with baseline. Our plan initially was to enrol a total of 15 patients. However, low concentrations were observed consistently at 96 h in the initial nine patients and hence we performed an interim analysis. Statistical power for CL was 95.5% for nine patients, which was considered adequate for a paediatric PK study. Per FDA guidelines, a paediatric PK study must be prospectively powered to target a 95% CI within 60% and 140% of the geometric mean estimates of CL for a given drug with at least 80% power.28 Enrolment was therefore stopped after nine patients. Table 4. Micafungin target attainment evaluation Patient Concentration (mg/L) at: 24 h 48 h 72 h 96 h 1 4.72 1.59 0.59 0.26 2 3.15 0.74 0.39 0.07 3 5.15 1.04 0.25 <0.05 (0.06) 4 3.92 1.22 0.38 0.16 5 4.03 1.05 0.38 0.07 6 3.55 1.56 0.37 0.19 7 5.15 0.83 0.14 <0.05 (0.03) 8 5.08 0.96 0.13 <0.05 (0.09) 9 6.68 1.74 0.44 0.05 Mean 4.6 1.19 0.34 0.11 SD 1.07 0.36 0.15 0.08 Patient Concentration (mg/L) at: 24 h 48 h 72 h 96 h 1 4.72 1.59 0.59 0.26 2 3.15 0.74 0.39 0.07 3 5.15 1.04 0.25 <0.05 (0.06) 4 3.92 1.22 0.38 0.16 5 4.03 1.05 0.38 0.07 6 3.55 1.56 0.37 0.19 7 5.15 0.83 0.14 <0.05 (0.03) 8 5.08 0.96 0.13 <0.05 (0.09) 9 6.68 1.74 0.44 0.05 Mean 4.6 1.19 0.34 0.11 SD 1.07 0.36 0.15 0.08 Values in parentheses are extrapolated concentrations at 96 h. Table 4. Micafungin target attainment evaluation Patient Concentration (mg/L) at: 24 h 48 h 72 h 96 h 1 4.72 1.59 0.59 0.26 2 3.15 0.74 0.39 0.07 3 5.15 1.04 0.25 <0.05 (0.06) 4 3.92 1.22 0.38 0.16 5 4.03 1.05 0.38 0.07 6 3.55 1.56 0.37 0.19 7 5.15 0.83 0.14 <0.05 (0.03) 8 5.08 0.96 0.13 <0.05 (0.09) 9 6.68 1.74 0.44 0.05 Mean 4.6 1.19 0.34 0.11 SD 1.07 0.36 0.15 0.08 Patient Concentration (mg/L) at: 24 h 48 h 72 h 96 h 1 4.72 1.59 0.59 0.26 2 3.15 0.74 0.39 0.07 3 5.15 1.04 0.25 <0.05 (0.06) 4 3.92 1.22 0.38 0.16 5 4.03 1.05 0.38 0.07 6 3.55 1.56 0.37 0.19 7 5.15 0.83 0.14 <0.05 (0.03) 8 5.08 0.96 0.13 <0.05 (0.09) 9 6.68 1.74 0.44 0.05 Mean 4.6 1.19 0.34 0.11 SD 1.07 0.36 0.15 0.08 Values in parentheses are extrapolated concentrations at 96 h. Population PK data and model evaluation Population PK data were best described by a two-compartment model. Body weight was included in the final model as a significant covariate predictive for micafungin clearance and volume of distribution. Body weight accounted for 30% and 38% of variability for CL and V, respectively. The population PK parameter estimates generated in the final model were CLpop = 0.78 L/h, Vcpop = 13.9 L, Qpop = 1.1 L/h and Vppop = 5.9 L for a typical patient with a body weight of 70 kg (Table 5). The success rate of the bootstrap analysis was 99.3%. Goodness-of-fit plots of the final model showed significant improvement of model fit (Figure S2). All PK model parameter estimates were within the 95% CIs and deviated less than 10% from the mean value obtained by the bootstrap analysis, indicating the homogeneity of variances (Table 5). The prediction-corrected visual predictive check (Figure 1) showed that the median and the 5th and 95th percentile prediction intervals were in good agreement with the observations. The mg/kg-based dosing strategy resulted in the different PK profiles across different body weight cohorts because of the allometric relationship between micafungin clearance and body weight (Figure S3). In patients with high micafungin clearance (at the 97.5th percentile), 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies showed at least 99% and 81% target attainment of time above MIC of 0.2 mg/L, respectively (Figure 2); a 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Table 5. Population PK parameter estimates and bootstrap results in the final model Parameter Population analysis, mean (% RSE) Bootstrap analysis (n = 1000) mean %diff (95% CI) Fixed effects  CLpop (L/h/70 kg) 0.78 (4.4%) 0.78 0.0% (0.72–0.83)  Vcpop (L/70 kg) 13.9 (6.0%) 13.9 0.0% (12.2–15.6)  Qpop (L/h/70 kg) 1.1 (20.4%) 1.1 0.0% (0.5–1.6)  Vppop (L/70 kg) 5.9 (8.7%) 6.0 1.7% (4.8–7.0)  exponent of allometry fixed to 0.75 for CL and Q, and 1.0 for Vc and Vp – – Inter-individual variability (% CV)  ωCL 20.5% (17.9%) 20.1 2.0% (13.2–25.9)  ωVc 31.2% (16.0%) 30.9 1.0% (17.0–40.6)  ωQ 78.3% (18.2%) 76.0 2.9% (45.3–101)  ωVp fixed to 0 – – Random residual variability (mg/mL)  ɛprop 0.020 (18%) 0.019 5.0% (0.013–0.026)  ɛadd fixed to 0 – – Parameter Population analysis, mean (% RSE) Bootstrap analysis (n = 1000) mean %diff (95% CI) Fixed effects  CLpop (L/h/70 kg) 0.78 (4.4%) 0.78 0.0% (0.72–0.83)  Vcpop (L/70 kg) 13.9 (6.0%) 13.9 0.0% (12.2–15.6)  Qpop (L/h/70 kg) 1.1 (20.4%) 1.1 0.0% (0.5–1.6)  Vppop (L/70 kg) 5.9 (8.7%) 6.0 1.7% (4.8–7.0)  exponent of allometry fixed to 0.75 for CL and Q, and 1.0 for Vc and Vp – – Inter-individual variability (% CV)  ωCL 20.5% (17.9%) 20.1 2.0% (13.2–25.9)  ωVc 31.2% (16.0%) 30.9 1.0% (17.0–40.6)  ωQ 78.3% (18.2%) 76.0 2.9% (45.3–101)  ωVp fixed to 0 – – Random residual variability (mg/mL)  ɛprop 0.020 (18%) 0.019 5.0% (0.013–0.026)  ɛadd fixed to 0 – – CLpop, population mean of micafungin clearance normalized by allometrically scaled body weight (L/h/70 kg); Vcpop, population mean of micafungin volume of distribution in the central compartment (L/70 kg); Qpop, population mean of inter-compartment clearance (L/h/70 kg); Vppop, population mean of volume of distribution in the peripheral compartment (L/70 kg); RSE, relative standard error; %diff, percentage difference of the parameters between the means of population and bootstrap analysis. A two-compartment model best described the data. Only body weight was included in the final model as a covariate for CL and V. The success rate of the bootstrap analysis was 99.3%. Table 5. Population PK parameter estimates and bootstrap results in the final model Parameter Population analysis, mean (% RSE) Bootstrap analysis (n = 1000) mean %diff (95% CI) Fixed effects  CLpop (L/h/70 kg) 0.78 (4.4%) 0.78 0.0% (0.72–0.83)  Vcpop (L/70 kg) 13.9 (6.0%) 13.9 0.0% (12.2–15.6)  Qpop (L/h/70 kg) 1.1 (20.4%) 1.1 0.0% (0.5–1.6)  Vppop (L/70 kg) 5.9 (8.7%) 6.0 1.7% (4.8–7.0)  exponent of allometry fixed to 0.75 for CL and Q, and 1.0 for Vc and Vp – – Inter-individual variability (% CV)  ωCL 20.5% (17.9%) 20.1 2.0% (13.2–25.9)  ωVc 31.2% (16.0%) 30.9 1.0% (17.0–40.6)  ωQ 78.3% (18.2%) 76.0 2.9% (45.3–101)  ωVp fixed to 0 – – Random residual variability (mg/mL)  ɛprop 0.020 (18%) 0.019 5.0% (0.013–0.026)  ɛadd fixed to 0 – – Parameter Population analysis, mean (% RSE) Bootstrap analysis (n = 1000) mean %diff (95% CI) Fixed effects  CLpop (L/h/70 kg) 0.78 (4.4%) 0.78 0.0% (0.72–0.83)  Vcpop (L/70 kg) 13.9 (6.0%) 13.9 0.0% (12.2–15.6)  Qpop (L/h/70 kg) 1.1 (20.4%) 1.1 0.0% (0.5–1.6)  Vppop (L/70 kg) 5.9 (8.7%) 6.0 1.7% (4.8–7.0)  exponent of allometry fixed to 0.75 for CL and Q, and 1.0 for Vc and Vp – – Inter-individual variability (% CV)  ωCL 20.5% (17.9%) 20.1 2.0% (13.2–25.9)  ωVc 31.2% (16.0%) 30.9 1.0% (17.0–40.6)  ωQ 78.3% (18.2%) 76.0 2.9% (45.3–101)  ωVp fixed to 0 – – Random residual variability (mg/mL)  ɛprop 0.020 (18%) 0.019 5.0% (0.013–0.026)  ɛadd fixed to 0 – – CLpop, population mean of micafungin clearance normalized by allometrically scaled body weight (L/h/70 kg); Vcpop, population mean of micafungin volume of distribution in the central compartment (L/70 kg); Qpop, population mean of inter-compartment clearance (L/h/70 kg); Vppop, population mean of volume of distribution in the peripheral compartment (L/70 kg); RSE, relative standard error; %diff, percentage difference of the parameters between the means of population and bootstrap analysis. A two-compartment model best described the data. Only body weight was included in the final model as a covariate for CL and V. The success rate of the bootstrap analysis was 99.3%. Figure 1. View largeDownload slide Prediction-corrected visual predictive check. Open circles represent prediction-corrected micafungin observations. The continuous line represents the observed median value. The top and bottom broken lines represent the observed 5th and 95th percentile values. Shaded areas indicate the CIs of the 5th, 50th and 95th percentiles of each simulated value. Figure 1. View largeDownload slide Prediction-corrected visual predictive check. Open circles represent prediction-corrected micafungin observations. The continuous line represents the observed median value. The top and bottom broken lines represent the observed 5th and 95th percentile values. Shaded areas indicate the CIs of the 5th, 50th and 95th percentiles of each simulated value. Figure 2. View largeDownload slide Simulation of target attainment for different dosing regimens and body weight cohorts based on target MIC >0.2 mg/L (vertical black line). T > MIC, cumulative percentage of a 24 h period that total micafungin concentration exceeds the target MIC. In patients with a higher boundary of CL (97.5th percentile), 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies showed at least 99% and 81% target attainment of T > MIC of 0.2 mg/L, respectively. A 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Figure 2. View largeDownload slide Simulation of target attainment for different dosing regimens and body weight cohorts based on target MIC >0.2 mg/L (vertical black line). T > MIC, cumulative percentage of a 24 h period that total micafungin concentration exceeds the target MIC. In patients with a higher boundary of CL (97.5th percentile), 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies showed at least 99% and 81% target attainment of T > MIC of 0.2 mg/L, respectively. A 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Discussion We studied the PK of higher-dose micafungin at 5 mg/kg for antifungal prophylaxis in children undergoing HSCT. Our primary goal was to show that potentially protective concentrations will be present at 96 h which will enable a more practical twice-weekly dosing schedule. In combination with data from our previous 3 mg/kg micafungin study, we also developed a population PK model, which has not been done previously in children undergoing HSCT. In addition, the model was used in a simulation analysis to evaluate the PK profile and target attainment for several dosing scenarios. Our study shows that PK parameters at 5 mg/kg are comparable with those at 3 mg/kg (from our previous study17) suggesting the linearity of micafungin PK in the range from 3 to 5 mg/kg. Seibel et al.18 studied multiple dosing regimens of micafungin in children 2–17 years of age with leukaemia who received micafungin for febrile neutropenia. Clearance in the group that received a micafungin dose of 4 mg/kg was also similar to that seen in our study. AUC0–24 of 5 mg/kg micafungin increased in a dose-proportional linear fashion when compared with 4 mg/kg18 and 3 mg/kg17 doses of micafungin. The volume of distribution (Vss) at 5 mg/kg was also comparable with previous paediatric PK data.17,18,22 Overall, micafungin PK characteristics at 5 mg/kg appear to be consistent with previous paediatric data. We considered carefully whether the micafungin concentrations achieved at the end of 96 h were adequate for antifungal prophylaxis. Based on available data regarding susceptibility, we believe that concentrations are likely inadequate at 96 h following the 5 mg/kg dose. Although plasma concentrations above the MIC are preferable for treatment regimens, there is lack of MIC susceptibility data for prophylactic regimens. It is therefore unclear if similar concentrations are necessary for prophylaxis. Moreover, the chosen target concentration of >0.2 mg/L is based on in vitro MIC data and may not necessarily correlate with in vivo activity. Additionally, Gumbo et al.33 have demonstrated prolonged antifungal effects of micafungin in neutropenic mice with disseminated C. glabrata. This animal study showed that micafungin has a true in vivo post antifungal effect (i.e. ongoing antifungal activity at concentrations below the MIC), which for doses of 3 mg/kg in mice lasted for around 5 days after the decline of tissue concentrations below the MIC for C. glabrata. Moreover, when the whole 10 day cumulative dose (30 mg/kg) was administered, micafungin’s effect lasted for up to 7 days. The post-antifungal effect for micafungin against Candida species can range from 0.9 to >20.1 h depending upon the concentration tested, with higher concentrations producing the longest post-antifungal effect.34 Furthermore, Bochennek et al.35 analysed the safety and efficacy of micafungin in 21 children at high risk for invasive fungal infection receiving prophylactic micafungin between 3 and 4 mg/kg twice weekly. Proven or probable breakthrough invasive fungal infections did not occur in any of the patients. Although these data support twice-weekly administration of micafungin, the study by Bochennek et al.35 predominantly included patients with haematological malignancies, questioning the generalizability of these findings to an HSCT setting where patients are clearly more immune compromised. Our population PK model showed that body weight alone accounted for a significant proportion of variability in clearance and volume of distribution. Hope et al.21 similarly showed that body weight was able to explain a significant proportion of the variability in clearance and volume of distribution of micafungin in their population PK model. However, a significant proportion of variability remains unexplained. This suggests that other covariates not evaluated in this analysis may be important determinants of micafungin PK. Micafungin is metabolized in the liver to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-O-methyltransferase. M-5 is formed by hydroxylation at the side chain (ω-1 position) of micafungin catalysed by cytochrome P450 (CYP) isozymes.36 It is plausible that a proportion of variability in PK is due to maturational differences in enzyme activity and/or expression with age, especially considering the age range of our cohort (1 year-10 years). Although there is a paucity of data on the relationship between micafungin PK and ontogeny of the above hepatic enzymes, in one study, by Hope et al.,37 higher M-5 exposure was observed in younger patients, possibly related to the ontogeny of catechol-O-methyltransferase. Our population PK model was successfully used to simulate three different dosing regimens of micafungin to predict the corresponding probability of target attainment. Given the inadequate target attainment at 96 h, we looked to see if micafungin at 5 mg/kg every 72 h would achieve target attainment comparable with regimens currently used in clinical practice for prophylaxis (i.e. 1 mg/kg daily or 3 mg/kg every other day). In children with higher body weight, target attainment is more likely to be achieved with 5 mg/kg every 72 h. In comparison, patients with lower body weight achieved lower trough concentrations resulting in lower target attainment. This can be explained by the higher body weight-adjusted clearance observed in children with lower body weight. This is not surprising given the non-linear relationship between body weight and clearance, resulting from inherent physiological constraints.38 Hope et al.22 studied the population PK of micafungin in children 2–17 years of age at dosages between 0.5 and 4 mg/kg/day and reported comparable findings. Progressively higher dosages were required as weight declined, to ensure an equivalent magnitude of drug exposure to that observed in larger children, more so in children between 10 and 15 kg. Population PK estimates of CL (CLpop) and V (Vcpop, population mean of volume of distribution in central compartment) in our model were comparable to their allometric model for a typical patient with a body weight of 70 kg. The difference in body weight-adjusted CL was corrected by the allometric scaling exponent of 0.75 used in our model. Therefore, allometrically scaled body weight-adjusted CL was comparable between children with lower and higher body weights. One of the limitations of our study was the small sample size. However, given the consistent PK results and adequate statistical power for the estimation of micafungin CL, we believe that enrolling more patients would have probably yielded similar PK results with limited additional benefit. In conclusion, micafungin at 5 mg/kg dosing did not generate adequate concentrations at the end of 96 h for antifungal prophylaxis in children undergoing HSCT. A population PK model was developed and used to simulate three different dosing regimens of micafungin to predict the corresponding probability of target attainment. Our simulation data suggest that 5 mg/kg every 72 h could be an option for antifungal prophylaxis in children with higher body weight. While the post-antifungal effect might make it acceptable, a cautious approach is still needed when applying this dosing strategy to patients with lower body weight, typically very young children. Ultimately, the efficacy of this dosing regimen will need to be determined by a clinical efficacy study, ideally a randomized controlled trial. Funding This study was supported by an unrestricted research grant from Astellas Pharma US, Inc. Astellas Pharma US, Inc. did not participate in study design or interpretation of results or manuscript. Transparency declarations None to declare. Supplementary data Figures S1 to S3 are available as Supplementary data at JAC Online. References 1 Barnes PD , Marr KA. Risks, diagnosis and outcomes of invasive fungal infections in haematopoietic stem cell transplant recipients . Br J Haematol 2007 ; 139 : 519 – 31 . Google Scholar CrossRef Search ADS PubMed 2 Tomblyn M , Chiller T , Einsele H et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective . Biol Blood Marrow Transplant 2009 ; 15 : 1143 – 238 . Google Scholar CrossRef Search ADS PubMed 3 Science M , Robinson PD , MacDonald T et al. Guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic stem cell transplant recipients . Pediatr Blood Cancer 2014 ; 61 : 393 – 400 . 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Allometric size: the scientific theory and extension to normal fat mass . Eur J Pharm Sci 2017 ; 109S : S59 – 64 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Micafungin antifungal prophylaxis in children undergoing HSCT: can we give higher doses, less frequently? A pharmacokinetic study

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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0305-7453
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1460-2091
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10.1093/jac/dky030
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Abstract

Abstract Background Micafungin has a distinct advantage for antifungal prophylaxis in HSCT owing to its better safety profile, specifically in terms of hepatic and renal toxicity. In children, prophylactic micafungin is given as either 1 mg/kg every day or 3 mg/kg every other day. Objectives We performed a prospective single-centre observational study that investigated the pharmacokinetics (PK) of a single 5 mg/kg dose of micafungin in young children undergoing HSCT, to ascertain the eventual feasibility of twice-weekly prophylactic administration. Methods Nine children, ≤10 years of age undergoing HSCT, were enrolled and received a single intravenous dose of 5 mg/kg micafungin. Blood samples were obtained for PK analysis. Micafungin plasma concentration of >0.2 mg/L was chosen for target attainment (i.e. considered adequate prophylactic concentration). In addition, a population PK model was developed based on current and our previous PK study data. We also evaluated PK model-based simulation of PK profiles and target attainment using Monte Carlo simulation, for several dosing scenarios. Results Mean clearance was 15.3 mL/h/kg (range 11.0–21.4 mL/h/kg) and the mean elimination half-life was 11.6 h (range 7.8–16.6 h). The mean concentration at 96 h was 0.11 mg/L (range 0.03–0.26 mg/L). Eleven percent (n = 1) of patients achieved target attainment at the end of 96 h. Simulation data showed that 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies achieved at least 99% and 81% target attainment, respectively, whereas a 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Conclusions Micafungin at 5 mg/kg dosing did not achieve target attainment at the end of 96 h for antifungal prophylaxis in children undergoing HSCT. Simulation data suggest that a dosing strategy of micafungin at 5 mg/kg every 72 h is more likely to achieve target attainment in children with a higher body weight in comparison with children with a lower body weight. A cautious approach is advisable when using a high, but less frequent, dosing strategy in very young children. Introduction Disseminated fungal disease causes significant morbidity and mortality in children undergoing allogeneic HSCT.1–3 Graft-versus-host disease (GVHD) after allogeneic HSCT requires significant immunosuppression and, in turn, increases the risk of invasive fungal disease.2,4 The leading causes of opportunistic fungal disease in these patients are Candida and Aspergillus species.5,6 The life-threatening nature of invasive fungal disease necessitates antifungal prophylaxis for all patients undergoing HSCT. Several options are available for antifungal prophylaxis, but each has its own limitations and none has been found to be ideal. Oral triazoles are limited by poor absorption, inter-individual variability in metabolism and hepatic toxicity,7 whereas prophylaxis with amphotericin B is limited by nephrotoxicity.8 An alternative approach to prophylaxis is the use of intravenous micafungin, an antifungal agent of the echinocandin class, which has a more favourable safety profile compared with azoles and amphotericin B with low frequencies of hepatic and renal toxicity.9 Micafungin acts by inhibiting the production of 1,3-β-D-glucan, a key component in fungal cell wall synthesis.9 A semisynthetic lipopeptide, micafungin possesses in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species, including activity against azole-resistant Candida.9–13 The pharmacokinetics (PK) of micafungin has been studied in children in different groups and, in general, micafungin was also found to have a favourable safety profile.14–18 Children who undergo HSCT receive prophylactic micafungin at 1 mg/kg once daily or 3 mg/kg/dose every other day as previously shown by our group.17,19 Micafungin can only be administered intravenously and the family is responsible for administering the medication following discharge from the hospital. Prolonged antifungal prophylaxis is often required in children undergoing HSCT and the frequent administration places an additional burden on the family. A less frequent dosing regimen would therefore be desirable. In adults, Neofytos et al.20 studied the safety and efficacy of intermittent administration of high-dose intravenous micafungin (≥300 mg micafungin 2–3 times weekly) in patients with acute leukaemia and allogeneic HSCT recipients. Although micafungin levels were not obtained in this study, micafungin was well tolerated overall with low (6.0% of patients) incidence of breakthrough fungal infection. We hypothesized that higher-dose micafungin at 5 mg/kg would generate adequate concentrations at the end of 96 h, leading to a more practical twice-weekly dosing regimen for antifungal prophylaxis. To ascertain the feasibility of eventual twice-weekly prophylactic administration, we performed a PK study of micafungin following a single dose of 5 mg/kg in young children undergoing HSCT. Population PK models greatly assist in delineating optimal dosing regimens and have been developed for micafungin in infants and children.21,22 However, a population PK model for micafungin has not been developed in children undergoing HSCT, a unique population in which several factors can influence and alter drug PK. We developed a population PK model for micafungin in children undergoing HSCT and the model was used in a simulation analysis to evaluate PK profile and target attainment (i.e. considered adequate prophylactic concentration) for several dosing scenarios. Methods Study design This was a prospective single-centre observational clinical trial to characterize the PK of 5 mg/kg micafungin every four days in young children undergoing HSCT. Patients receiving HSCT for whom antifungal prophylaxis was clinically indicated were eligible for the study. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used to evaluate adverse events. The study included children aged ≤10 years, because the goal of our study was to evaluate the PK of micafungin in young children. Dose selection was based on our previous experience with 3 mg/kg alternate-day micafungin PK,17 and exploration of different dosing regimens using Monte Carlo PK/pharmacodynamic simulation (SimLab, Monte Carlo analysis tool, Medimatics, Maastricht, The Netherlands). Based on our simulation results, it was estimated that a 5 mg/kg dose administered every 96 h would likely result in a plasma total concentration greater than the MIC for susceptible fungal pathogens. Lack of population PK data of micafungin in children undergoing HSCT made it difficult to assume that PK of micafungin is linear in this patient population and that it could simply be extrapolated from the 3 mg/kg dose studied previously. Micamine (Astellas Pharma US, Inc., Deerfield, IL, USA) is a sterile, lyophilized product for intravenous infusion that contains micafungin sodium. The drug was reconstituted per the manufacturer’s instructions to give a micafungin solution of approximately 10 mg/mL. For infusion, this was added to 100 mL of 0.9% sodium chloride and the final concentration for infusion was kept between 0.5 and 1.5 mg/mL. The diluted solution was protected from light. All participants received a single dose of 5 mg/kg micafungin intravenously over 1 h. Ethics The study design was approved by the Cincinnati Children’s Hospital Medical Center’s institutional review board (IRB) and consent was obtained from each child’s parents before the child was enrolled in the study. An investigator-initiated Investigational New Drug (IND) approval was obtained from the FDA. PK sampling Serial blood samples were drawn around the single dose of micafungin. Venous blood samples (2.0 mL) were obtained from an indwelling catheter immediately before the micafungin infusion (i.e. time 0), at 1 h (i.e. at the end of the infusion), then at 1.5, 2, 4, 6, 8, 10, 24, 36, 48, 60, 72, 84 and 96 h after the start of the micafungin infusion. All patients had a double-lumen central venous catheter and, in accordance with standard practice, all specimens were drawn from the lumen where the micafungin was not infused.23 Micafungin assay The concentration of micafungin in plasma was determined by a modified validated HPLC assay24 in the Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. The lower limit of quantification (LLoQ) for this assay was 0.05 mg/mL. The intra-day coefficients of variation (CV) ranged from 1.28% to 9.87%. Inter-day CV for 0.5, 7.5 and 18.75 mg/L controls were 8.10%, 5.44% and 5.58%, respectively. Target attainment evaluation The MIC is a value that has been used to predict the probability of clinical success, detect resistant populations or both. CLSI and EUCAST data show that susceptibility to micafungin among Candida species can be variable.25 Micafungin is highly potent against the most common clinically relevant Candida species including Candida albicans, Candida glabrata and Candida tropicalis, all with MIC values of ≤0.06 mg/L. Higher MIC values have been observed for Candida parapsilosis (0.25–2 mg/L) and Candida guilliermondii (0.5–2 mg/L) although both species can respond clinically to micafungin therapy despite the elevated MICs.25 Susceptibility data for micafungin at our institution (Table 1) were similar and an MIC of ≤0.2 mg/L was adequate for C. albicans, C. glabrata, C. tropicalis and Candida krusei. Our observed MIC was 0.5 mg/L for C.guilliermondii and 1–2 mg/L for C. parapsilosis. It should be noted that free (not bound to protein) micafungin concentrations are considered in these estimates. Unlike with Candida species, MICs are difficult to determine for Aspergillus species and the minimum effective concentration (MEC), which leads to swollen, stubby hyphae and clumping when visualized on microscopy, is a better measure of susceptibility.26 Micafungin also has in vitro activity against Aspergillus species and an MEC of ≤0.015 mg/L is effective against common Aspergillus species.25 Similar MEC values (≤0.015 mg/L) for Aspergillus species were also observed at our institution. Based on the above MIC and MEC data, a plasma total micafungin concentration of >0.2 mg/L was chosen for target attainment, as it would cover most common clinically relevant and susceptible Aspergillus and Candida species. We considered total concentrations for target attainment and not free concentrations as it is not clear whether the free drug hypothesis can be applicable to micafungin. Ishikawa et al.27 suggest that the observed antifungal activity of micafungin is mostly superior to that predicted based on protein binding. These authors evaluated the relationship between micafungin concentration and its in vitro antifungal activity in serum. Serum samples were obtained from adults undergoing HSCT and receiving micafungin for either prophylaxis or treatment for probable fungal disease. Antifungal activity was proportional to the actual total concentration of micafungin measured by HPLC (protein bound and unbound), with the suggestion that, although micafungin is highly protein bound, binding to serum proteins is weak and, if fungi susceptible to micafungin are present, micafungin is easily released from the protein-bound form in a rapid equilibrium, to bind to target pathogens, thus exerting its antifungal activity. Table 1. Institutionala micafungin susceptibility data for Candida and Aspergillus species during the study period Organism Total number of isolates MIC (mg/L) Number of isolates C. albicans 19 ≤0.008 9 0.015 9 0.06 1 C. tropicalis 7 0.015 2 0.03 5 C. glabrata 6 ≤0.008 2 0.015 3 0.03 1 C. krusei 6 0.12 5 0.25 1 C. parapsilosis 4 1 2 2 2 Candida lusitaniae 3 0.06 2 0.12 1 C. guilliermondii 1 0.5 1 Aspergillus species 2 ≤0.015b 2 Organism Total number of isolates MIC (mg/L) Number of isolates C. albicans 19 ≤0.008 9 0.015 9 0.06 1 C. tropicalis 7 0.015 2 0.03 5 C. glabrata 6 ≤0.008 2 0.015 3 0.03 1 C. krusei 6 0.12 5 0.25 1 C. parapsilosis 4 1 2 2 2 Candida lusitaniae 3 0.06 2 0.12 1 C. guilliermondii 1 0.5 1 Aspergillus species 2 ≤0.015b 2 a Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. b Minimum effective concentration (MEC). Table 1. Institutionala micafungin susceptibility data for Candida and Aspergillus species during the study period Organism Total number of isolates MIC (mg/L) Number of isolates C. albicans 19 ≤0.008 9 0.015 9 0.06 1 C. tropicalis 7 0.015 2 0.03 5 C. glabrata 6 ≤0.008 2 0.015 3 0.03 1 C. krusei 6 0.12 5 0.25 1 C. parapsilosis 4 1 2 2 2 Candida lusitaniae 3 0.06 2 0.12 1 C. guilliermondii 1 0.5 1 Aspergillus species 2 ≤0.015b 2 Organism Total number of isolates MIC (mg/L) Number of isolates C. albicans 19 ≤0.008 9 0.015 9 0.06 1 C. tropicalis 7 0.015 2 0.03 5 C. glabrata 6 ≤0.008 2 0.015 3 0.03 1 C. krusei 6 0.12 5 0.25 1 C. parapsilosis 4 1 2 2 2 Candida lusitaniae 3 0.06 2 0.12 1 C. guilliermondii 1 0.5 1 Aspergillus species 2 ≤0.015b 2 a Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. b Minimum effective concentration (MEC). PK analysis Individual plasma concentrations were obtained before the micafungin infusion (i.e. at time 0), at 1 h (i.e. at the end of the infusion), then at 1.5, 2, 4, 6, 8, 10, 24, 36, 48, 60, 72, 84 and 96 h after the start of the micafungin infusion. Descriptive individual PK parameters AUC (AUC0–24, AUC0–48, AUC0–72 and AUC0–96), plasma Cmax, plasma Cmin (at 96 h), t½, Vss and CL were calculated using non-compartmental analysis (WinNonlin, version 6.4). The apparent terminal kel was estimated for each subject by non-linear regression analysis. The AUC was determined when possible using the linear trapezoidal method with the ‘partial area’ option of 0 to 24, 48, 72 or 96 h, using each patient’s kel estimate, which was based on at least six to eight observations. In instances when the micafungin concentration reached the LLoQ before the 96 h timepoint, the 96 h concentration was calculated by extrapolating the terminal slope on a log scale. Data are presented as mean ± SD or median and range. Statistical power was calculated to achieve a target of 95% CI within 60% and 140% of the geometric mean estimates of micafungin clearance. Per FDA guidelines, statistical power for paediatric PK studies is generally set at 80% or higher.28 Micafungin PK parameters following the administrations of 5 mg/kg and 3 mg/kg (our previous study17) were compared in order to evaluate the dose–concentration relationship. Micafungin CL, normalized by allometrically scaled body weight (L/h/70 kg), and V, normalized by body weight (L/70 kg), at 3 mg/kg and 5 mg/kg were compared using an unpaired t-test (GraphPad Prism ver 7.02, La Jolla, CA, USA). Population PK analysis and Monte Carlo simulation A population PK model was developed using 267 observations collected from 24 patients who received either a 3 mg/kg dose (published data, n = 15) or a 5 mg/kg dose (current study, n = 9) with the non-linear mixed-effect modelling software NONMEM version 7.2 (ICON Development Solutions, Ellicott City, MD, USA29) interfaced with Perl-speaks-NONMEM (PsN) version 3.5.3 and Pirana version 2.8.0. The first-order conditional estimation (FOCE) approach with η-ɛ interaction was used for all analyses. An exponential model was used to describe between-subject variability (BSV).29,30 PK parameters were assumed to log-normal distribution. For residual unexplained variability, an additive, proportional or combined model was considered. As for covariate analysis, only body weight was evaluated because of the data availability and an allometric function with a fixed coefficient of 0.75 and 1.0 was used to evaluate as a covariate for CL and V, respectively.31 Stepwise forward inclusion (P < 0.05) and backward elimination (P < 0.01) were applied for the covariate analysis. The final model was evaluated based on goodness-of-fit plots, bootstrap analysis and prediction-corrected visual predictive check using Xpose 4.4.0.32 Micafungin PK profiles for 10, 20 and 30 kg patients receiving the following three dosing scenarios were simulated based on the developed population PK model: 5 mg/kg with 3 day-interval dosing, 3 mg/kg alternate-day dosing or 1 mg/kg daily dosing. In the simulations, the distributions of CL (2.5th to 97.5th percentiles) were taken into account. Monte Carlo simulations of these dosing regimens were performed to evaluate the percentage of target attainment for the time above MIC in 500 subjects using MicLab software (Version 2.62, Medimatics). Results Nine patients were enrolled and their demographics are shown in Table 2. The median age of patients was 4.2 years (range 1.3–9.9 years). Seven patients were male and two were female. All patients had normal renal and liver function at baseline. All patients received a 5 mg/kg dose of micafungin intravenously. PK parameter estimates of micafungin for all nine patients are summarized in Table 3. The mean Cmax observed at the end of the micafungin infusion was 23.4 mg/L (range 15.4–28 mg/L). The mean t½ was 11.6 h (range 7.8–16.6 h). Micafungin at 5 mg/kg exhibited linear PK. We also compared micafungin PK parameters from this study with micafungin PK parameters at 3 mg/kg from our previous study. Mean values of individual predicted PK parameter estimates at 5 mg/kg and 3 mg/kg were not significantly different [CL = 0.85 ± 0.21 (L/h/70 kg) versus 0.73 ± 0.13 (L/h/70 kg), P = 0.15; V = 21.4 ± 4.2 (L/70 kg) versus 18.2 ± 6.3 (L/70 kg), P = 0.16]. Seibel et al.18 studied multiple dosing regimens of micafungin in children 2–17 years of age with leukaemia who received micafungin for febrile neutropenia. CL in the group that received a micafungin dose of 4 mg/kg was also similar (mean 17.2 ± 2.5 mL/h/kg) to that seen in our study. Vss at 5 mg/kg was also comparable with previous paediatric PK data.17,18,22 A comparison of AUC showed that AUC0–24 increased in a dose-proportional linear fashion. The mean AUC0–24 in this study was 242 ± 50.5 h·mg/L compared with the previously reported 191.4 ± 21.2 h·mg/L for a 4 mg/kg dose of micafungin18 and 128.5 ± 35.9 h·mg/L for a 3 mg/kg dose of micafungin.17 CL when adjusted for body weight was higher in children with lower body weight compared with children with higher body weight, across a body weight range of 7–32 kg (Figure S1a, available as Supplementary data at JAC Online). In contrast, allometrically scaled body weight-adjusted CL was comparable in children with lower and higher body weight (Figure S1b). Table 2. Patient demographics Patient Age (years) Gender Diagnosis Weight (kg) Height (cm) Body surface area (m2) Creatinine (mg/dL) AST (IU/mL) ALT (IU/mL) Bilirubin (mg/dL) 1 4.2 male thalassaemia 16.9 104 0.7 0.28 20 15 0.3 2 1.3 male juvenile myelomonocytic leukaemia 10.3 77 0.47 0.23 25 15 0.3 3 9.9 male adrenoleucodystrophy 26.9 136.5 1.01 0.45 22 18 0.2 4 6.3 male neuroblastoma 22.2 118.5 0.85 0.27 33 37 0.2 5 1.9 female sickle cell anaemia 11.6 82 0.51 0.24 18 25 0.6 6 3.9 male Diamond–Blackfan anaemia 11.6 87.5 0.53 0.26 17 48 0.3 7 5.5 male Fanconi anaemia 14.9 103.5 0.65 0.46 74 41 0.4 8 3.0 male neuroblastoma 13.4 91 0.58 0.35 38 47 0.1 9 5.7 female Fanconi anaemia 20.9 106.4 0.79 0.36 21 20 0.5 Median 4.2 14.9 103.5 0.65 0.28 22 25 0.3 Min 1.3 10.3 77 0.47 0.23 18 15 0.1 Max 9.9 26.9 137 1.01 0.46 74 48 0.6 Patient Age (years) Gender Diagnosis Weight (kg) Height (cm) Body surface area (m2) Creatinine (mg/dL) AST (IU/mL) ALT (IU/mL) Bilirubin (mg/dL) 1 4.2 male thalassaemia 16.9 104 0.7 0.28 20 15 0.3 2 1.3 male juvenile myelomonocytic leukaemia 10.3 77 0.47 0.23 25 15 0.3 3 9.9 male adrenoleucodystrophy 26.9 136.5 1.01 0.45 22 18 0.2 4 6.3 male neuroblastoma 22.2 118.5 0.85 0.27 33 37 0.2 5 1.9 female sickle cell anaemia 11.6 82 0.51 0.24 18 25 0.6 6 3.9 male Diamond–Blackfan anaemia 11.6 87.5 0.53 0.26 17 48 0.3 7 5.5 male Fanconi anaemia 14.9 103.5 0.65 0.46 74 41 0.4 8 3.0 male neuroblastoma 13.4 91 0.58 0.35 38 47 0.1 9 5.7 female Fanconi anaemia 20.9 106.4 0.79 0.36 21 20 0.5 Median 4.2 14.9 103.5 0.65 0.28 22 25 0.3 Min 1.3 10.3 77 0.47 0.23 18 15 0.1 Max 9.9 26.9 137 1.01 0.46 74 48 0.6 Table 2. Patient demographics Patient Age (years) Gender Diagnosis Weight (kg) Height (cm) Body surface area (m2) Creatinine (mg/dL) AST (IU/mL) ALT (IU/mL) Bilirubin (mg/dL) 1 4.2 male thalassaemia 16.9 104 0.7 0.28 20 15 0.3 2 1.3 male juvenile myelomonocytic leukaemia 10.3 77 0.47 0.23 25 15 0.3 3 9.9 male adrenoleucodystrophy 26.9 136.5 1.01 0.45 22 18 0.2 4 6.3 male neuroblastoma 22.2 118.5 0.85 0.27 33 37 0.2 5 1.9 female sickle cell anaemia 11.6 82 0.51 0.24 18 25 0.6 6 3.9 male Diamond–Blackfan anaemia 11.6 87.5 0.53 0.26 17 48 0.3 7 5.5 male Fanconi anaemia 14.9 103.5 0.65 0.46 74 41 0.4 8 3.0 male neuroblastoma 13.4 91 0.58 0.35 38 47 0.1 9 5.7 female Fanconi anaemia 20.9 106.4 0.79 0.36 21 20 0.5 Median 4.2 14.9 103.5 0.65 0.28 22 25 0.3 Min 1.3 10.3 77 0.47 0.23 18 15 0.1 Max 9.9 26.9 137 1.01 0.46 74 48 0.6 Patient Age (years) Gender Diagnosis Weight (kg) Height (cm) Body surface area (m2) Creatinine (mg/dL) AST (IU/mL) ALT (IU/mL) Bilirubin (mg/dL) 1 4.2 male thalassaemia 16.9 104 0.7 0.28 20 15 0.3 2 1.3 male juvenile myelomonocytic leukaemia 10.3 77 0.47 0.23 25 15 0.3 3 9.9 male adrenoleucodystrophy 26.9 136.5 1.01 0.45 22 18 0.2 4 6.3 male neuroblastoma 22.2 118.5 0.85 0.27 33 37 0.2 5 1.9 female sickle cell anaemia 11.6 82 0.51 0.24 18 25 0.6 6 3.9 male Diamond–Blackfan anaemia 11.6 87.5 0.53 0.26 17 48 0.3 7 5.5 male Fanconi anaemia 14.9 103.5 0.65 0.46 74 41 0.4 8 3.0 male neuroblastoma 13.4 91 0.58 0.35 38 47 0.1 9 5.7 female Fanconi anaemia 20.9 106.4 0.79 0.36 21 20 0.5 Median 4.2 14.9 103.5 0.65 0.28 22 25 0.3 Min 1.3 10.3 77 0.47 0.23 18 15 0.1 Max 9.9 26.9 137 1.01 0.46 74 48 0.6 Table 3. Mean (SD) PK parameter estimates after single-dose 5 mg/kg micafungin in nine patients Parameter Units Mean SD Min Max Cmax mg/L 23.4 4.3 15.4 28.5 Cmin (at 96 h) mg/L 0.12 0.07 0.05 0.26 Vss L/kg 0.26 0.09 0.12 0.39 CL mL/h/kg 15.3 2.8 11.0 21.4 t½ h 11.6 2.7 7.8 16.6 AUC0–24 h·mg/L 242 50.5 169 328 AUC0–48 h·mg/L 307 63.7 217 429 AUC0–72 h·mg/L 323 64.5 229 450 AUC0–96 h·mg/L 328 64.1 233 455 Parameter Units Mean SD Min Max Cmax mg/L 23.4 4.3 15.4 28.5 Cmin (at 96 h) mg/L 0.12 0.07 0.05 0.26 Vss L/kg 0.26 0.09 0.12 0.39 CL mL/h/kg 15.3 2.8 11.0 21.4 t½ h 11.6 2.7 7.8 16.6 AUC0–24 h·mg/L 242 50.5 169 328 AUC0–48 h·mg/L 307 63.7 217 429 AUC0–72 h·mg/L 323 64.5 229 450 AUC0–96 h·mg/L 328 64.1 233 455 Cmax, peak plasma concentration; Cmin, trough plasma concentration; Vss, volume of distribution at steady-state; CL, total body clearance; t½,elimination half-life; AUC0–24, AUC0–48, AUC0–72 and AUC0–96, area under the plasma concentration–time curve extrapolated from 0 to 24 h, 0 to 48 h, 0 to 72 h and 0 to 96 h, respectively. Table 3. Mean (SD) PK parameter estimates after single-dose 5 mg/kg micafungin in nine patients Parameter Units Mean SD Min Max Cmax mg/L 23.4 4.3 15.4 28.5 Cmin (at 96 h) mg/L 0.12 0.07 0.05 0.26 Vss L/kg 0.26 0.09 0.12 0.39 CL mL/h/kg 15.3 2.8 11.0 21.4 t½ h 11.6 2.7 7.8 16.6 AUC0–24 h·mg/L 242 50.5 169 328 AUC0–48 h·mg/L 307 63.7 217 429 AUC0–72 h·mg/L 323 64.5 229 450 AUC0–96 h·mg/L 328 64.1 233 455 Parameter Units Mean SD Min Max Cmax mg/L 23.4 4.3 15.4 28.5 Cmin (at 96 h) mg/L 0.12 0.07 0.05 0.26 Vss L/kg 0.26 0.09 0.12 0.39 CL mL/h/kg 15.3 2.8 11.0 21.4 t½ h 11.6 2.7 7.8 16.6 AUC0–24 h·mg/L 242 50.5 169 328 AUC0–48 h·mg/L 307 63.7 217 429 AUC0–72 h·mg/L 323 64.5 229 450 AUC0–96 h·mg/L 328 64.1 233 455 Cmax, peak plasma concentration; Cmin, trough plasma concentration; Vss, volume of distribution at steady-state; CL, total body clearance; t½,elimination half-life; AUC0–24, AUC0–48, AUC0–72 and AUC0–96, area under the plasma concentration–time curve extrapolated from 0 to 24 h, 0 to 48 h, 0 to 72 h and 0 to 96 h, respectively. Micafungin plasma concentrations at different timepoints and target attainment evaluation are shown in Table 4. Six patients had measurable plasma concentrations of micafungin at 96 h with a range of 0.05–0.26 mg/L, whereas concentrations were extrapolated in the three patients whose concentrations were below the LLoQ (range 0.03–0.09 mg/L). The mean concentration at the end of 96 h was 0.11 mg/L. At the end of 96 h, only one patient had concentration >0.2 mg/L. The plasma concentration of micafungin at 72 h, however, ranged between 0.13 and 0.59 mg/L and seven patients (78%) achieved a concentration >0.2 mg/L at the end of 72 h. Micafungin was well tolerated without infusional side effects in all patients. There was no significant change in renal function or liver function tests at the end of 96 h compared with baseline. Our plan initially was to enrol a total of 15 patients. However, low concentrations were observed consistently at 96 h in the initial nine patients and hence we performed an interim analysis. Statistical power for CL was 95.5% for nine patients, which was considered adequate for a paediatric PK study. Per FDA guidelines, a paediatric PK study must be prospectively powered to target a 95% CI within 60% and 140% of the geometric mean estimates of CL for a given drug with at least 80% power.28 Enrolment was therefore stopped after nine patients. Table 4. Micafungin target attainment evaluation Patient Concentration (mg/L) at: 24 h 48 h 72 h 96 h 1 4.72 1.59 0.59 0.26 2 3.15 0.74 0.39 0.07 3 5.15 1.04 0.25 <0.05 (0.06) 4 3.92 1.22 0.38 0.16 5 4.03 1.05 0.38 0.07 6 3.55 1.56 0.37 0.19 7 5.15 0.83 0.14 <0.05 (0.03) 8 5.08 0.96 0.13 <0.05 (0.09) 9 6.68 1.74 0.44 0.05 Mean 4.6 1.19 0.34 0.11 SD 1.07 0.36 0.15 0.08 Patient Concentration (mg/L) at: 24 h 48 h 72 h 96 h 1 4.72 1.59 0.59 0.26 2 3.15 0.74 0.39 0.07 3 5.15 1.04 0.25 <0.05 (0.06) 4 3.92 1.22 0.38 0.16 5 4.03 1.05 0.38 0.07 6 3.55 1.56 0.37 0.19 7 5.15 0.83 0.14 <0.05 (0.03) 8 5.08 0.96 0.13 <0.05 (0.09) 9 6.68 1.74 0.44 0.05 Mean 4.6 1.19 0.34 0.11 SD 1.07 0.36 0.15 0.08 Values in parentheses are extrapolated concentrations at 96 h. Table 4. Micafungin target attainment evaluation Patient Concentration (mg/L) at: 24 h 48 h 72 h 96 h 1 4.72 1.59 0.59 0.26 2 3.15 0.74 0.39 0.07 3 5.15 1.04 0.25 <0.05 (0.06) 4 3.92 1.22 0.38 0.16 5 4.03 1.05 0.38 0.07 6 3.55 1.56 0.37 0.19 7 5.15 0.83 0.14 <0.05 (0.03) 8 5.08 0.96 0.13 <0.05 (0.09) 9 6.68 1.74 0.44 0.05 Mean 4.6 1.19 0.34 0.11 SD 1.07 0.36 0.15 0.08 Patient Concentration (mg/L) at: 24 h 48 h 72 h 96 h 1 4.72 1.59 0.59 0.26 2 3.15 0.74 0.39 0.07 3 5.15 1.04 0.25 <0.05 (0.06) 4 3.92 1.22 0.38 0.16 5 4.03 1.05 0.38 0.07 6 3.55 1.56 0.37 0.19 7 5.15 0.83 0.14 <0.05 (0.03) 8 5.08 0.96 0.13 <0.05 (0.09) 9 6.68 1.74 0.44 0.05 Mean 4.6 1.19 0.34 0.11 SD 1.07 0.36 0.15 0.08 Values in parentheses are extrapolated concentrations at 96 h. Population PK data and model evaluation Population PK data were best described by a two-compartment model. Body weight was included in the final model as a significant covariate predictive for micafungin clearance and volume of distribution. Body weight accounted for 30% and 38% of variability for CL and V, respectively. The population PK parameter estimates generated in the final model were CLpop = 0.78 L/h, Vcpop = 13.9 L, Qpop = 1.1 L/h and Vppop = 5.9 L for a typical patient with a body weight of 70 kg (Table 5). The success rate of the bootstrap analysis was 99.3%. Goodness-of-fit plots of the final model showed significant improvement of model fit (Figure S2). All PK model parameter estimates were within the 95% CIs and deviated less than 10% from the mean value obtained by the bootstrap analysis, indicating the homogeneity of variances (Table 5). The prediction-corrected visual predictive check (Figure 1) showed that the median and the 5th and 95th percentile prediction intervals were in good agreement with the observations. The mg/kg-based dosing strategy resulted in the different PK profiles across different body weight cohorts because of the allometric relationship between micafungin clearance and body weight (Figure S3). In patients with high micafungin clearance (at the 97.5th percentile), 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies showed at least 99% and 81% target attainment of time above MIC of 0.2 mg/L, respectively (Figure 2); a 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Table 5. Population PK parameter estimates and bootstrap results in the final model Parameter Population analysis, mean (% RSE) Bootstrap analysis (n = 1000) mean %diff (95% CI) Fixed effects  CLpop (L/h/70 kg) 0.78 (4.4%) 0.78 0.0% (0.72–0.83)  Vcpop (L/70 kg) 13.9 (6.0%) 13.9 0.0% (12.2–15.6)  Qpop (L/h/70 kg) 1.1 (20.4%) 1.1 0.0% (0.5–1.6)  Vppop (L/70 kg) 5.9 (8.7%) 6.0 1.7% (4.8–7.0)  exponent of allometry fixed to 0.75 for CL and Q, and 1.0 for Vc and Vp – – Inter-individual variability (% CV)  ωCL 20.5% (17.9%) 20.1 2.0% (13.2–25.9)  ωVc 31.2% (16.0%) 30.9 1.0% (17.0–40.6)  ωQ 78.3% (18.2%) 76.0 2.9% (45.3–101)  ωVp fixed to 0 – – Random residual variability (mg/mL)  ɛprop 0.020 (18%) 0.019 5.0% (0.013–0.026)  ɛadd fixed to 0 – – Parameter Population analysis, mean (% RSE) Bootstrap analysis (n = 1000) mean %diff (95% CI) Fixed effects  CLpop (L/h/70 kg) 0.78 (4.4%) 0.78 0.0% (0.72–0.83)  Vcpop (L/70 kg) 13.9 (6.0%) 13.9 0.0% (12.2–15.6)  Qpop (L/h/70 kg) 1.1 (20.4%) 1.1 0.0% (0.5–1.6)  Vppop (L/70 kg) 5.9 (8.7%) 6.0 1.7% (4.8–7.0)  exponent of allometry fixed to 0.75 for CL and Q, and 1.0 for Vc and Vp – – Inter-individual variability (% CV)  ωCL 20.5% (17.9%) 20.1 2.0% (13.2–25.9)  ωVc 31.2% (16.0%) 30.9 1.0% (17.0–40.6)  ωQ 78.3% (18.2%) 76.0 2.9% (45.3–101)  ωVp fixed to 0 – – Random residual variability (mg/mL)  ɛprop 0.020 (18%) 0.019 5.0% (0.013–0.026)  ɛadd fixed to 0 – – CLpop, population mean of micafungin clearance normalized by allometrically scaled body weight (L/h/70 kg); Vcpop, population mean of micafungin volume of distribution in the central compartment (L/70 kg); Qpop, population mean of inter-compartment clearance (L/h/70 kg); Vppop, population mean of volume of distribution in the peripheral compartment (L/70 kg); RSE, relative standard error; %diff, percentage difference of the parameters between the means of population and bootstrap analysis. A two-compartment model best described the data. Only body weight was included in the final model as a covariate for CL and V. The success rate of the bootstrap analysis was 99.3%. Table 5. Population PK parameter estimates and bootstrap results in the final model Parameter Population analysis, mean (% RSE) Bootstrap analysis (n = 1000) mean %diff (95% CI) Fixed effects  CLpop (L/h/70 kg) 0.78 (4.4%) 0.78 0.0% (0.72–0.83)  Vcpop (L/70 kg) 13.9 (6.0%) 13.9 0.0% (12.2–15.6)  Qpop (L/h/70 kg) 1.1 (20.4%) 1.1 0.0% (0.5–1.6)  Vppop (L/70 kg) 5.9 (8.7%) 6.0 1.7% (4.8–7.0)  exponent of allometry fixed to 0.75 for CL and Q, and 1.0 for Vc and Vp – – Inter-individual variability (% CV)  ωCL 20.5% (17.9%) 20.1 2.0% (13.2–25.9)  ωVc 31.2% (16.0%) 30.9 1.0% (17.0–40.6)  ωQ 78.3% (18.2%) 76.0 2.9% (45.3–101)  ωVp fixed to 0 – – Random residual variability (mg/mL)  ɛprop 0.020 (18%) 0.019 5.0% (0.013–0.026)  ɛadd fixed to 0 – – Parameter Population analysis, mean (% RSE) Bootstrap analysis (n = 1000) mean %diff (95% CI) Fixed effects  CLpop (L/h/70 kg) 0.78 (4.4%) 0.78 0.0% (0.72–0.83)  Vcpop (L/70 kg) 13.9 (6.0%) 13.9 0.0% (12.2–15.6)  Qpop (L/h/70 kg) 1.1 (20.4%) 1.1 0.0% (0.5–1.6)  Vppop (L/70 kg) 5.9 (8.7%) 6.0 1.7% (4.8–7.0)  exponent of allometry fixed to 0.75 for CL and Q, and 1.0 for Vc and Vp – – Inter-individual variability (% CV)  ωCL 20.5% (17.9%) 20.1 2.0% (13.2–25.9)  ωVc 31.2% (16.0%) 30.9 1.0% (17.0–40.6)  ωQ 78.3% (18.2%) 76.0 2.9% (45.3–101)  ωVp fixed to 0 – – Random residual variability (mg/mL)  ɛprop 0.020 (18%) 0.019 5.0% (0.013–0.026)  ɛadd fixed to 0 – – CLpop, population mean of micafungin clearance normalized by allometrically scaled body weight (L/h/70 kg); Vcpop, population mean of micafungin volume of distribution in the central compartment (L/70 kg); Qpop, population mean of inter-compartment clearance (L/h/70 kg); Vppop, population mean of volume of distribution in the peripheral compartment (L/70 kg); RSE, relative standard error; %diff, percentage difference of the parameters between the means of population and bootstrap analysis. A two-compartment model best described the data. Only body weight was included in the final model as a covariate for CL and V. The success rate of the bootstrap analysis was 99.3%. Figure 1. View largeDownload slide Prediction-corrected visual predictive check. Open circles represent prediction-corrected micafungin observations. The continuous line represents the observed median value. The top and bottom broken lines represent the observed 5th and 95th percentile values. Shaded areas indicate the CIs of the 5th, 50th and 95th percentiles of each simulated value. Figure 1. View largeDownload slide Prediction-corrected visual predictive check. Open circles represent prediction-corrected micafungin observations. The continuous line represents the observed median value. The top and bottom broken lines represent the observed 5th and 95th percentile values. Shaded areas indicate the CIs of the 5th, 50th and 95th percentiles of each simulated value. Figure 2. View largeDownload slide Simulation of target attainment for different dosing regimens and body weight cohorts based on target MIC >0.2 mg/L (vertical black line). T > MIC, cumulative percentage of a 24 h period that total micafungin concentration exceeds the target MIC. In patients with a higher boundary of CL (97.5th percentile), 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies showed at least 99% and 81% target attainment of T > MIC of 0.2 mg/L, respectively. A 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Figure 2. View largeDownload slide Simulation of target attainment for different dosing regimens and body weight cohorts based on target MIC >0.2 mg/L (vertical black line). T > MIC, cumulative percentage of a 24 h period that total micafungin concentration exceeds the target MIC. In patients with a higher boundary of CL (97.5th percentile), 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies showed at least 99% and 81% target attainment of T > MIC of 0.2 mg/L, respectively. A 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Discussion We studied the PK of higher-dose micafungin at 5 mg/kg for antifungal prophylaxis in children undergoing HSCT. Our primary goal was to show that potentially protective concentrations will be present at 96 h which will enable a more practical twice-weekly dosing schedule. In combination with data from our previous 3 mg/kg micafungin study, we also developed a population PK model, which has not been done previously in children undergoing HSCT. In addition, the model was used in a simulation analysis to evaluate the PK profile and target attainment for several dosing scenarios. Our study shows that PK parameters at 5 mg/kg are comparable with those at 3 mg/kg (from our previous study17) suggesting the linearity of micafungin PK in the range from 3 to 5 mg/kg. Seibel et al.18 studied multiple dosing regimens of micafungin in children 2–17 years of age with leukaemia who received micafungin for febrile neutropenia. Clearance in the group that received a micafungin dose of 4 mg/kg was also similar to that seen in our study. AUC0–24 of 5 mg/kg micafungin increased in a dose-proportional linear fashion when compared with 4 mg/kg18 and 3 mg/kg17 doses of micafungin. The volume of distribution (Vss) at 5 mg/kg was also comparable with previous paediatric PK data.17,18,22 Overall, micafungin PK characteristics at 5 mg/kg appear to be consistent with previous paediatric data. We considered carefully whether the micafungin concentrations achieved at the end of 96 h were adequate for antifungal prophylaxis. Based on available data regarding susceptibility, we believe that concentrations are likely inadequate at 96 h following the 5 mg/kg dose. Although plasma concentrations above the MIC are preferable for treatment regimens, there is lack of MIC susceptibility data for prophylactic regimens. It is therefore unclear if similar concentrations are necessary for prophylaxis. Moreover, the chosen target concentration of >0.2 mg/L is based on in vitro MIC data and may not necessarily correlate with in vivo activity. Additionally, Gumbo et al.33 have demonstrated prolonged antifungal effects of micafungin in neutropenic mice with disseminated C. glabrata. This animal study showed that micafungin has a true in vivo post antifungal effect (i.e. ongoing antifungal activity at concentrations below the MIC), which for doses of 3 mg/kg in mice lasted for around 5 days after the decline of tissue concentrations below the MIC for C. glabrata. Moreover, when the whole 10 day cumulative dose (30 mg/kg) was administered, micafungin’s effect lasted for up to 7 days. The post-antifungal effect for micafungin against Candida species can range from 0.9 to >20.1 h depending upon the concentration tested, with higher concentrations producing the longest post-antifungal effect.34 Furthermore, Bochennek et al.35 analysed the safety and efficacy of micafungin in 21 children at high risk for invasive fungal infection receiving prophylactic micafungin between 3 and 4 mg/kg twice weekly. Proven or probable breakthrough invasive fungal infections did not occur in any of the patients. Although these data support twice-weekly administration of micafungin, the study by Bochennek et al.35 predominantly included patients with haematological malignancies, questioning the generalizability of these findings to an HSCT setting where patients are clearly more immune compromised. Our population PK model showed that body weight alone accounted for a significant proportion of variability in clearance and volume of distribution. Hope et al.21 similarly showed that body weight was able to explain a significant proportion of the variability in clearance and volume of distribution of micafungin in their population PK model. However, a significant proportion of variability remains unexplained. This suggests that other covariates not evaluated in this analysis may be important determinants of micafungin PK. Micafungin is metabolized in the liver to M-1 (catechol form) by arylsulfatase, with further metabolism to M-2 (methoxy form) by catechol-O-methyltransferase. M-5 is formed by hydroxylation at the side chain (ω-1 position) of micafungin catalysed by cytochrome P450 (CYP) isozymes.36 It is plausible that a proportion of variability in PK is due to maturational differences in enzyme activity and/or expression with age, especially considering the age range of our cohort (1 year-10 years). Although there is a paucity of data on the relationship between micafungin PK and ontogeny of the above hepatic enzymes, in one study, by Hope et al.,37 higher M-5 exposure was observed in younger patients, possibly related to the ontogeny of catechol-O-methyltransferase. Our population PK model was successfully used to simulate three different dosing regimens of micafungin to predict the corresponding probability of target attainment. Given the inadequate target attainment at 96 h, we looked to see if micafungin at 5 mg/kg every 72 h would achieve target attainment comparable with regimens currently used in clinical practice for prophylaxis (i.e. 1 mg/kg daily or 3 mg/kg every other day). In children with higher body weight, target attainment is more likely to be achieved with 5 mg/kg every 72 h. In comparison, patients with lower body weight achieved lower trough concentrations resulting in lower target attainment. This can be explained by the higher body weight-adjusted clearance observed in children with lower body weight. This is not surprising given the non-linear relationship between body weight and clearance, resulting from inherent physiological constraints.38 Hope et al.22 studied the population PK of micafungin in children 2–17 years of age at dosages between 0.5 and 4 mg/kg/day and reported comparable findings. Progressively higher dosages were required as weight declined, to ensure an equivalent magnitude of drug exposure to that observed in larger children, more so in children between 10 and 15 kg. Population PK estimates of CL (CLpop) and V (Vcpop, population mean of volume of distribution in central compartment) in our model were comparable to their allometric model for a typical patient with a body weight of 70 kg. The difference in body weight-adjusted CL was corrected by the allometric scaling exponent of 0.75 used in our model. Therefore, allometrically scaled body weight-adjusted CL was comparable between children with lower and higher body weights. One of the limitations of our study was the small sample size. However, given the consistent PK results and adequate statistical power for the estimation of micafungin CL, we believe that enrolling more patients would have probably yielded similar PK results with limited additional benefit. In conclusion, micafungin at 5 mg/kg dosing did not generate adequate concentrations at the end of 96 h for antifungal prophylaxis in children undergoing HSCT. A population PK model was developed and used to simulate three different dosing regimens of micafungin to predict the corresponding probability of target attainment. Our simulation data suggest that 5 mg/kg every 72 h could be an option for antifungal prophylaxis in children with higher body weight. While the post-antifungal effect might make it acceptable, a cautious approach is still needed when applying this dosing strategy to patients with lower body weight, typically very young children. Ultimately, the efficacy of this dosing regimen will need to be determined by a clinical efficacy study, ideally a randomized controlled trial. Funding This study was supported by an unrestricted research grant from Astellas Pharma US, Inc. Astellas Pharma US, Inc. did not participate in study design or interpretation of results or manuscript. Transparency declarations None to declare. Supplementary data Figures S1 to S3 are available as Supplementary data at JAC Online. References 1 Barnes PD , Marr KA. Risks, diagnosis and outcomes of invasive fungal infections in haematopoietic stem cell transplant recipients . Br J Haematol 2007 ; 139 : 519 – 31 . Google Scholar CrossRef Search ADS PubMed 2 Tomblyn M , Chiller T , Einsele H et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective . Biol Blood Marrow Transplant 2009 ; 15 : 1143 – 238 . Google Scholar CrossRef Search ADS PubMed 3 Science M , Robinson PD , MacDonald T et al. Guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic stem cell transplant recipients . Pediatr Blood Cancer 2014 ; 61 : 393 – 400 . 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Allometric size: the scientific theory and extension to normal fat mass . Eur J Pharm Sci 2017 ; 109S : S59 – 64 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Feb 21, 2018

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