Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients: factors affecting trough plasma concentrations

Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients:... Abstract Objectives This study describes therapeutic drug monitoring (TDM) of posaconazole suspension and modified release (MR) tablets in lung transplant (LTx) recipients and evaluates factors that may affect posaconazole trough plasma concentration (Cmin). Methods A single-centre, retrospective study evaluating posaconazole Cmin in LTx recipients receiving posaconazole suspension or MR tablets between January 2014 and December 2016. Results Forty-seven LTx patients received posaconazole suspension, and 78 received the MR tablet formulation; a total of 421 and 617 Cmin measurements were made, respectively. Posaconazole was concurrently administered with proton pump inhibitor in ≥ 90% of patients. The median (IQR) of initial posaconazole Cmin following 300 mg daily of posaconazole tablet was significantly higher than that of 800 mg daily of posaconazole suspension [1.65 (0.97–2.13) mg/L versus 0.81 (0.48–1.15) mg/L, P < 0.01]. Variability in posaconazole Cmin was apparent regardless of the formulations prescribed and dose adjustments were routinely undertaken to maintain therapeutic Cmin. A clear dose–response relationship was observed in patients receiving posaconazole MR tablets. Non-specific adverse events (fatigue, tremor, lethargy, sweating, nausea/vomiting and weight loss) were reported in 3/78 (4%) patients receiving posaconazole MR tablets. Posaconazole Cmin in these three patients was determined to be 9.6, 6.2 and 2.3 mg/L. Conclusions The current study has provided clinically important insights into the TDM of posaconazole in LTx recipients. Routine TDM should be undertaken in LTx recipients receiving posaconazole suspension and/or MR tablets. Introduction Posaconazole is a broad-spectrum antifungal with in vitro activity against various fungi including the mucormycetes. Its safety and efficacy in patients with haematological malignancies has been extensively reported.1–3 Recent studies have suggested that posaconazole suspension in lung transplant (LTx) recipients may potentially be effective as a pre-emptive therapy.4,5 Owing to variability in trough plasma concentration (Cmin), a number of international consensus guidelines have recommended therapeutic drug monitoring (TDM) to be performed in patients receiving posaconazole suspension.6–8 These recommendations, however, were mostly extrapolated from observations in the haematology setting. Although variability in Cmin following administration of posaconazole suspension in LTx patients has recently been reported,4,9 factors that could contribute to such variability remain to be fully elucidated. Additionally, posaconazole suspension may remain an important alternative in patients with swallowing difficulties or in countries where the modified release (MR) tablet is unavailable. Currently, little is known about the role of TDM following administration of posaconazole MR tablets in LTx recipients. Whilst posaconazole MR tablets offer the benefits of improved gastrointestinal absorption and bioavailability,10 these benefits have only been documented in patients with haematological malignancies1,11 or in healthy individuals.12 Therefore, this study aims to describe posaconazole Cmin in LTx recipients receiving posaconazole suspension and/or MR tablets and explores factors influencing posaconazole Cmin in this patient cohort. Methods Study design and participants This was a retrospective observational study evaluating posaconazole Cmin in LTx recipients at The Alfred Hospital, Melbourne, Australia. At our institution, a triple immunosuppressant therapy, consisting of tacrolimus, azathioprine or mycophenolate mofetil and prednisolone, is prescribed to all patients post-LTx.13 An antifungal is generally prescribed pre-emptively following isolation of fungi from respiratory specimens, including bronchoalveolar lavage and/or sputum, or empirically based on the presence of clinical/radiological signs and symptoms.4,13 Although voriconazole remains the first-line antifungal at The Alfred, it is replaced by posaconazole when: (i) patients are intolerant of voriconazole; (ii) voriconazole Cmin remains sub-therapeutic despite two increases in voriconazole dose; (iii) pre-emptive therapy is indicated against fungal colonization caused by organisms with limited voriconazole susceptibility; or (iv) there is a history of squamous cell carcinoma. The usual starting dose of posaconazole suspension or MR tablets was 400 mg twice daily with food or 300 mg daily without regard to food. Patients were counselled to take posaconazole suspension with or immediately after food and not to crush/chew posaconazole MR tablets. Additionally, patients were educated on the importance of taking their medication strictly as prescribed and were encouraged to discuss any concern with the treating doctors, pharmacists and nurses. Following Australian regulatory approval, posaconazole MR tablets have largely replaced the suspension at The Alfred since September 2015. From January 2009 to December 2016, the LTx database and pharmacy dispensing records were searched to identify study participants. LTx recipients aged 18 years or older who received posaconazole suspension and/or MR tablets and had posaconazole Cmin measured from 1 January 2014 to 31 December 2016 were included in the study. Ethics This study was approved by the Human Research Ethics Committee of The Alfred Hospital (approval number: 82/15) and Monash University (CF15/681-2015000313). The requirement for informed consent was waived by both ethics committees. Clinical data collection Data were extracted from patient medical records and laboratory reports. These included demographic information, indications for LTx, BMI, details of posaconazole therapy (formulation, dosing regimen, indications, Cmin and monitoring frequency, and documented adverse events), concomitant medications and episodes of hospitalization, ICU stay, enteral feeding, diarrhoea, nausea/vomiting and gastroparesis during posaconazole use. Gastroparesis was confirmed by gastric emptying scintigraphy. In the absence of a documented event, administration of anti-diarrhoeal or anti-nausea medication was used as a surrogate for diarrhoea or nausea/vomiting, respectively. Adverse events were based on documentation in the medical records as recorded by treating doctors, nurses and pharmacists. Hepatotoxicity was defined as an increase in ALT or total bilirubin of >3 or >1.5 times the upper limit of normal, respectively.14 Definitions of fungal infection and colonization were adapted from the 2010 International Society for Heart and Lung Transplantation (ISHLT) consensus statements on definitions of infections in cardiothoracic transplant recipients.15 Colonization was defined as isolation of fungal organisms from the respiratory specimens in the absence of clinical and/or radiological signs/symptoms. Presumed infection was considered in patients with clinical and/or radiological signs/symptoms of infection without histopathological evidence. Proven infection required observation of fungal elements in the tissue or isolation of a fungal organism from a sterile site. TDM Throughout the course of posaconazole, TDM and dose adjustments were routinely performed during hospital stays and outpatient clinic visits to ensure therapeutic Cmin was achieved. To represent Cmin, blood samples were taken prior to administration of posaconazole in the inpatient setting. When measured in the outpatient clinic, patients were instructed to take posaconazole after the blood test. An in-house assay (ultra-performance LC–tandem MS, Waters Acquity system), validated by the National Association of Testing Authorities Australia, was used to measure posaconazole Cmin. A Cmin of at least 0.7 mg/L was considered therapeutic.7 Statistical analysis Data analysis was conducted using Stata 14.0 software (Stata Corp, College Station, TX, USA). Patient characteristics were summarized using descriptive statistics. When appropriate, the Wilcoxon–Mann–Whitney/Kruskal–Wallis test or Fisher’s exact/χ2 test was used to assess the difference between continuous or categorical variables, respectively. To adjust for steady state, only posaconazole Cmin measured at least 5 days after dosing were included in the analysis.12,16 Posaconazole Cmin resulting from suspected non-adherence, as recorded by treating clinicians, were excluded. Multilevel linear regression (with a random effect for patient accounting for correlation amongst repeated measurements of the same individuals) was used to determine and evaluate clinical factors that may potentially influence posaconazole Cmin (dependent variable). Natural logarithmic transformation of posaconazole Cmin was performed to improve normality and interpretability of the dependent variable. Coefficients from the regression model were exponentiated and interpreted as proportional (percent) changes in the geometric mean of Cmin, in which the geometric mean is a measure of central tendency that is usually similar in value to the median. A P value of ≤0.05 was considered statistically significant. Results Patient characteristics A total of 125 patients were included in the study; 47 received posaconazole suspension, whilst the remaining 78 received posaconazole MR tablets. Proton pump inhibitor (PPI) was concomitantly administered for the treatment/prophylaxis of gastro-oesophageal reflux disease in most patients receiving posaconazole suspension [43/47 (91%)] or MR tablets [70/78 (90%)]. Demographic information and indications for LTx and posaconazole are presented in Table 1. Table 1. Patient demographic and clinical characteristics Variable  Posaconazole suspension, n (%) unless otherwise specified, N = 47  Posaconazole tablets, n (%) unless otherwise specified, N = 78  Male  35 (74)  48 (62)  Age at first posaconazole Cmin measurement (years), median (IQR)  51 (34–61)  59 (45–65)  BMI at first posaconazole Cmin measurementa (kg/m2), median (IQR),  23.1 (19.3–27.0)  23.1 (19.9–27.6)  Indications for LTx at initial posaconazole Cmin measurement   COPD  7 (15)  32 (41)   interstitial lung disease  7 (15)  12 (15)   cystic fibrosis  10 (21)  10 (13)   bronchiectasis  8 (17)  9 (12)   bronchiolitis obliterans syndrome (re-transplant)  9 (19)  7 (9)   alpha-1 antitrypsin deficiency  2 (4)  6 (8)   others  4b (9)  2c (3)  Indications for posaconazole   pre-emptive therapy for post-transplant colonization  27 (57)  58 (74)    Aspergillus fumigatus  14 (52)  30 (52)    Aspergillus niger  1 (4)  3 (5)    unspecified Aspergillus spp.  7 (26)  17 (29)    Scedosporium prolificans  2 (7)  1 (2)    A. fumigatus + A. niger  1 (4)  1 (2)    Aspergillus spp. + S. prolificans  1 (4)  2 (3)    others  1d (4)  4e (7)   pre-emptive therapy for pre-transplant Aspergillus colonization  7 (15)  5 (6)   treatment of presumed infection  12 (26)  14 (18)    A. fumigatus  5 (42)  3 (21)    unspecified Aspergillus spp.  1 (8)  1 (7)    unidentified fungi  5 (42)  9 (64)    others  1f (8)  1g (7)   treatment of proven infection  1h (2)  1i (1)  Variable  Posaconazole suspension, n (%) unless otherwise specified, N = 47  Posaconazole tablets, n (%) unless otherwise specified, N = 78  Male  35 (74)  48 (62)  Age at first posaconazole Cmin measurement (years), median (IQR)  51 (34–61)  59 (45–65)  BMI at first posaconazole Cmin measurementa (kg/m2), median (IQR),  23.1 (19.3–27.0)  23.1 (19.9–27.6)  Indications for LTx at initial posaconazole Cmin measurement   COPD  7 (15)  32 (41)   interstitial lung disease  7 (15)  12 (15)   cystic fibrosis  10 (21)  10 (13)   bronchiectasis  8 (17)  9 (12)   bronchiolitis obliterans syndrome (re-transplant)  9 (19)  7 (9)   alpha-1 antitrypsin deficiency  2 (4)  6 (8)   others  4b (9)  2c (3)  Indications for posaconazole   pre-emptive therapy for post-transplant colonization  27 (57)  58 (74)    Aspergillus fumigatus  14 (52)  30 (52)    Aspergillus niger  1 (4)  3 (5)    unspecified Aspergillus spp.  7 (26)  17 (29)    Scedosporium prolificans  2 (7)  1 (2)    A. fumigatus + A. niger  1 (4)  1 (2)    Aspergillus spp. + S. prolificans  1 (4)  2 (3)    others  1d (4)  4e (7)   pre-emptive therapy for pre-transplant Aspergillus colonization  7 (15)  5 (6)   treatment of presumed infection  12 (26)  14 (18)    A. fumigatus  5 (42)  3 (21)    unspecified Aspergillus spp.  1 (8)  1 (7)    unidentified fungi  5 (42)  9 (64)    others  1f (8)  1g (7)   treatment of proven infection  1h (2)  1i (1)  a BMI was measured within 14 days of initiating posaconazole. b Included 2 congenital heart disease and 2 pulmonary hypertension. c Included 2 pulmonary hypertension. d Included 1 Rhizomucor spp. e Included 2 Aspergillus flavus, 1 Rhizopus microsporus and 1 A. fumigatus + A. flavus. f Included 1 A. fumigatus + Aspergillus nidulans. g Included 1 Mucor circinelloides. h Included 1 Scedosporium apiospermum. i Included 1 Aspergillus terreus + S. apiospermum. Posaconazole suspension A total of 421 Cmin measurements, a median (IQR) of 8 (3–13) per patient, were performed in the 47 patients receiving posaconazole suspension. Most patients [36/47 (77%)] received a starting dose of 400 mg twice daily. The initial Cmin, measured at a median (IQR) of 6 (4–10) days post-initiation of posaconazole suspension, following 400 mg twice daily of posaconazole suspension during concomitant PPI therapy, had a median (IQR) value of 0.81 (0.48–1.15) mg/L. Dose adjustments were undertaken in 26/47 (55%) patients to maintain therapeutic Cmin (Figure 1). Inter- and intra-patient variability was apparent amongst patients receiving 800 mg daily of posaconazole suspension (Figure 2). Figure 1. View largeDownload slide Overall Cmin measured at least 5 days post-administration of posaconazole suspension during concomitant PPI therapy and the corresponding daily dose. Each circle represents one instance of an individual patient’s Cmin (43 patients, 322 measurements). The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 1. View largeDownload slide Overall Cmin measured at least 5 days post-administration of posaconazole suspension during concomitant PPI therapy and the corresponding daily dose. Each circle represents one instance of an individual patient’s Cmin (43 patients, 322 measurements). The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 2. View largeDownload slide Inter- and intra-patient variability in Cmin following 800 mg daily of posaconazole suspension. Shown are 10 individual patients who had seven or more Cmin measured, whilst on PPI therapy. The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 2. View largeDownload slide Inter- and intra-patient variability in Cmin following 800 mg daily of posaconazole suspension. Shown are 10 individual patients who had seven or more Cmin measured, whilst on PPI therapy. The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Posaconazole MR tablets The 78 patients receiving posaconazole MR tablets had a total of 617 posaconazole Cmin measurements. In 72/78 (92%) patients, 300 mg daily was prescribed as a starting dose. The median (IQR) posaconazole Cmin, which was measured during concurrent PPI administration at a median (IQR) of 7 (6–10) days following the initial 300 mg daily dose was 1.65 (0.97–2.13) mg/L. Although switching from posaconazole suspension to MR tablets afforded an increase in Cmin (Figure 3), variability in Cmin remained and dose adjustments were required in 57/78 (73%) patients to maintain a Cmin between 0.7 and 2 mg/L (Figure 4). Inter- and intra-patient variability in Cmin was reported in patients receiving 200 and 300 mg daily of posaconazole tablets (Figure 5). Figure 3. View largeDownload slide Posaconazole Cmin in patients, who had five or more Cmin measurements, switching over from posaconazole suspension to tablets. Each point represents the median posaconazole Cmin of an individual patient. In these patients, the median (IQR) daily dose of posaconazole suspension was 960 (800–1600) mg, whilst that of posaconazole tablets was 300 (200–400) mg. Figure 3. View largeDownload slide Posaconazole Cmin in patients, who had five or more Cmin measurements, switching over from posaconazole suspension to tablets. Each point represents the median posaconazole Cmin of an individual patient. In these patients, the median (IQR) daily dose of posaconazole suspension was 960 (800–1600) mg, whilst that of posaconazole tablets was 300 (200–400) mg. Figure 4. View largeDownload slide Overall Cmin measured at least 5 days post-administration of posaconazole tablets during concomitant PPI therapy and the corresponding daily dose. Each circle represents one instance of an individual patient’s Cmin (70 patients, 536 measurements). The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 4. View largeDownload slide Overall Cmin measured at least 5 days post-administration of posaconazole tablets during concomitant PPI therapy and the corresponding daily dose. Each circle represents one instance of an individual patient’s Cmin (70 patients, 536 measurements). The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 5. View largeDownload slide Inter- and intra-patient variability in Cmin following 200 and 300 mg daily of posaconazole tablets. Shown are individual patients who had seven or more Cmin measured, whilst on PPI therapy. The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 5. View largeDownload slide Inter- and intra-patient variability in Cmin following 200 and 300 mg daily of posaconazole tablets. Shown are individual patients who had seven or more Cmin measured, whilst on PPI therapy. The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Posaconazole Cmin and adverse events Adverse events were documented in two patients receiving posaconazole suspension. Posaconazole suspension was ceased in one patient following agitation that developed 5 days post-initiation of therapy, and in the other owing to concern about abnormal liver functions after 6 months of continuous therapy. Although the ALT and total bilirubin of the latter patient were not substantially higher than the upper limits of normal (66 and 21 U/L, respectively), alkaline phosphatase of 1056 U/L prompted the cessation of posaconazole suspension. Posaconazole Cmin for these two patients at the time when the adverse events were documented was 0.35 and 1.39 mg/L, respectively. Cessation of posaconazole led to resolution of the agitation and gradual improvement of the liver functions, respectively. Of the patients receiving posaconazole MR tablets, three reported sudden onset of fatigue, tremor, lethargy, sweating, nausea/vomiting and weight loss. Posaconazole Cmin following a daily dose of 300 mg, in these patients when the symptoms first developed, were 9.6, 6.2 and 2.33 mg/L. Complete resolution of the symptoms was achieved following dose and Cmin reduction to <2 mg/L. No episode of clinically significant hepatotoxicity was observed. Factors related to posaconazole Cmin Multilevel linear regression analysis found that in patients receiving posaconazole suspension, administration of enteral feeding was associated with 30% reduction in Cmin (Table 2). Conversely, male gender, treatment in an outpatient setting or gastroparesis was associated with a 42%, 15% or 70% increase in the Cmin, respectively. Whereas daily doses larger than 800 mg did not appear to consistently result in higher Cmin, a dose of 1600 mg daily was associated with a 45% increase in Cmin (Table 2). Table 2. Univariate and multilevel linear regression to examine factors influencing posaconazole suspension Cmin Variable  Univariate analysis   Multilevel linear regression   coefficient (95% CI)  P  coefficient (95% CI)  P  Male  0.73 (0.58 to 0.87)  <0.01  0.35 (0.03 to 0.67)  0.03  Age  0.02 (0.01 to 0.02)  <0.01  0.01 (−0.01 to 0.20)  0.24  BMI  0.02 (0.01 to 0.04)  <0.01  excluded due to missing values—only 170 observations were available  Cystic fibrosis  −0.52 (−0.65 to −0.34)  <0.01  −0.22 (−0.66 to 0.22)  0.33  ICU  −0.37 (−0.81 to 0.07)  0.10  −0.31 (−0.43 to 0.49)  0.90  Outpatient  0.12 (−0.03 to 0.27)  0.12  0.14 (0.02 to 0.25)  0.02  Enteral feed  −0.77 (−0.95 to −0.58)  <0.01  −0.35 (−0.70 to 0.00)  0.05  Diarrhoea  −0.26 (−0.52 to −0.01)  0.05  −0.10 (−0.36 to 0.15)  0.43  Nausea  −0.53 (−0.74 to −0.31)  <0.01  −0.10 (−0.30 to 0.10)  0.34  Gastroparesis  0.27 (0.06 to 0.48)  0.01  0.53 (0.22 to 0.84)  0.01  H2 antagonist  −0.13 (−0.28 to 0.01)  0.07  −0.13 (−0.31 to 0.06)  0.18  Daily dose (mg)    <0.01    <0.01   800  reference         200  −0.44 (−1.13 to 0.25)  0.21  −0.78 (−1.32 to −0.25)  <0.01   300  −0.34 (−1.18 to 0.51)  0.43  −0.70 (−1.35 to −0.04)  0.04   400  0.22 (−0.08 to 0.54)  0.15  −0.08 (−0.38 to 0.21)  0.58   600  0.31 (−0.22 to 0.85)  0.25  −0.01 (−0.42 to 0.41)  0.99   640  0.47 (−0.72 to 1.66)  0.44  −0.04 (−0.92 to 0.84)  0.93   960  −0.06 (−0.30 to 0.19)  0.64  −0.11 (−0.33 to 0.12)  0.35   1000  −0.09 (−0.94 to 0.75)  0.83  −0.20 (−0.83 to 0.42)  0.52   1200  −0.45 (−0.64 to −0.26)  <0.01  0.02 (−0.16 to 0.20)  0.84   1440  −0.93 (−1.46 to −0.39)  <0.01  −0.28 (−0.72 to 0.16)  0.21   1600  0.12 (−0.16 to 0.40)  0.42  0.37 (0.01 to 0.64)  <0.01   1800  −0.87 (−1.19 to −0.55)  <0.01  0.08 (−0.24 to 0.41)  0.61   2400  −0.69 (−1.03 to −0.35)  <0.01  0.32 (−0.01 to 0.69)  0.10  Variable  Univariate analysis   Multilevel linear regression   coefficient (95% CI)  P  coefficient (95% CI)  P  Male  0.73 (0.58 to 0.87)  <0.01  0.35 (0.03 to 0.67)  0.03  Age  0.02 (0.01 to 0.02)  <0.01  0.01 (−0.01 to 0.20)  0.24  BMI  0.02 (0.01 to 0.04)  <0.01  excluded due to missing values—only 170 observations were available  Cystic fibrosis  −0.52 (−0.65 to −0.34)  <0.01  −0.22 (−0.66 to 0.22)  0.33  ICU  −0.37 (−0.81 to 0.07)  0.10  −0.31 (−0.43 to 0.49)  0.90  Outpatient  0.12 (−0.03 to 0.27)  0.12  0.14 (0.02 to 0.25)  0.02  Enteral feed  −0.77 (−0.95 to −0.58)  <0.01  −0.35 (−0.70 to 0.00)  0.05  Diarrhoea  −0.26 (−0.52 to −0.01)  0.05  −0.10 (−0.36 to 0.15)  0.43  Nausea  −0.53 (−0.74 to −0.31)  <0.01  −0.10 (−0.30 to 0.10)  0.34  Gastroparesis  0.27 (0.06 to 0.48)  0.01  0.53 (0.22 to 0.84)  0.01  H2 antagonist  −0.13 (−0.28 to 0.01)  0.07  −0.13 (−0.31 to 0.06)  0.18  Daily dose (mg)    <0.01    <0.01   800  reference         200  −0.44 (−1.13 to 0.25)  0.21  −0.78 (−1.32 to −0.25)  <0.01   300  −0.34 (−1.18 to 0.51)  0.43  −0.70 (−1.35 to −0.04)  0.04   400  0.22 (−0.08 to 0.54)  0.15  −0.08 (−0.38 to 0.21)  0.58   600  0.31 (−0.22 to 0.85)  0.25  −0.01 (−0.42 to 0.41)  0.99   640  0.47 (−0.72 to 1.66)  0.44  −0.04 (−0.92 to 0.84)  0.93   960  −0.06 (−0.30 to 0.19)  0.64  −0.11 (−0.33 to 0.12)  0.35   1000  −0.09 (−0.94 to 0.75)  0.83  −0.20 (−0.83 to 0.42)  0.52   1200  −0.45 (−0.64 to −0.26)  <0.01  0.02 (−0.16 to 0.20)  0.84   1440  −0.93 (−1.46 to −0.39)  <0.01  −0.28 (−0.72 to 0.16)  0.21   1600  0.12 (−0.16 to 0.40)  0.42  0.37 (0.01 to 0.64)  <0.01   1800  −0.87 (−1.19 to −0.55)  <0.01  0.08 (−0.24 to 0.41)  0.61   2400  −0.69 (−1.03 to −0.35)  <0.01  0.32 (−0.01 to 0.69)  0.10  Bold formatting signifies statistically significant covariates. For posaconazole MR tablets, multilevel regression analysis suggested that posaconazole Cmin was 48% lower in cystic fibrosis patients, whereas administration of posaconazole MR tablets in an outpatient setting or the presence of underlying gastroparesis was associated with a 25% or 30% increase in posaconazole Cmin, respectively (Table 3). In contrast to posaconazole suspension, a clear dose–response relationship was observed in patients receiving posaconazole MR tablets (Table 3). Table 3. Univariate and multilevel linear regression to examine factors influencing posaconazole tablet Cmin Variable  Univariate analysis   Multilevel linear regression   coefficient (95% CI)  P  coefficient (95% CI)  P  Male  0.05 (−0.04 to 0.14)  0.28  −0.05 (−0.30 to 0.19)  0.66  Age  0.01 (0.00 to 0.01)  <0.01  0.01 (−0.01 to 0.02)  0.34  BMI  0.00 (0.00 to 0.01)  0.67  excluded due to missing values— only 297 observations were available  Cystic fibrosis  −0.38 (−0.52 to −0.24)  <0.01  −0.66 (−1.17 to −0.15)  0.01  Outpatient  0.24 (0.14 to 0.35)  <0.01  0.22 (0.13 to 0.31)  <0.01  Enteral feed  −0.35 (−0.53 to −0.17)  <0.01  0.04 (−0.16 to 0.25)  0.18  Diarrhoea  0.03 (−0.16 to 0.22)  0.76  0 (−0.20 to 0.2)  0.68  Nausea  −0.19 (−0.30 to −0.08)  <0.01  −0.05 (−0.13 to 0.12)  0.94  Gastroparesis  0.06 (−0.06 to 0.18)  0.31  0.26 (0.12 to 0.41)  <0.01  H2 antagonist  −0.17 (−0.26 to −0.07)  <0.01  0.09 (−0.09 to 0.26)  0.33  Daily dose (mg)    <0.01    <0.01   300  reference         100  −0.26 (−0.43 to −0.10)  <0.01  −1.03 (−1.19 to −0.87)  <0.01   200  −0.17 (−0.28 to −0.06)  <0.01  −0.33 (−0.42 to −0.24)  <0.01   400  −0.18 (−0.36 to −0.01)  0.04  0.29 (0.14 to 0.43)  <0.01   500  −0.34 (−0.57 to −0.10)  <0.01  0.53 (0.31 to 0.75)  <0.01   600  0.04 (−0.45 to 0.54)  0.86  0.92 (0.55 to 1.29)  <0.01  Variable  Univariate analysis   Multilevel linear regression   coefficient (95% CI)  P  coefficient (95% CI)  P  Male  0.05 (−0.04 to 0.14)  0.28  −0.05 (−0.30 to 0.19)  0.66  Age  0.01 (0.00 to 0.01)  <0.01  0.01 (−0.01 to 0.02)  0.34  BMI  0.00 (0.00 to 0.01)  0.67  excluded due to missing values— only 297 observations were available  Cystic fibrosis  −0.38 (−0.52 to −0.24)  <0.01  −0.66 (−1.17 to −0.15)  0.01  Outpatient  0.24 (0.14 to 0.35)  <0.01  0.22 (0.13 to 0.31)  <0.01  Enteral feed  −0.35 (−0.53 to −0.17)  <0.01  0.04 (−0.16 to 0.25)  0.18  Diarrhoea  0.03 (−0.16 to 0.22)  0.76  0 (−0.20 to 0.2)  0.68  Nausea  −0.19 (−0.30 to −0.08)  <0.01  −0.05 (−0.13 to 0.12)  0.94  Gastroparesis  0.06 (−0.06 to 0.18)  0.31  0.26 (0.12 to 0.41)  <0.01  H2 antagonist  −0.17 (−0.26 to −0.07)  <0.01  0.09 (−0.09 to 0.26)  0.33  Daily dose (mg)    <0.01    <0.01   300  reference         100  −0.26 (−0.43 to −0.10)  <0.01  −1.03 (−1.19 to −0.87)  <0.01   200  −0.17 (−0.28 to −0.06)  <0.01  −0.33 (−0.42 to −0.24)  <0.01   400  −0.18 (−0.36 to −0.01)  0.04  0.29 (0.14 to 0.43)  <0.01   500  −0.34 (−0.57 to −0.10)  <0.01  0.53 (0.31 to 0.75)  <0.01   600  0.04 (−0.45 to 0.54)  0.86  0.92 (0.55 to 1.29)  <0.01  The bold formatting signifies statistically significant covariates. Discussion To the best of our knowledge, this is the first and largest study exploring the TDM of posaconazole MR tablets in the LTx setting to date. The data suggested that variability in Cmin remained despite the administration of posaconazole MR tablets. Importantly, clinical factors that may potentially affect the posaconazole Cmin in LTx patients taking posaconazole MR tablets were identified for the first time. Our study suggested that, when taking patient factors into account, escalating the posaconazole suspension dose to beyond 800 mg daily did not appear to result in consistent increases in Cmin. However, we noted that a dose of 1600 mg daily of posaconazole suspension in the present study resulted in significantly higher Cmin, consistent with the work of Shields et al.9 In our study, 1600 mg daily of posaconazole was administered in either two or four divided doses. The median (IQR) of posaconazole Cmin following twice daily or four times daily administration was not statistically different: 0.97 (0.89–1.28) versus 1.03 (0.56–1.75), P = 0.76. Although the reasons behind this observation were unknown, no adverse events were documented following administration of 1600 mg daily of posaconazole suspension in our study. However, episodes of liver toxicity and gastrointestinal adverse events following 1600 mg daily of posaconazole suspension have been reported by others.9 Therefore, the use of posaconazole suspension beyond the manufacturer’s recommended dose to boost Cmin requires careful consideration. Compared with the suspension, posaconazole MR tablets were associated with higher Cmin in our study, consistent with findings from the haematology setting.2,11 Owing to pharmacokinetic characteristics,1 the median initial Cmin following 300 mg daily of posaconazole MR tablets was >1 mg/L. The MR tablets, thus, may offer an advantage over the suspension when rapid achievement of a high posaconazole Cmin is required. Given the small number of patients or events, and different follow-up periods, we were unable to determine the clinical effectiveness of posaconazole MR tablets or the association between posaconazole Cmin and clinical response. Nevertheless, the efficacy of posaconazole suspension in LTx recipients has been reported.4,5 In the present study, variability in posaconazole Cmin remained despite administration of the MR tablet formulation. Our experience suggested that administration of 300 mg daily of posaconazole MR tablets resulted in Cmin >1 mg/L in more than 75% of patients. Similarly, Stelzer et al.17 also demonstrated a significant Cmin variability amongst LTx recipients receiving 300 mg daily of posaconazole MR tablets (Cmin ranged from 0.4 to 8.7 mg/L). At our institution, dose reduction/increment, by 100 mg daily, was routinely undertaken to maintain a Cmin between 0.7 and 2 mg/L. Interestingly, in this study, the use of 100 mg daily of posaconazole MR tablets was sufficient to afford therapeutic Cmin in some patients, although a daily dose of up to 600 mg was required in others. Hence, it would be useful to identify patients who are prone to develop sub- or supra-therapeutic Cmin prior to commencement of posaconazole, so that an appropriate dose can be instituted. Notably, factors contributing to Cmin variability amongst patients with haematological malignancies and LTx recipients are not entirely identical, potentially owing to the differences between these two groups of patients (e.g. physiological variables). Dolton et al.18 had previously reported concurrent ranitidine or metoclopramide therapy, underlying diarrhoea or mucositis as predictors for lower Cmin in patients with underlying haematological malignancies who received posaconazole suspension. Similarly, in their cohort of haematological malignancy patients and recipients of haematopoietic stem cell transplant with graft-versus-host disease who received posaconazole MR tablets, Tang et al.19 reported that sub-therapeutic Cmin was more likely to occur during episodes of diarrhoea or concurrent proton pump inhibitor therapy. We, however, did not observe such associations in our LTx patient cohort, regardless of the posaconazole formulation taken. Although diarrhoea or nausea/vomiting in the current study was associated with lower posaconazole Cmin in the univariate analysis, multilevel linear regression analysis did not reveal any statistically significant association. Whilst these gastrointestinal disturbances following LTx are common, they are generally mild in nature.20 Thus, their impact on posaconazole absorption is potentially minimal. When enteral feedings were administered to compensate for reduced oral intake in LTx patients, significantly lower Cmin was observed in patients receiving posaconazole suspension. In contrast, such association was not observed in those receiving posaconazole MR tablets, supporting the previous finding that their absorption is not affected by food.10 In contrast, patients with gastroparesis, which is a common complication following LTx,21 were found to have a higher Cmin in the current study regardless of the posaconazole formulation administered. Delay in gastrointestinal transit may have increased posaconazole absorption from the gut. The current study found a significantly lower median posaconazole Cmin in patients with cystic fibrosis. However, when adjusted for the other variables in the multilevel linear regression model, this difference was no longer significant in patients taking posaconazole suspension. In those taking posaconazole MR tablets, however, the relationship between underlying cystic fibrosis and posaconazole Cmin remained. Inherent to reduced gastrointestinal absorption and increased drug clearance, patients with cystic fibrosis often experience altered dispositions of many drugs.22 A recent study demonstrated significantly lower posaconazole exposure in LTx recipients with cystic fibrosis who received posaconazole suspension.23 Although the pharmacokinetics of posaconazole MR tablets in this patient population has yet to be evaluated, posaconazole Cmin should be closely monitored in these patients until further data are available. Given that PPI was concomitantly administered in ≥90% of our patients, we were unable to evaluate the impact of PPI on posaconazole Cmin in the present study. A previous study has demonstrated that concomitant administration of posaconazole suspension with PPI in LTx recipients resulted in significantly lower posaconazole Cmin,9 although the authors only adjusted for oral administration and concomitant H2 antagonist administration in their model. Although no study has quantified the effect of concomitant PPI therapy and posaconazole MR tablets in the LTx setting, Stelzer et al.17 did demonstrate a lower posaconazole Cmin in patients receiving concomitant 80 mg daily of pantoprazole compared with those receiving 40 mg daily. Given the negligible impact of gastric pH on posaconazole MR tablet absorption, the impact of PPI would likely be minimal, as previously reported in healthy individuals24 and patients with haematological malignancies.2 In the current study, despite having controlled for concomitant medications and other variables, both inter- and intra-patient variability in posaconazole Cmin remained, consistent with findings from other studies.17,25 We were, however, unable to rule out the possibility of other important patient factors that could potentially influence posaconazole Cmin. Genetic polymorphisms of P-glycoprotein (P-gp) or UDP-glucuronosyltransferases (UGT), for example, have been reported to affect the plasma concentration of certain drugs.26,27 Although Sansone-Parsons et al.28 demonstrated a lack of association between P-gp polymorphism and posaconazole clearance, the impact of UGT polymorphism on the metabolism of posaconazole is yet to be reported. Further investigation is required. The present study is the first to report symptoms of lethargy, sweating, weight loss and fatigue in three patients with posaconazole Cmin >2 mg/L. Although unable to be definitively attributed to posaconazole toxicity, these symptoms completely resolved when posaconazole Cmin was reduced to <2 mg/L. Of interest, Parkes et al.29 recently reported visual hallucinations and cognitive impairment in a patient receiving posaconazole tablets. The posaconazole Cmin in this patient, when the symptoms developed, was 10.10 mg/L. Posaconazole tablets were subsequently withheld and improvement in symptoms was observed following reduction in posaconazole Cmin. Consistent with findings from previous studies,11,30 no episodes of hepatotoxicity were documented in the 42 patients with Cmin >2 mg/L in our study. Nevertheless, it is worth noting that a recent study of patients with haematological malignancies reported episodes of hyperbilirubinaemia, although not attributed to posaconazole, in patients with Cmin >1.83 mg/L.3 Given that the relationship between posaconazole Cmin and adverse events has yet to be established,1,11 further surveillance is warranted. In conclusion, this study has provided clinically important insights into the TDM of posaconazole in LTx patients receiving posaconazole suspension and/or MR tablets. Non-specific signs or symptoms of adverse effects were documented in some patients with Cmin >2 mg/L, although no episodes of liver toxicity were observed. Further study should aim to delineate the patient factors relating to posaconazole Cmin variability in the LTx setting, which we were unable to investigate. Owing to the inter- and intra-patient variability, findings from the current study support the need for regular TDM in LTx patients prescribed posaconazole suspension and/or MR tablets. Funding This was an investigator-initiated study supported by internal funding. Transparency declarations C. O. M. has received grants from Merck Sharp and Dohme (MSD) and Gilead Sciences, has sat on advisory boards for MSD and has received honoraria from Pfizer. M. A. S. has received grants from Pfizer, MSD and Gilead Sciences. D. C. M. K. has sat on advisory boards for Pfizer and MSD, and has received financial/travel support unrelated to the current work from Roche, Pfizer and MSD. All other authors: none to declare. References 1 Cornely OA, Duarte RF, Haider S et al.   Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother  2016; 71: 718– 26. Google Scholar CrossRef Search ADS PubMed  2 Cumpston A, Caddell R, Shillingburg A et al.   Superior serum concentrations with posaconazole delayed-release tablets compared to suspension formulation in hematological malignancies. Antimicrob Agents Chemother  2015; 59: 4424– 8. Google Scholar CrossRef Search ADS PubMed  3 Tverdek FP, Heo ST, Aitken SL et al.   Real-life assessment of the safety and effectiveness of the new tablet and intravenous formulations of posaconazole in the prophylaxis of invasive fungal infections: analysis of 343 courses. Antimicrob Agents Chemother  2017; 61: e00188– 17. Google Scholar CrossRef Search ADS PubMed  4 Jeong W, Snell GI, Levvey BJ et al.   Clinical effectiveness of early posaconazole suspension pre-emptive therapy in lung transplant recipients: the Alfred’s experience. J Antimicrob Chemother  2017; 72: 2089– 92. Google Scholar CrossRef Search ADS PubMed  5 Robinson CL, Chau C, Yerkovich ST et al.   Posaconazole in lung transplant recipients: use, tolerability, and efficacy. Transpl Infect Dis  2016; 18: 302– 8. Google Scholar CrossRef Search ADS PubMed  6 Ashbee HR, Barnes RA, Johnson EM et al.   Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother  2014; 69: 1162– 76. Google Scholar CrossRef Search ADS PubMed  7 Chau MM, Kong DCM, van Hal SJ et al.   Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern Med J  2014; 44: 1364– 88. Google Scholar CrossRef Search ADS PubMed  8 Husain S, Sole A, Alexander BD et al.   The 2015 International Society for Heart and Lung Transplantation guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: executive summary. J Heart Lung Transplant  2016; 35: 261– 82. Google Scholar CrossRef Search ADS PubMed  9 Shields RK, Clancy CJ, Vadnerkar A et al.   Posaconazole serum concentrations among cardiothoracic transplant recipients: factors impacting trough levels and correlation with clinical response to therapy. Antimicrob Agents Chemother  2011; 55: 1308– 11. Google Scholar CrossRef Search ADS PubMed  10 Krishna G, Ma L, Martinho M et al.   Single-dose phase I study to evaluate the pharmacokinetics of posaconazole in new tablet and capsule formulations relative to oral suspension. Antimicrob Agents Chemother  2012; 56: 4196– 201. 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Los Angeles, CA: Terasaki Foundation Laboratory, 2015; 99– 108. 14 Gomes MZR, Jiang Y, Mulanovich VE et al.   Effectiveness of primary anti-aspergillus prophylaxis during remission induction chemotherapy of acute myeloid leukemia. Antimicrob Agents Chemother  2014; 58: 2775– 80. Google Scholar CrossRef Search ADS PubMed  15 Husain S, Mooney ML, Danziger-Isakov L et al.   A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients. J Heart Lung Transplant  2011; 30: 361– 74. Google Scholar CrossRef Search ADS PubMed  16 Gubbins PO, Krishna G, Sansone-Parsons A et al.   Pharmacokinetics and safety of oral posaconazole in neutropenic stem cell transplant recipients. Antimicrob Agents Chemother  2006; 50: 1993– 9. Google Scholar CrossRef Search ADS PubMed  17 Stelzer D, Weber A, Ihle F et al.   Comparing azole plasma trough levels in lung transplant recipients: percentage of therapeutic levels and intrapatient variability. Ther Drug Monit  2017; 39: 93– 101. Google Scholar CrossRef Search ADS PubMed  18 Dolton MJ, Ray JE, Marriott D, McLachlan AJ. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother  2012; 56: 2806– 13. Google Scholar CrossRef Search ADS PubMed  19 Tang LA, Marini BL, Benitez L et al.   Risk factors for subtherapeutic levels of posaconazole tablet. J Antimicrob Chemother  2017; 72: 2902– 5. Google Scholar CrossRef Search ADS PubMed  20 Bravo C, Gispert P, Borro JM et al.   Prevalence and management of gastrointestinal complications in lung transplant patients: MITOS Study Group. Transplant Proc  2007; 39: 2409– 12. Google Scholar CrossRef Search ADS PubMed  21 D’Ovidio F, Singer LG, Hadjiliadis D et al.   Prevalence of gastroesophageal reflux in end-stage lung disease candidates for lung transplant. Ann Thorac Surg  2005; 80: 1254– 60. Google Scholar CrossRef Search ADS PubMed  22 Rey E, Treluyer JM, Pons G. Drug disposition in cystic fibrosis. Clin Pharmacokinet  1998; 35: 313– 29. Google Scholar CrossRef Search ADS PubMed  23 Zhang H, Nguyen MH, Clancy CJ et al.   Pharmacokinetics of posaconazole suspension in lung transplant patients with and without cystic fibrosis. Antimicrob Agents Chemother  2016; 60: 3558– 62. Google Scholar CrossRef Search ADS PubMed  24 Kraft WK, Chang PS, van Iersel MLPS et al.   Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects. Antimicrob Agents Chemother  2014; 58: 4020– 5. Google Scholar CrossRef Search ADS PubMed  25 Jeong W, Haywood P, Shanmuganathan N et al.   Safety, clinical effectiveness and trough plasma concentrations of intravenous posaconazole in patients with haematological malignancies and/or undergoing allogeneic haematopoietic stem cell transplantation: off-trial experience. J Antimicrob Chemother  2016; 71: 3540– 7. 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Google Scholar CrossRef Search ADS PubMed  30 Pettit NN, Miceli MH, Rivera CG et al.   Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation. J Antimicrob Chemother  2017; 72: 2355– 8. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients: factors affecting trough plasma concentrations

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Oxford University Press
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© The Author 2017. 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/dkx440
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Abstract

Abstract Objectives This study describes therapeutic drug monitoring (TDM) of posaconazole suspension and modified release (MR) tablets in lung transplant (LTx) recipients and evaluates factors that may affect posaconazole trough plasma concentration (Cmin). Methods A single-centre, retrospective study evaluating posaconazole Cmin in LTx recipients receiving posaconazole suspension or MR tablets between January 2014 and December 2016. Results Forty-seven LTx patients received posaconazole suspension, and 78 received the MR tablet formulation; a total of 421 and 617 Cmin measurements were made, respectively. Posaconazole was concurrently administered with proton pump inhibitor in ≥ 90% of patients. The median (IQR) of initial posaconazole Cmin following 300 mg daily of posaconazole tablet was significantly higher than that of 800 mg daily of posaconazole suspension [1.65 (0.97–2.13) mg/L versus 0.81 (0.48–1.15) mg/L, P < 0.01]. Variability in posaconazole Cmin was apparent regardless of the formulations prescribed and dose adjustments were routinely undertaken to maintain therapeutic Cmin. A clear dose–response relationship was observed in patients receiving posaconazole MR tablets. Non-specific adverse events (fatigue, tremor, lethargy, sweating, nausea/vomiting and weight loss) were reported in 3/78 (4%) patients receiving posaconazole MR tablets. Posaconazole Cmin in these three patients was determined to be 9.6, 6.2 and 2.3 mg/L. Conclusions The current study has provided clinically important insights into the TDM of posaconazole in LTx recipients. Routine TDM should be undertaken in LTx recipients receiving posaconazole suspension and/or MR tablets. Introduction Posaconazole is a broad-spectrum antifungal with in vitro activity against various fungi including the mucormycetes. Its safety and efficacy in patients with haematological malignancies has been extensively reported.1–3 Recent studies have suggested that posaconazole suspension in lung transplant (LTx) recipients may potentially be effective as a pre-emptive therapy.4,5 Owing to variability in trough plasma concentration (Cmin), a number of international consensus guidelines have recommended therapeutic drug monitoring (TDM) to be performed in patients receiving posaconazole suspension.6–8 These recommendations, however, were mostly extrapolated from observations in the haematology setting. Although variability in Cmin following administration of posaconazole suspension in LTx patients has recently been reported,4,9 factors that could contribute to such variability remain to be fully elucidated. Additionally, posaconazole suspension may remain an important alternative in patients with swallowing difficulties or in countries where the modified release (MR) tablet is unavailable. Currently, little is known about the role of TDM following administration of posaconazole MR tablets in LTx recipients. Whilst posaconazole MR tablets offer the benefits of improved gastrointestinal absorption and bioavailability,10 these benefits have only been documented in patients with haematological malignancies1,11 or in healthy individuals.12 Therefore, this study aims to describe posaconazole Cmin in LTx recipients receiving posaconazole suspension and/or MR tablets and explores factors influencing posaconazole Cmin in this patient cohort. Methods Study design and participants This was a retrospective observational study evaluating posaconazole Cmin in LTx recipients at The Alfred Hospital, Melbourne, Australia. At our institution, a triple immunosuppressant therapy, consisting of tacrolimus, azathioprine or mycophenolate mofetil and prednisolone, is prescribed to all patients post-LTx.13 An antifungal is generally prescribed pre-emptively following isolation of fungi from respiratory specimens, including bronchoalveolar lavage and/or sputum, or empirically based on the presence of clinical/radiological signs and symptoms.4,13 Although voriconazole remains the first-line antifungal at The Alfred, it is replaced by posaconazole when: (i) patients are intolerant of voriconazole; (ii) voriconazole Cmin remains sub-therapeutic despite two increases in voriconazole dose; (iii) pre-emptive therapy is indicated against fungal colonization caused by organisms with limited voriconazole susceptibility; or (iv) there is a history of squamous cell carcinoma. The usual starting dose of posaconazole suspension or MR tablets was 400 mg twice daily with food or 300 mg daily without regard to food. Patients were counselled to take posaconazole suspension with or immediately after food and not to crush/chew posaconazole MR tablets. Additionally, patients were educated on the importance of taking their medication strictly as prescribed and were encouraged to discuss any concern with the treating doctors, pharmacists and nurses. Following Australian regulatory approval, posaconazole MR tablets have largely replaced the suspension at The Alfred since September 2015. From January 2009 to December 2016, the LTx database and pharmacy dispensing records were searched to identify study participants. LTx recipients aged 18 years or older who received posaconazole suspension and/or MR tablets and had posaconazole Cmin measured from 1 January 2014 to 31 December 2016 were included in the study. Ethics This study was approved by the Human Research Ethics Committee of The Alfred Hospital (approval number: 82/15) and Monash University (CF15/681-2015000313). The requirement for informed consent was waived by both ethics committees. Clinical data collection Data were extracted from patient medical records and laboratory reports. These included demographic information, indications for LTx, BMI, details of posaconazole therapy (formulation, dosing regimen, indications, Cmin and monitoring frequency, and documented adverse events), concomitant medications and episodes of hospitalization, ICU stay, enteral feeding, diarrhoea, nausea/vomiting and gastroparesis during posaconazole use. Gastroparesis was confirmed by gastric emptying scintigraphy. In the absence of a documented event, administration of anti-diarrhoeal or anti-nausea medication was used as a surrogate for diarrhoea or nausea/vomiting, respectively. Adverse events were based on documentation in the medical records as recorded by treating doctors, nurses and pharmacists. Hepatotoxicity was defined as an increase in ALT or total bilirubin of >3 or >1.5 times the upper limit of normal, respectively.14 Definitions of fungal infection and colonization were adapted from the 2010 International Society for Heart and Lung Transplantation (ISHLT) consensus statements on definitions of infections in cardiothoracic transplant recipients.15 Colonization was defined as isolation of fungal organisms from the respiratory specimens in the absence of clinical and/or radiological signs/symptoms. Presumed infection was considered in patients with clinical and/or radiological signs/symptoms of infection without histopathological evidence. Proven infection required observation of fungal elements in the tissue or isolation of a fungal organism from a sterile site. TDM Throughout the course of posaconazole, TDM and dose adjustments were routinely performed during hospital stays and outpatient clinic visits to ensure therapeutic Cmin was achieved. To represent Cmin, blood samples were taken prior to administration of posaconazole in the inpatient setting. When measured in the outpatient clinic, patients were instructed to take posaconazole after the blood test. An in-house assay (ultra-performance LC–tandem MS, Waters Acquity system), validated by the National Association of Testing Authorities Australia, was used to measure posaconazole Cmin. A Cmin of at least 0.7 mg/L was considered therapeutic.7 Statistical analysis Data analysis was conducted using Stata 14.0 software (Stata Corp, College Station, TX, USA). Patient characteristics were summarized using descriptive statistics. When appropriate, the Wilcoxon–Mann–Whitney/Kruskal–Wallis test or Fisher’s exact/χ2 test was used to assess the difference between continuous or categorical variables, respectively. To adjust for steady state, only posaconazole Cmin measured at least 5 days after dosing were included in the analysis.12,16 Posaconazole Cmin resulting from suspected non-adherence, as recorded by treating clinicians, were excluded. Multilevel linear regression (with a random effect for patient accounting for correlation amongst repeated measurements of the same individuals) was used to determine and evaluate clinical factors that may potentially influence posaconazole Cmin (dependent variable). Natural logarithmic transformation of posaconazole Cmin was performed to improve normality and interpretability of the dependent variable. Coefficients from the regression model were exponentiated and interpreted as proportional (percent) changes in the geometric mean of Cmin, in which the geometric mean is a measure of central tendency that is usually similar in value to the median. A P value of ≤0.05 was considered statistically significant. Results Patient characteristics A total of 125 patients were included in the study; 47 received posaconazole suspension, whilst the remaining 78 received posaconazole MR tablets. Proton pump inhibitor (PPI) was concomitantly administered for the treatment/prophylaxis of gastro-oesophageal reflux disease in most patients receiving posaconazole suspension [43/47 (91%)] or MR tablets [70/78 (90%)]. Demographic information and indications for LTx and posaconazole are presented in Table 1. Table 1. Patient demographic and clinical characteristics Variable  Posaconazole suspension, n (%) unless otherwise specified, N = 47  Posaconazole tablets, n (%) unless otherwise specified, N = 78  Male  35 (74)  48 (62)  Age at first posaconazole Cmin measurement (years), median (IQR)  51 (34–61)  59 (45–65)  BMI at first posaconazole Cmin measurementa (kg/m2), median (IQR),  23.1 (19.3–27.0)  23.1 (19.9–27.6)  Indications for LTx at initial posaconazole Cmin measurement   COPD  7 (15)  32 (41)   interstitial lung disease  7 (15)  12 (15)   cystic fibrosis  10 (21)  10 (13)   bronchiectasis  8 (17)  9 (12)   bronchiolitis obliterans syndrome (re-transplant)  9 (19)  7 (9)   alpha-1 antitrypsin deficiency  2 (4)  6 (8)   others  4b (9)  2c (3)  Indications for posaconazole   pre-emptive therapy for post-transplant colonization  27 (57)  58 (74)    Aspergillus fumigatus  14 (52)  30 (52)    Aspergillus niger  1 (4)  3 (5)    unspecified Aspergillus spp.  7 (26)  17 (29)    Scedosporium prolificans  2 (7)  1 (2)    A. fumigatus + A. niger  1 (4)  1 (2)    Aspergillus spp. + S. prolificans  1 (4)  2 (3)    others  1d (4)  4e (7)   pre-emptive therapy for pre-transplant Aspergillus colonization  7 (15)  5 (6)   treatment of presumed infection  12 (26)  14 (18)    A. fumigatus  5 (42)  3 (21)    unspecified Aspergillus spp.  1 (8)  1 (7)    unidentified fungi  5 (42)  9 (64)    others  1f (8)  1g (7)   treatment of proven infection  1h (2)  1i (1)  Variable  Posaconazole suspension, n (%) unless otherwise specified, N = 47  Posaconazole tablets, n (%) unless otherwise specified, N = 78  Male  35 (74)  48 (62)  Age at first posaconazole Cmin measurement (years), median (IQR)  51 (34–61)  59 (45–65)  BMI at first posaconazole Cmin measurementa (kg/m2), median (IQR),  23.1 (19.3–27.0)  23.1 (19.9–27.6)  Indications for LTx at initial posaconazole Cmin measurement   COPD  7 (15)  32 (41)   interstitial lung disease  7 (15)  12 (15)   cystic fibrosis  10 (21)  10 (13)   bronchiectasis  8 (17)  9 (12)   bronchiolitis obliterans syndrome (re-transplant)  9 (19)  7 (9)   alpha-1 antitrypsin deficiency  2 (4)  6 (8)   others  4b (9)  2c (3)  Indications for posaconazole   pre-emptive therapy for post-transplant colonization  27 (57)  58 (74)    Aspergillus fumigatus  14 (52)  30 (52)    Aspergillus niger  1 (4)  3 (5)    unspecified Aspergillus spp.  7 (26)  17 (29)    Scedosporium prolificans  2 (7)  1 (2)    A. fumigatus + A. niger  1 (4)  1 (2)    Aspergillus spp. + S. prolificans  1 (4)  2 (3)    others  1d (4)  4e (7)   pre-emptive therapy for pre-transplant Aspergillus colonization  7 (15)  5 (6)   treatment of presumed infection  12 (26)  14 (18)    A. fumigatus  5 (42)  3 (21)    unspecified Aspergillus spp.  1 (8)  1 (7)    unidentified fungi  5 (42)  9 (64)    others  1f (8)  1g (7)   treatment of proven infection  1h (2)  1i (1)  a BMI was measured within 14 days of initiating posaconazole. b Included 2 congenital heart disease and 2 pulmonary hypertension. c Included 2 pulmonary hypertension. d Included 1 Rhizomucor spp. e Included 2 Aspergillus flavus, 1 Rhizopus microsporus and 1 A. fumigatus + A. flavus. f Included 1 A. fumigatus + Aspergillus nidulans. g Included 1 Mucor circinelloides. h Included 1 Scedosporium apiospermum. i Included 1 Aspergillus terreus + S. apiospermum. Posaconazole suspension A total of 421 Cmin measurements, a median (IQR) of 8 (3–13) per patient, were performed in the 47 patients receiving posaconazole suspension. Most patients [36/47 (77%)] received a starting dose of 400 mg twice daily. The initial Cmin, measured at a median (IQR) of 6 (4–10) days post-initiation of posaconazole suspension, following 400 mg twice daily of posaconazole suspension during concomitant PPI therapy, had a median (IQR) value of 0.81 (0.48–1.15) mg/L. Dose adjustments were undertaken in 26/47 (55%) patients to maintain therapeutic Cmin (Figure 1). Inter- and intra-patient variability was apparent amongst patients receiving 800 mg daily of posaconazole suspension (Figure 2). Figure 1. View largeDownload slide Overall Cmin measured at least 5 days post-administration of posaconazole suspension during concomitant PPI therapy and the corresponding daily dose. Each circle represents one instance of an individual patient’s Cmin (43 patients, 322 measurements). The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 1. View largeDownload slide Overall Cmin measured at least 5 days post-administration of posaconazole suspension during concomitant PPI therapy and the corresponding daily dose. Each circle represents one instance of an individual patient’s Cmin (43 patients, 322 measurements). The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 2. View largeDownload slide Inter- and intra-patient variability in Cmin following 800 mg daily of posaconazole suspension. Shown are 10 individual patients who had seven or more Cmin measured, whilst on PPI therapy. The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 2. View largeDownload slide Inter- and intra-patient variability in Cmin following 800 mg daily of posaconazole suspension. Shown are 10 individual patients who had seven or more Cmin measured, whilst on PPI therapy. The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Posaconazole MR tablets The 78 patients receiving posaconazole MR tablets had a total of 617 posaconazole Cmin measurements. In 72/78 (92%) patients, 300 mg daily was prescribed as a starting dose. The median (IQR) posaconazole Cmin, which was measured during concurrent PPI administration at a median (IQR) of 7 (6–10) days following the initial 300 mg daily dose was 1.65 (0.97–2.13) mg/L. Although switching from posaconazole suspension to MR tablets afforded an increase in Cmin (Figure 3), variability in Cmin remained and dose adjustments were required in 57/78 (73%) patients to maintain a Cmin between 0.7 and 2 mg/L (Figure 4). Inter- and intra-patient variability in Cmin was reported in patients receiving 200 and 300 mg daily of posaconazole tablets (Figure 5). Figure 3. View largeDownload slide Posaconazole Cmin in patients, who had five or more Cmin measurements, switching over from posaconazole suspension to tablets. Each point represents the median posaconazole Cmin of an individual patient. In these patients, the median (IQR) daily dose of posaconazole suspension was 960 (800–1600) mg, whilst that of posaconazole tablets was 300 (200–400) mg. Figure 3. View largeDownload slide Posaconazole Cmin in patients, who had five or more Cmin measurements, switching over from posaconazole suspension to tablets. Each point represents the median posaconazole Cmin of an individual patient. In these patients, the median (IQR) daily dose of posaconazole suspension was 960 (800–1600) mg, whilst that of posaconazole tablets was 300 (200–400) mg. Figure 4. View largeDownload slide Overall Cmin measured at least 5 days post-administration of posaconazole tablets during concomitant PPI therapy and the corresponding daily dose. Each circle represents one instance of an individual patient’s Cmin (70 patients, 536 measurements). The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 4. View largeDownload slide Overall Cmin measured at least 5 days post-administration of posaconazole tablets during concomitant PPI therapy and the corresponding daily dose. Each circle represents one instance of an individual patient’s Cmin (70 patients, 536 measurements). The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 5. View largeDownload slide Inter- and intra-patient variability in Cmin following 200 and 300 mg daily of posaconazole tablets. Shown are individual patients who had seven or more Cmin measured, whilst on PPI therapy. The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Figure 5. View largeDownload slide Inter- and intra-patient variability in Cmin following 200 and 300 mg daily of posaconazole tablets. Shown are individual patients who had seven or more Cmin measured, whilst on PPI therapy. The crosses and dotted lines represent median and IQR, respectively. Cmin of 0.7 mg/L was considered therapeutic. Posaconazole Cmin and adverse events Adverse events were documented in two patients receiving posaconazole suspension. Posaconazole suspension was ceased in one patient following agitation that developed 5 days post-initiation of therapy, and in the other owing to concern about abnormal liver functions after 6 months of continuous therapy. Although the ALT and total bilirubin of the latter patient were not substantially higher than the upper limits of normal (66 and 21 U/L, respectively), alkaline phosphatase of 1056 U/L prompted the cessation of posaconazole suspension. Posaconazole Cmin for these two patients at the time when the adverse events were documented was 0.35 and 1.39 mg/L, respectively. Cessation of posaconazole led to resolution of the agitation and gradual improvement of the liver functions, respectively. Of the patients receiving posaconazole MR tablets, three reported sudden onset of fatigue, tremor, lethargy, sweating, nausea/vomiting and weight loss. Posaconazole Cmin following a daily dose of 300 mg, in these patients when the symptoms first developed, were 9.6, 6.2 and 2.33 mg/L. Complete resolution of the symptoms was achieved following dose and Cmin reduction to <2 mg/L. No episode of clinically significant hepatotoxicity was observed. Factors related to posaconazole Cmin Multilevel linear regression analysis found that in patients receiving posaconazole suspension, administration of enteral feeding was associated with 30% reduction in Cmin (Table 2). Conversely, male gender, treatment in an outpatient setting or gastroparesis was associated with a 42%, 15% or 70% increase in the Cmin, respectively. Whereas daily doses larger than 800 mg did not appear to consistently result in higher Cmin, a dose of 1600 mg daily was associated with a 45% increase in Cmin (Table 2). Table 2. Univariate and multilevel linear regression to examine factors influencing posaconazole suspension Cmin Variable  Univariate analysis   Multilevel linear regression   coefficient (95% CI)  P  coefficient (95% CI)  P  Male  0.73 (0.58 to 0.87)  <0.01  0.35 (0.03 to 0.67)  0.03  Age  0.02 (0.01 to 0.02)  <0.01  0.01 (−0.01 to 0.20)  0.24  BMI  0.02 (0.01 to 0.04)  <0.01  excluded due to missing values—only 170 observations were available  Cystic fibrosis  −0.52 (−0.65 to −0.34)  <0.01  −0.22 (−0.66 to 0.22)  0.33  ICU  −0.37 (−0.81 to 0.07)  0.10  −0.31 (−0.43 to 0.49)  0.90  Outpatient  0.12 (−0.03 to 0.27)  0.12  0.14 (0.02 to 0.25)  0.02  Enteral feed  −0.77 (−0.95 to −0.58)  <0.01  −0.35 (−0.70 to 0.00)  0.05  Diarrhoea  −0.26 (−0.52 to −0.01)  0.05  −0.10 (−0.36 to 0.15)  0.43  Nausea  −0.53 (−0.74 to −0.31)  <0.01  −0.10 (−0.30 to 0.10)  0.34  Gastroparesis  0.27 (0.06 to 0.48)  0.01  0.53 (0.22 to 0.84)  0.01  H2 antagonist  −0.13 (−0.28 to 0.01)  0.07  −0.13 (−0.31 to 0.06)  0.18  Daily dose (mg)    <0.01    <0.01   800  reference         200  −0.44 (−1.13 to 0.25)  0.21  −0.78 (−1.32 to −0.25)  <0.01   300  −0.34 (−1.18 to 0.51)  0.43  −0.70 (−1.35 to −0.04)  0.04   400  0.22 (−0.08 to 0.54)  0.15  −0.08 (−0.38 to 0.21)  0.58   600  0.31 (−0.22 to 0.85)  0.25  −0.01 (−0.42 to 0.41)  0.99   640  0.47 (−0.72 to 1.66)  0.44  −0.04 (−0.92 to 0.84)  0.93   960  −0.06 (−0.30 to 0.19)  0.64  −0.11 (−0.33 to 0.12)  0.35   1000  −0.09 (−0.94 to 0.75)  0.83  −0.20 (−0.83 to 0.42)  0.52   1200  −0.45 (−0.64 to −0.26)  <0.01  0.02 (−0.16 to 0.20)  0.84   1440  −0.93 (−1.46 to −0.39)  <0.01  −0.28 (−0.72 to 0.16)  0.21   1600  0.12 (−0.16 to 0.40)  0.42  0.37 (0.01 to 0.64)  <0.01   1800  −0.87 (−1.19 to −0.55)  <0.01  0.08 (−0.24 to 0.41)  0.61   2400  −0.69 (−1.03 to −0.35)  <0.01  0.32 (−0.01 to 0.69)  0.10  Variable  Univariate analysis   Multilevel linear regression   coefficient (95% CI)  P  coefficient (95% CI)  P  Male  0.73 (0.58 to 0.87)  <0.01  0.35 (0.03 to 0.67)  0.03  Age  0.02 (0.01 to 0.02)  <0.01  0.01 (−0.01 to 0.20)  0.24  BMI  0.02 (0.01 to 0.04)  <0.01  excluded due to missing values—only 170 observations were available  Cystic fibrosis  −0.52 (−0.65 to −0.34)  <0.01  −0.22 (−0.66 to 0.22)  0.33  ICU  −0.37 (−0.81 to 0.07)  0.10  −0.31 (−0.43 to 0.49)  0.90  Outpatient  0.12 (−0.03 to 0.27)  0.12  0.14 (0.02 to 0.25)  0.02  Enteral feed  −0.77 (−0.95 to −0.58)  <0.01  −0.35 (−0.70 to 0.00)  0.05  Diarrhoea  −0.26 (−0.52 to −0.01)  0.05  −0.10 (−0.36 to 0.15)  0.43  Nausea  −0.53 (−0.74 to −0.31)  <0.01  −0.10 (−0.30 to 0.10)  0.34  Gastroparesis  0.27 (0.06 to 0.48)  0.01  0.53 (0.22 to 0.84)  0.01  H2 antagonist  −0.13 (−0.28 to 0.01)  0.07  −0.13 (−0.31 to 0.06)  0.18  Daily dose (mg)    <0.01    <0.01   800  reference         200  −0.44 (−1.13 to 0.25)  0.21  −0.78 (−1.32 to −0.25)  <0.01   300  −0.34 (−1.18 to 0.51)  0.43  −0.70 (−1.35 to −0.04)  0.04   400  0.22 (−0.08 to 0.54)  0.15  −0.08 (−0.38 to 0.21)  0.58   600  0.31 (−0.22 to 0.85)  0.25  −0.01 (−0.42 to 0.41)  0.99   640  0.47 (−0.72 to 1.66)  0.44  −0.04 (−0.92 to 0.84)  0.93   960  −0.06 (−0.30 to 0.19)  0.64  −0.11 (−0.33 to 0.12)  0.35   1000  −0.09 (−0.94 to 0.75)  0.83  −0.20 (−0.83 to 0.42)  0.52   1200  −0.45 (−0.64 to −0.26)  <0.01  0.02 (−0.16 to 0.20)  0.84   1440  −0.93 (−1.46 to −0.39)  <0.01  −0.28 (−0.72 to 0.16)  0.21   1600  0.12 (−0.16 to 0.40)  0.42  0.37 (0.01 to 0.64)  <0.01   1800  −0.87 (−1.19 to −0.55)  <0.01  0.08 (−0.24 to 0.41)  0.61   2400  −0.69 (−1.03 to −0.35)  <0.01  0.32 (−0.01 to 0.69)  0.10  Bold formatting signifies statistically significant covariates. For posaconazole MR tablets, multilevel regression analysis suggested that posaconazole Cmin was 48% lower in cystic fibrosis patients, whereas administration of posaconazole MR tablets in an outpatient setting or the presence of underlying gastroparesis was associated with a 25% or 30% increase in posaconazole Cmin, respectively (Table 3). In contrast to posaconazole suspension, a clear dose–response relationship was observed in patients receiving posaconazole MR tablets (Table 3). Table 3. Univariate and multilevel linear regression to examine factors influencing posaconazole tablet Cmin Variable  Univariate analysis   Multilevel linear regression   coefficient (95% CI)  P  coefficient (95% CI)  P  Male  0.05 (−0.04 to 0.14)  0.28  −0.05 (−0.30 to 0.19)  0.66  Age  0.01 (0.00 to 0.01)  <0.01  0.01 (−0.01 to 0.02)  0.34  BMI  0.00 (0.00 to 0.01)  0.67  excluded due to missing values— only 297 observations were available  Cystic fibrosis  −0.38 (−0.52 to −0.24)  <0.01  −0.66 (−1.17 to −0.15)  0.01  Outpatient  0.24 (0.14 to 0.35)  <0.01  0.22 (0.13 to 0.31)  <0.01  Enteral feed  −0.35 (−0.53 to −0.17)  <0.01  0.04 (−0.16 to 0.25)  0.18  Diarrhoea  0.03 (−0.16 to 0.22)  0.76  0 (−0.20 to 0.2)  0.68  Nausea  −0.19 (−0.30 to −0.08)  <0.01  −0.05 (−0.13 to 0.12)  0.94  Gastroparesis  0.06 (−0.06 to 0.18)  0.31  0.26 (0.12 to 0.41)  <0.01  H2 antagonist  −0.17 (−0.26 to −0.07)  <0.01  0.09 (−0.09 to 0.26)  0.33  Daily dose (mg)    <0.01    <0.01   300  reference         100  −0.26 (−0.43 to −0.10)  <0.01  −1.03 (−1.19 to −0.87)  <0.01   200  −0.17 (−0.28 to −0.06)  <0.01  −0.33 (−0.42 to −0.24)  <0.01   400  −0.18 (−0.36 to −0.01)  0.04  0.29 (0.14 to 0.43)  <0.01   500  −0.34 (−0.57 to −0.10)  <0.01  0.53 (0.31 to 0.75)  <0.01   600  0.04 (−0.45 to 0.54)  0.86  0.92 (0.55 to 1.29)  <0.01  Variable  Univariate analysis   Multilevel linear regression   coefficient (95% CI)  P  coefficient (95% CI)  P  Male  0.05 (−0.04 to 0.14)  0.28  −0.05 (−0.30 to 0.19)  0.66  Age  0.01 (0.00 to 0.01)  <0.01  0.01 (−0.01 to 0.02)  0.34  BMI  0.00 (0.00 to 0.01)  0.67  excluded due to missing values— only 297 observations were available  Cystic fibrosis  −0.38 (−0.52 to −0.24)  <0.01  −0.66 (−1.17 to −0.15)  0.01  Outpatient  0.24 (0.14 to 0.35)  <0.01  0.22 (0.13 to 0.31)  <0.01  Enteral feed  −0.35 (−0.53 to −0.17)  <0.01  0.04 (−0.16 to 0.25)  0.18  Diarrhoea  0.03 (−0.16 to 0.22)  0.76  0 (−0.20 to 0.2)  0.68  Nausea  −0.19 (−0.30 to −0.08)  <0.01  −0.05 (−0.13 to 0.12)  0.94  Gastroparesis  0.06 (−0.06 to 0.18)  0.31  0.26 (0.12 to 0.41)  <0.01  H2 antagonist  −0.17 (−0.26 to −0.07)  <0.01  0.09 (−0.09 to 0.26)  0.33  Daily dose (mg)    <0.01    <0.01   300  reference         100  −0.26 (−0.43 to −0.10)  <0.01  −1.03 (−1.19 to −0.87)  <0.01   200  −0.17 (−0.28 to −0.06)  <0.01  −0.33 (−0.42 to −0.24)  <0.01   400  −0.18 (−0.36 to −0.01)  0.04  0.29 (0.14 to 0.43)  <0.01   500  −0.34 (−0.57 to −0.10)  <0.01  0.53 (0.31 to 0.75)  <0.01   600  0.04 (−0.45 to 0.54)  0.86  0.92 (0.55 to 1.29)  <0.01  The bold formatting signifies statistically significant covariates. Discussion To the best of our knowledge, this is the first and largest study exploring the TDM of posaconazole MR tablets in the LTx setting to date. The data suggested that variability in Cmin remained despite the administration of posaconazole MR tablets. Importantly, clinical factors that may potentially affect the posaconazole Cmin in LTx patients taking posaconazole MR tablets were identified for the first time. Our study suggested that, when taking patient factors into account, escalating the posaconazole suspension dose to beyond 800 mg daily did not appear to result in consistent increases in Cmin. However, we noted that a dose of 1600 mg daily of posaconazole suspension in the present study resulted in significantly higher Cmin, consistent with the work of Shields et al.9 In our study, 1600 mg daily of posaconazole was administered in either two or four divided doses. The median (IQR) of posaconazole Cmin following twice daily or four times daily administration was not statistically different: 0.97 (0.89–1.28) versus 1.03 (0.56–1.75), P = 0.76. Although the reasons behind this observation were unknown, no adverse events were documented following administration of 1600 mg daily of posaconazole suspension in our study. However, episodes of liver toxicity and gastrointestinal adverse events following 1600 mg daily of posaconazole suspension have been reported by others.9 Therefore, the use of posaconazole suspension beyond the manufacturer’s recommended dose to boost Cmin requires careful consideration. Compared with the suspension, posaconazole MR tablets were associated with higher Cmin in our study, consistent with findings from the haematology setting.2,11 Owing to pharmacokinetic characteristics,1 the median initial Cmin following 300 mg daily of posaconazole MR tablets was >1 mg/L. The MR tablets, thus, may offer an advantage over the suspension when rapid achievement of a high posaconazole Cmin is required. Given the small number of patients or events, and different follow-up periods, we were unable to determine the clinical effectiveness of posaconazole MR tablets or the association between posaconazole Cmin and clinical response. Nevertheless, the efficacy of posaconazole suspension in LTx recipients has been reported.4,5 In the present study, variability in posaconazole Cmin remained despite administration of the MR tablet formulation. Our experience suggested that administration of 300 mg daily of posaconazole MR tablets resulted in Cmin >1 mg/L in more than 75% of patients. Similarly, Stelzer et al.17 also demonstrated a significant Cmin variability amongst LTx recipients receiving 300 mg daily of posaconazole MR tablets (Cmin ranged from 0.4 to 8.7 mg/L). At our institution, dose reduction/increment, by 100 mg daily, was routinely undertaken to maintain a Cmin between 0.7 and 2 mg/L. Interestingly, in this study, the use of 100 mg daily of posaconazole MR tablets was sufficient to afford therapeutic Cmin in some patients, although a daily dose of up to 600 mg was required in others. Hence, it would be useful to identify patients who are prone to develop sub- or supra-therapeutic Cmin prior to commencement of posaconazole, so that an appropriate dose can be instituted. Notably, factors contributing to Cmin variability amongst patients with haematological malignancies and LTx recipients are not entirely identical, potentially owing to the differences between these two groups of patients (e.g. physiological variables). Dolton et al.18 had previously reported concurrent ranitidine or metoclopramide therapy, underlying diarrhoea or mucositis as predictors for lower Cmin in patients with underlying haematological malignancies who received posaconazole suspension. Similarly, in their cohort of haematological malignancy patients and recipients of haematopoietic stem cell transplant with graft-versus-host disease who received posaconazole MR tablets, Tang et al.19 reported that sub-therapeutic Cmin was more likely to occur during episodes of diarrhoea or concurrent proton pump inhibitor therapy. We, however, did not observe such associations in our LTx patient cohort, regardless of the posaconazole formulation taken. Although diarrhoea or nausea/vomiting in the current study was associated with lower posaconazole Cmin in the univariate analysis, multilevel linear regression analysis did not reveal any statistically significant association. Whilst these gastrointestinal disturbances following LTx are common, they are generally mild in nature.20 Thus, their impact on posaconazole absorption is potentially minimal. When enteral feedings were administered to compensate for reduced oral intake in LTx patients, significantly lower Cmin was observed in patients receiving posaconazole suspension. In contrast, such association was not observed in those receiving posaconazole MR tablets, supporting the previous finding that their absorption is not affected by food.10 In contrast, patients with gastroparesis, which is a common complication following LTx,21 were found to have a higher Cmin in the current study regardless of the posaconazole formulation administered. Delay in gastrointestinal transit may have increased posaconazole absorption from the gut. The current study found a significantly lower median posaconazole Cmin in patients with cystic fibrosis. However, when adjusted for the other variables in the multilevel linear regression model, this difference was no longer significant in patients taking posaconazole suspension. In those taking posaconazole MR tablets, however, the relationship between underlying cystic fibrosis and posaconazole Cmin remained. Inherent to reduced gastrointestinal absorption and increased drug clearance, patients with cystic fibrosis often experience altered dispositions of many drugs.22 A recent study demonstrated significantly lower posaconazole exposure in LTx recipients with cystic fibrosis who received posaconazole suspension.23 Although the pharmacokinetics of posaconazole MR tablets in this patient population has yet to be evaluated, posaconazole Cmin should be closely monitored in these patients until further data are available. Given that PPI was concomitantly administered in ≥90% of our patients, we were unable to evaluate the impact of PPI on posaconazole Cmin in the present study. A previous study has demonstrated that concomitant administration of posaconazole suspension with PPI in LTx recipients resulted in significantly lower posaconazole Cmin,9 although the authors only adjusted for oral administration and concomitant H2 antagonist administration in their model. Although no study has quantified the effect of concomitant PPI therapy and posaconazole MR tablets in the LTx setting, Stelzer et al.17 did demonstrate a lower posaconazole Cmin in patients receiving concomitant 80 mg daily of pantoprazole compared with those receiving 40 mg daily. Given the negligible impact of gastric pH on posaconazole MR tablet absorption, the impact of PPI would likely be minimal, as previously reported in healthy individuals24 and patients with haematological malignancies.2 In the current study, despite having controlled for concomitant medications and other variables, both inter- and intra-patient variability in posaconazole Cmin remained, consistent with findings from other studies.17,25 We were, however, unable to rule out the possibility of other important patient factors that could potentially influence posaconazole Cmin. Genetic polymorphisms of P-glycoprotein (P-gp) or UDP-glucuronosyltransferases (UGT), for example, have been reported to affect the plasma concentration of certain drugs.26,27 Although Sansone-Parsons et al.28 demonstrated a lack of association between P-gp polymorphism and posaconazole clearance, the impact of UGT polymorphism on the metabolism of posaconazole is yet to be reported. Further investigation is required. The present study is the first to report symptoms of lethargy, sweating, weight loss and fatigue in three patients with posaconazole Cmin >2 mg/L. Although unable to be definitively attributed to posaconazole toxicity, these symptoms completely resolved when posaconazole Cmin was reduced to <2 mg/L. Of interest, Parkes et al.29 recently reported visual hallucinations and cognitive impairment in a patient receiving posaconazole tablets. The posaconazole Cmin in this patient, when the symptoms developed, was 10.10 mg/L. Posaconazole tablets were subsequently withheld and improvement in symptoms was observed following reduction in posaconazole Cmin. Consistent with findings from previous studies,11,30 no episodes of hepatotoxicity were documented in the 42 patients with Cmin >2 mg/L in our study. Nevertheless, it is worth noting that a recent study of patients with haematological malignancies reported episodes of hyperbilirubinaemia, although not attributed to posaconazole, in patients with Cmin >1.83 mg/L.3 Given that the relationship between posaconazole Cmin and adverse events has yet to be established,1,11 further surveillance is warranted. In conclusion, this study has provided clinically important insights into the TDM of posaconazole in LTx patients receiving posaconazole suspension and/or MR tablets. Non-specific signs or symptoms of adverse effects were documented in some patients with Cmin >2 mg/L, although no episodes of liver toxicity were observed. Further study should aim to delineate the patient factors relating to posaconazole Cmin variability in the LTx setting, which we were unable to investigate. Owing to the inter- and intra-patient variability, findings from the current study support the need for regular TDM in LTx patients prescribed posaconazole suspension and/or MR tablets. Funding This was an investigator-initiated study supported by internal funding. Transparency declarations C. O. M. has received grants from Merck Sharp and Dohme (MSD) and Gilead Sciences, has sat on advisory boards for MSD and has received honoraria from Pfizer. M. A. S. has received grants from Pfizer, MSD and Gilead Sciences. D. C. M. K. has sat on advisory boards for Pfizer and MSD, and has received financial/travel support unrelated to the current work from Roche, Pfizer and MSD. All other authors: none to declare. References 1 Cornely OA, Duarte RF, Haider S et al.   Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. J Antimicrob Chemother  2016; 71: 718– 26. Google Scholar CrossRef Search ADS PubMed  2 Cumpston A, Caddell R, Shillingburg A et al.   Superior serum concentrations with posaconazole delayed-release tablets compared to suspension formulation in hematological malignancies. Antimicrob Agents Chemother  2015; 59: 4424– 8. Google Scholar CrossRef Search ADS PubMed  3 Tverdek FP, Heo ST, Aitken SL et al.   Real-life assessment of the safety and effectiveness of the new tablet and intravenous formulations of posaconazole in the prophylaxis of invasive fungal infections: analysis of 343 courses. Antimicrob Agents Chemother  2017; 61: e00188– 17. Google Scholar CrossRef Search ADS PubMed  4 Jeong W, Snell GI, Levvey BJ et al.   Clinical effectiveness of early posaconazole suspension pre-emptive therapy in lung transplant recipients: the Alfred’s experience. J Antimicrob Chemother  2017; 72: 2089– 92. 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Ther Drug Monit  2017; 39: 93– 101. Google Scholar CrossRef Search ADS PubMed  18 Dolton MJ, Ray JE, Marriott D, McLachlan AJ. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother  2012; 56: 2806– 13. Google Scholar CrossRef Search ADS PubMed  19 Tang LA, Marini BL, Benitez L et al.   Risk factors for subtherapeutic levels of posaconazole tablet. J Antimicrob Chemother  2017; 72: 2902– 5. Google Scholar CrossRef Search ADS PubMed  20 Bravo C, Gispert P, Borro JM et al.   Prevalence and management of gastrointestinal complications in lung transplant patients: MITOS Study Group. Transplant Proc  2007; 39: 2409– 12. Google Scholar CrossRef Search ADS PubMed  21 D’Ovidio F, Singer LG, Hadjiliadis D et al.   Prevalence of gastroesophageal reflux in end-stage lung disease candidates for lung transplant. Ann Thorac Surg  2005; 80: 1254– 60. Google Scholar CrossRef Search ADS PubMed  22 Rey E, Treluyer JM, Pons G. 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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 1, 2018

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