Caspofungin dosage adjustments are not required for patients with Child–Pugh B or C cirrhosis

Caspofungin dosage adjustments are not required for patients with Child–Pugh B or C cirrhosis Abstract Background Controversies remain over caspofungin dosage adjustments in cirrhosis, particularly Child–Pugh (CP) B or C. The product information for of caspofungin recommends a maintenance dose reduction from 50 to 35 mg for patients with CP-B cirrhosis. Objectives To quantify the impact of cirrhosis and the severity of hepatic impairment on the pharmacokinetics (PK) of caspofungin. Patients and methods We performed PK studies of a single 70 mg dose of caspofungin in patients with decompensated CP-B (n = 10) or CP-C (n = 10) cirrhosis and of multiple doses in 21 non-cirrhotic ICU patients with hypoalbuminaemia. A Monte Carlo simulation was performed to investigate the impact of a maintenance dose reduction from 50 to 35 mg on the steady-state area under the 24 h concentration–time curve. Results We observed a marginal reduction of caspofungin clearance in a PK study in patients with decompensated CP-B or CP-C cirrhosis. Dose reduction to 35 mg in cirrhotic patients resulted in lower drug exposure than with the approved dose in non-cirrhotic patients. Conclusions In contrast to the product information, we recommend giving the full dose of caspofungin regardless of the presence and severity of cirrhosis to avoid a subtherapeutic exposure. Introduction Invasive fungal disease (IFD), particularly invasive candidiasis, poses a serious health problem for patients with advanced liver disease, due to the patients’ immunocompromised state and their requirement for large doses of broad-spectrum antibiotics, as well as the invasive procedures and intensive care management involved.1,2 Caspofungin is one of the three echinocandins that are the preferred therapeutic option for IFD.3 Recently, we demonstrated that the recommended dose reduction in non-cirrhotic critically ill patients, with a Child–Pugh (CP) score of B (mainly driven by hypoalbuminaemia), may lead to suboptimal exposure, suggesting that the effect of CP-B on caspofungin pharmacokinetics (PK) is less pronounced than previously thought.4 This suboptimal exposure leaves patients at risk of treatment failure.5 A study in a small population of eight cirrhotic subjects suggested a reduction of 50% in clearance of caspofungin in patients with moderate hepatic impairment (CP-B), justifying the dose reduction declared in the product information. Currently, we do not have PK data for caspofungin in patients with severe hepatic dysfunction (CP-C).6 We performed a pooled PK analysis in a large cohort of cirrhotic (CP-B and CP-C) as well as non-cirrhotic critically ill patients (with hypoalbuminaemia resulting in artificial CP-B) to quantify the impact of cirrhosis and the severity of hepatic impairment on the PK of caspofungin to ultimately prevent subtherapeutic exposure to caspofungin. Patients and methods Patients In the first study, we prospectively recruited 20 cirrhotic patients [10 with moderate hepatic impairment CP-B (≥7 and ≤9) and 10 with severe hepatic impairment CP-C (≥10)] admitted with an acute decompensation without IFD to our Liver Unit over a period of 1 year (EudraCT number: 2013-002079-16). The diagnosis of cirrhosis was established by biopsy or based on a clear combination of clinical, radiological and biochemical criteria. These patients all received a single 70 mg dose of caspofungin as a 1 h intravenous infusion. Blood samples were collected before and at 1, 2, 4, 8, 12, 24, 48, 72 and 96 h after infusion. The second study consisted of 21 non-cirrhotic ICU patients with hypoalbuminaemia. This cohort and its PK sampling have been described in detail previously.4,7 Briefly stated, all ICU patients with suspected or proven IFD received caspofungin at licensed dosages and underwent intensive PK sampling on multiple occasions together with measurements of daily trough concentrations. Plasma concentrations of caspofungin were determined using validated HPLC with fluorescence detection.8 Ethics The protocol was approved by the local ethics committee and written informed consent was obtained from all participants. PK analysis This was performed with non-linear mixed-effects modelling using the software package NONMEM version 7.3, with Piraña as an interface for Perl Speaks Nonmem and R statistics.9 Throughout the analysis, the first-order conditional estimation with interaction method was used. The 95% CI and relative standard errors of estimates (%RSE) of all parameter estimates were calculated with sampling importance resampling.10 A previously developed model for caspofungin in critically ill patients was used as a starting point of our analysis.4 PK parameters were allometrically scaled to total body weight and all parameters were scaled to a typical individual with a total body weight of 70 kg, as proposed recently.11 Presence of cirrhosis as well as the severity of hepatic impairment (CP-B versus CP-C) were tested as binary covariates on clearance with a 5% significance level. An a posteriori power analysis was performed with the base model without covariates, by means of stochastic simulation and estimation (n = 500 replicates of our pooled data set), to establish the power to detect 25% change in clearance at a significance level of 5%. With the final PK model a Monte Carlo simulation (n = 1000) was performed to investigate the impact of a maintenance dose (after a loading dose of 70 mg) reduction from 50 to 35 mg on the steady-state area under the 24 h concentration–time curve (AUC24) as recommended in the caspofungin product information for a CP-B score for a typical individual of 70 kg in the presence and absence of found covariates. Results The characteristics of the two cohorts are summarized in Table 1. There were 31 patients with CP-B [both cirrhotic (n = 10) and non-cirrhotic (n = 21)] who were compared with 10 cirrhotic patients with CP-C. Table 1. Demographic characteristics of patients Variable Cirrhotic CP-B patients (n = 10) Cirrhotic CP-C patients (n = 10) Non-cirrhotic patients with hypoalbuminaemia (n = 21) Age (years) 57 (41–68) 56 (40–64) 73 (45–80) Male 6 6 13 Body weight (kg) 75 (62–107) 73 (50–112) 75 (52–104) Biopsy-proven cirrhosis 7 8 0 Alcoholic hepatitis 3 8 0 Total bilirubin (mg/dL) 1.8 (1–4.2) 4.9 (3–22) 0.4 (0.2–1.8) INR 1.43 (1.11–1.74) 1.59 (1.39–2.86) NA Serum creatinine (mg/dL) 0.8 (0.6–1.2) 0.7 (0.5–1.3) 1.2 (0.44–2.27) Serum albumin (g/L) 31 (20–39) 27 (21–32) 21 (9–29) Ascites grade 0/1/2/3 0/5/5/0 0/1/6/3 0/0/0/0 Hepatic encephalopathy 0/1/2 0/8/2 0/7/3 0/0/0 Variable Cirrhotic CP-B patients (n = 10) Cirrhotic CP-C patients (n = 10) Non-cirrhotic patients with hypoalbuminaemia (n = 21) Age (years) 57 (41–68) 56 (40–64) 73 (45–80) Male 6 6 13 Body weight (kg) 75 (62–107) 73 (50–112) 75 (52–104) Biopsy-proven cirrhosis 7 8 0 Alcoholic hepatitis 3 8 0 Total bilirubin (mg/dL) 1.8 (1–4.2) 4.9 (3–22) 0.4 (0.2–1.8) INR 1.43 (1.11–1.74) 1.59 (1.39–2.86) NA Serum creatinine (mg/dL) 0.8 (0.6–1.2) 0.7 (0.5–1.3) 1.2 (0.44–2.27) Serum albumin (g/L) 31 (20–39) 27 (21–32) 21 (9–29) Ascites grade 0/1/2/3 0/5/5/0 0/1/6/3 0/0/0/0 Hepatic encephalopathy 0/1/2 0/8/2 0/7/3 0/0/0 INR, international normalized ratio; NA, not available. Results are presented as median (minimum–maximum) or number. Table 1. Demographic characteristics of patients Variable Cirrhotic CP-B patients (n = 10) Cirrhotic CP-C patients (n = 10) Non-cirrhotic patients with hypoalbuminaemia (n = 21) Age (years) 57 (41–68) 56 (40–64) 73 (45–80) Male 6 6 13 Body weight (kg) 75 (62–107) 73 (50–112) 75 (52–104) Biopsy-proven cirrhosis 7 8 0 Alcoholic hepatitis 3 8 0 Total bilirubin (mg/dL) 1.8 (1–4.2) 4.9 (3–22) 0.4 (0.2–1.8) INR 1.43 (1.11–1.74) 1.59 (1.39–2.86) NA Serum creatinine (mg/dL) 0.8 (0.6–1.2) 0.7 (0.5–1.3) 1.2 (0.44–2.27) Serum albumin (g/L) 31 (20–39) 27 (21–32) 21 (9–29) Ascites grade 0/1/2/3 0/5/5/0 0/1/6/3 0/0/0/0 Hepatic encephalopathy 0/1/2 0/8/2 0/7/3 0/0/0 Variable Cirrhotic CP-B patients (n = 10) Cirrhotic CP-C patients (n = 10) Non-cirrhotic patients with hypoalbuminaemia (n = 21) Age (years) 57 (41–68) 56 (40–64) 73 (45–80) Male 6 6 13 Body weight (kg) 75 (62–107) 73 (50–112) 75 (52–104) Biopsy-proven cirrhosis 7 8 0 Alcoholic hepatitis 3 8 0 Total bilirubin (mg/dL) 1.8 (1–4.2) 4.9 (3–22) 0.4 (0.2–1.8) INR 1.43 (1.11–1.74) 1.59 (1.39–2.86) NA Serum creatinine (mg/dL) 0.8 (0.6–1.2) 0.7 (0.5–1.3) 1.2 (0.44–2.27) Serum albumin (g/L) 31 (20–39) 27 (21–32) 21 (9–29) Ascites grade 0/1/2/3 0/5/5/0 0/1/6/3 0/0/0/0 Hepatic encephalopathy 0/1/2 0/8/2 0/7/3 0/0/0 INR, international normalized ratio; NA, not available. Results are presented as median (minimum–maximum) or number. A two-compartment structural model described our data well and the results are shown in Table S1 and Figures S1 and S2 (available as Supplementary data at JAC Online). The power analysis showed that, in our analysis, we had a power of 96.8% and 91.2% to detect a 25% change in clearance due to cirrhosis and severe hepatic impairment, respectively. Clearance of caspofungin in non-cirrhotic patients was 0.52 L/h (95% CI: 0.45–0.59 L/h) and this was found to decrease marginally by 20.8% in cirrhotic patients (95% CI: 9%–32.6%) (P < 0.005). The severity of hepatic dysfunction (21 non-cirrhotic misclassified CP-B patients combined with 10 cirrhotic CP-B patients versus 10 cirrhotic CP-C patients) did not explain the variability in caspofungin clearance. Moreover, the absence of any effect of the severity of hepatic dysfunction is confirmed by a further analysis where clearance was independently investigated in all three groups (non-cirrhotic patients, cirrhotic CP-B patients and CP-C patients). The estimated relative clearances were 100%, 79.7% and 78.8% for non-cirrhotic misclassified CP-B patients, for cirrhotic CP-B patients and for cirrhotic CP-C patients, respectively, with no significant difference between the latter two groups. Figure 1 shows the steady-state AUC0–24 of the Monte Carlo simulation for administration of 50 or 35 mg of caspofungin in presence or absence of cirrhosis for a typical 70 kg person. As observed, dose reduction to 35 mg in cirrhotic patients, compliant with the drug product information, resulted in lower drug exposure than in the approved dose in non-cirrhotic patients or healthy volunteers. Figure 1. View largeDownload slide Box and whisker plot of predicted AUC24 at steady-state with or without cirrhosis and a maintenance dose of 35 or 50 mg for a typical individual of 70 kg. The broken line indicates the typical AUC24 in healthy volunteers at the approved dose. Each box shows the median and the IQR of the predictions and the whiskers extend to the minimum and maximum values. Figure 1. View largeDownload slide Box and whisker plot of predicted AUC24 at steady-state with or without cirrhosis and a maintenance dose of 35 or 50 mg for a typical individual of 70 kg. The broken line indicates the typical AUC24 in healthy volunteers at the approved dose. Each box shows the median and the IQR of the predictions and the whiskers extend to the minimum and maximum values. Discussion To our knowledge, this is the first study to provide caspofungin PK data for CP-C cirrhotic patients. Our findings show that cirrhosis had only a limited impact on clearance of caspofungin, as observed by the reduction of 20.8% (P < 0.005). Moreover, we observed that CP-C does not further decrease clearance of caspofungin compared with CP-B. As further reduction in clearance is likely with worse hepatic function, we postulate that, considering the high power of our analysis to detect a clinically relevant effect, this effect will be small. The impact of cirrhosis is far less pronounced compared with the initial PK study where a 1.8-fold increase in caspofungin AUC was observed in eight patients with CP-B cirrhosis when compared with healthy volunteers.6 This discrepancy might be explained by differences in the design of the PK studies. Our study included a larger number of cirrhotic patients (n = 20). Moreover, we provide PK data of caspofungin of cirrhotic patients in acute decompensation requiring hospitalization, which mimics the clinical context of IFD in cirrhosis. In contrast, Mistry et al.6 performed their PK study in patients with stable cirrhosis for at least 2 months without any decompensation episode. On the other hand, the lack of a healthy control group is a limitation of our study. Other case reports also suggested that the recommended dose reduction of caspofungin in decompensated cirrhotic patients resulted in low exposure and, therefore, the approved dosing regimen should be reconsidered.12,13 Caspofungin is extensively bound to albumin.14,15 Hypoalbuminaemia might lead to changes in caspofungin free fraction. Reducing the dose of caspofungin in non-cirrhotic patients misclassified as CP-B due to isolated hypoalbuminaemia results in significantly lower exposure.4 Hypoalbuminaemia is a part of the liver dysfunction observed in cirrhosis. In our cohort of cirrhotic patients, we cannot dissociate the impact of hypoalbuminaemia from the other sources of impaired hepatic function. We believe that reducing the dose of caspofungin in cirrhotic patients with moderate (CP-B) and severe hepatic impairment (CP-C) results in an unwanted decrease in exposure. As the efficacy of caspofungin is best described by the AUC24 to MIC ratio, reduced exposure may lead to suboptimal clinical outcomes. Specifically in the setting of emerging echinocandin resistance all efforts must be taken to optimize dosing to maximize therapeutic efficacy. We do not recommend dose reduction for caspofungin regardless of the presence and severity of hepatic failure in order to ensure optimal treatment. Funding The work was supported in part by Merck & Co., Inc. Transparency declarations R. J. B. has served as a consultant to Astellas Pharma, Inc., F2G, Gilead Sciences, Merck Sharpe and Dohme Corp. and Pfizer, Inc., and has received unrestricted and research grants from Astellas Pharma, Inc., Gilead Sciences, Merck Sharpe and Dohme Corp. and Pfizer, Inc. All payments were invoiced by the Radboudumc. All other authors: none to declare. Supplementary data Table S1 and Figures S1 and S2 are available as Supplementary data at JAC Online. References 1 Gustot T , Felleiter P , Pickkers P et al. Impact of infection on the prognosis of critically ill cirrhotic patients: results from a large worldwide study . Liver Int 2014 ; 34 : 1496 – 503 . Google Scholar CrossRef Search ADS PubMed 2 Alexopoulou A , Vasilieva L , Agiasotelli D et al. Fungal infections in patients with cirrhosis . J Hepatol 2015 ; 63 : 1043 – 5 . Google Scholar CrossRef Search ADS PubMed 3 Pappas PG , Kauffman CA , Andes DR et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America . Clin Infect Dis 2016 ; 62 : e1 – 50 . Google Scholar CrossRef Search ADS PubMed 4 Martial LC , Brüggemann RJM , Schouten JA et al. Dose reduction of caspofungin in intensive care unit patients with Child Pugh B will result in suboptimal exposure . Clin Pharmacokinet 2016 ; 55 : 723 – 33 . Google Scholar CrossRef Search ADS PubMed 5 Andes D , Diekema DJ , Pfaller MA et al. In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species . Antimicrob Agents Chemother 2010 ; 54 : 2497 – 506 . Google Scholar CrossRef Search ADS PubMed 6 Mistry GC , Migoya E , Deutsch PJ et al. Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations . J Clin Pharmacol 2007 ; 47 : 951 – 61 . Google Scholar CrossRef Search ADS PubMed 7 Muilwijk EW , Schouten JA , van Leeuwen HJ et al. Pharmacokinetics of caspofungin in ICU patients . J Antimicrob Chemother 2014 ; 69 : 3294 – 9 . Google Scholar CrossRef Search ADS PubMed 8 Spriet I , Annaert P , Meersseman P et al. Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation . J Antimicrob Chemother 2009 ; 63 : 767 – 70 . Google Scholar CrossRef Search ADS PubMed 9 Keizer RJ , Karlsson MO , Hooker A. Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose . CPT Pharmacometrics Syst Pharmacol 2013 ; 2 : e50. Google Scholar CrossRef Search ADS PubMed 10 Dosne A-G , Bergstrand M , Harling K et al. Improving the estimation of parameter uncertainty distributions in nonlinear mixed effects models using sampling importance resampling . J Pharmacokinet Pharmacodyn 2016 ; 43 : 583 – 96 . Google Scholar CrossRef Search ADS PubMed 11 Holford NHG , Anderson BJ. 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 12 van der Elst KCM , Veringa A , Zijlstra JG et al. Low caspofungin exposure in patients in intensive care units . Antimicrob Agents Chemother 2017 ; 61 : e01582 – 16 . Google Scholar PubMed 13 Spriet I , Meersseman W , Annaert P et al. Pharmacokinetics of caspofungin in a critically ill patient with liver cirrhosis . Eur J Clin Pharmacol 2011 ; 67 : 753 – 5 . Google Scholar CrossRef Search ADS PubMed 14 Stone JA , Xu X , Winchell GA et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma . Antimicrob Agents Chemother 2004 ; 48 : 815 – 23 . Google Scholar CrossRef Search ADS PubMed 15 Nguyen TH , Hoppe-Tichy T , Geiss HK et al. Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit . J Antimicrob Chemother 2007 ; 60 : 100 – 6 . 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. 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Caspofungin dosage adjustments are not required for patients with Child–Pugh B or C cirrhosis

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Abstract

Abstract Background Controversies remain over caspofungin dosage adjustments in cirrhosis, particularly Child–Pugh (CP) B or C. The product information for of caspofungin recommends a maintenance dose reduction from 50 to 35 mg for patients with CP-B cirrhosis. Objectives To quantify the impact of cirrhosis and the severity of hepatic impairment on the pharmacokinetics (PK) of caspofungin. Patients and methods We performed PK studies of a single 70 mg dose of caspofungin in patients with decompensated CP-B (n = 10) or CP-C (n = 10) cirrhosis and of multiple doses in 21 non-cirrhotic ICU patients with hypoalbuminaemia. A Monte Carlo simulation was performed to investigate the impact of a maintenance dose reduction from 50 to 35 mg on the steady-state area under the 24 h concentration–time curve. Results We observed a marginal reduction of caspofungin clearance in a PK study in patients with decompensated CP-B or CP-C cirrhosis. Dose reduction to 35 mg in cirrhotic patients resulted in lower drug exposure than with the approved dose in non-cirrhotic patients. Conclusions In contrast to the product information, we recommend giving the full dose of caspofungin regardless of the presence and severity of cirrhosis to avoid a subtherapeutic exposure. Introduction Invasive fungal disease (IFD), particularly invasive candidiasis, poses a serious health problem for patients with advanced liver disease, due to the patients’ immunocompromised state and their requirement for large doses of broad-spectrum antibiotics, as well as the invasive procedures and intensive care management involved.1,2 Caspofungin is one of the three echinocandins that are the preferred therapeutic option for IFD.3 Recently, we demonstrated that the recommended dose reduction in non-cirrhotic critically ill patients, with a Child–Pugh (CP) score of B (mainly driven by hypoalbuminaemia), may lead to suboptimal exposure, suggesting that the effect of CP-B on caspofungin pharmacokinetics (PK) is less pronounced than previously thought.4 This suboptimal exposure leaves patients at risk of treatment failure.5 A study in a small population of eight cirrhotic subjects suggested a reduction of 50% in clearance of caspofungin in patients with moderate hepatic impairment (CP-B), justifying the dose reduction declared in the product information. Currently, we do not have PK data for caspofungin in patients with severe hepatic dysfunction (CP-C).6 We performed a pooled PK analysis in a large cohort of cirrhotic (CP-B and CP-C) as well as non-cirrhotic critically ill patients (with hypoalbuminaemia resulting in artificial CP-B) to quantify the impact of cirrhosis and the severity of hepatic impairment on the PK of caspofungin to ultimately prevent subtherapeutic exposure to caspofungin. Patients and methods Patients In the first study, we prospectively recruited 20 cirrhotic patients [10 with moderate hepatic impairment CP-B (≥7 and ≤9) and 10 with severe hepatic impairment CP-C (≥10)] admitted with an acute decompensation without IFD to our Liver Unit over a period of 1 year (EudraCT number: 2013-002079-16). The diagnosis of cirrhosis was established by biopsy or based on a clear combination of clinical, radiological and biochemical criteria. These patients all received a single 70 mg dose of caspofungin as a 1 h intravenous infusion. Blood samples were collected before and at 1, 2, 4, 8, 12, 24, 48, 72 and 96 h after infusion. The second study consisted of 21 non-cirrhotic ICU patients with hypoalbuminaemia. This cohort and its PK sampling have been described in detail previously.4,7 Briefly stated, all ICU patients with suspected or proven IFD received caspofungin at licensed dosages and underwent intensive PK sampling on multiple occasions together with measurements of daily trough concentrations. Plasma concentrations of caspofungin were determined using validated HPLC with fluorescence detection.8 Ethics The protocol was approved by the local ethics committee and written informed consent was obtained from all participants. PK analysis This was performed with non-linear mixed-effects modelling using the software package NONMEM version 7.3, with Piraña as an interface for Perl Speaks Nonmem and R statistics.9 Throughout the analysis, the first-order conditional estimation with interaction method was used. The 95% CI and relative standard errors of estimates (%RSE) of all parameter estimates were calculated with sampling importance resampling.10 A previously developed model for caspofungin in critically ill patients was used as a starting point of our analysis.4 PK parameters were allometrically scaled to total body weight and all parameters were scaled to a typical individual with a total body weight of 70 kg, as proposed recently.11 Presence of cirrhosis as well as the severity of hepatic impairment (CP-B versus CP-C) were tested as binary covariates on clearance with a 5% significance level. An a posteriori power analysis was performed with the base model without covariates, by means of stochastic simulation and estimation (n = 500 replicates of our pooled data set), to establish the power to detect 25% change in clearance at a significance level of 5%. With the final PK model a Monte Carlo simulation (n = 1000) was performed to investigate the impact of a maintenance dose (after a loading dose of 70 mg) reduction from 50 to 35 mg on the steady-state area under the 24 h concentration–time curve (AUC24) as recommended in the caspofungin product information for a CP-B score for a typical individual of 70 kg in the presence and absence of found covariates. Results The characteristics of the two cohorts are summarized in Table 1. There were 31 patients with CP-B [both cirrhotic (n = 10) and non-cirrhotic (n = 21)] who were compared with 10 cirrhotic patients with CP-C. Table 1. Demographic characteristics of patients Variable Cirrhotic CP-B patients (n = 10) Cirrhotic CP-C patients (n = 10) Non-cirrhotic patients with hypoalbuminaemia (n = 21) Age (years) 57 (41–68) 56 (40–64) 73 (45–80) Male 6 6 13 Body weight (kg) 75 (62–107) 73 (50–112) 75 (52–104) Biopsy-proven cirrhosis 7 8 0 Alcoholic hepatitis 3 8 0 Total bilirubin (mg/dL) 1.8 (1–4.2) 4.9 (3–22) 0.4 (0.2–1.8) INR 1.43 (1.11–1.74) 1.59 (1.39–2.86) NA Serum creatinine (mg/dL) 0.8 (0.6–1.2) 0.7 (0.5–1.3) 1.2 (0.44–2.27) Serum albumin (g/L) 31 (20–39) 27 (21–32) 21 (9–29) Ascites grade 0/1/2/3 0/5/5/0 0/1/6/3 0/0/0/0 Hepatic encephalopathy 0/1/2 0/8/2 0/7/3 0/0/0 Variable Cirrhotic CP-B patients (n = 10) Cirrhotic CP-C patients (n = 10) Non-cirrhotic patients with hypoalbuminaemia (n = 21) Age (years) 57 (41–68) 56 (40–64) 73 (45–80) Male 6 6 13 Body weight (kg) 75 (62–107) 73 (50–112) 75 (52–104) Biopsy-proven cirrhosis 7 8 0 Alcoholic hepatitis 3 8 0 Total bilirubin (mg/dL) 1.8 (1–4.2) 4.9 (3–22) 0.4 (0.2–1.8) INR 1.43 (1.11–1.74) 1.59 (1.39–2.86) NA Serum creatinine (mg/dL) 0.8 (0.6–1.2) 0.7 (0.5–1.3) 1.2 (0.44–2.27) Serum albumin (g/L) 31 (20–39) 27 (21–32) 21 (9–29) Ascites grade 0/1/2/3 0/5/5/0 0/1/6/3 0/0/0/0 Hepatic encephalopathy 0/1/2 0/8/2 0/7/3 0/0/0 INR, international normalized ratio; NA, not available. Results are presented as median (minimum–maximum) or number. Table 1. Demographic characteristics of patients Variable Cirrhotic CP-B patients (n = 10) Cirrhotic CP-C patients (n = 10) Non-cirrhotic patients with hypoalbuminaemia (n = 21) Age (years) 57 (41–68) 56 (40–64) 73 (45–80) Male 6 6 13 Body weight (kg) 75 (62–107) 73 (50–112) 75 (52–104) Biopsy-proven cirrhosis 7 8 0 Alcoholic hepatitis 3 8 0 Total bilirubin (mg/dL) 1.8 (1–4.2) 4.9 (3–22) 0.4 (0.2–1.8) INR 1.43 (1.11–1.74) 1.59 (1.39–2.86) NA Serum creatinine (mg/dL) 0.8 (0.6–1.2) 0.7 (0.5–1.3) 1.2 (0.44–2.27) Serum albumin (g/L) 31 (20–39) 27 (21–32) 21 (9–29) Ascites grade 0/1/2/3 0/5/5/0 0/1/6/3 0/0/0/0 Hepatic encephalopathy 0/1/2 0/8/2 0/7/3 0/0/0 Variable Cirrhotic CP-B patients (n = 10) Cirrhotic CP-C patients (n = 10) Non-cirrhotic patients with hypoalbuminaemia (n = 21) Age (years) 57 (41–68) 56 (40–64) 73 (45–80) Male 6 6 13 Body weight (kg) 75 (62–107) 73 (50–112) 75 (52–104) Biopsy-proven cirrhosis 7 8 0 Alcoholic hepatitis 3 8 0 Total bilirubin (mg/dL) 1.8 (1–4.2) 4.9 (3–22) 0.4 (0.2–1.8) INR 1.43 (1.11–1.74) 1.59 (1.39–2.86) NA Serum creatinine (mg/dL) 0.8 (0.6–1.2) 0.7 (0.5–1.3) 1.2 (0.44–2.27) Serum albumin (g/L) 31 (20–39) 27 (21–32) 21 (9–29) Ascites grade 0/1/2/3 0/5/5/0 0/1/6/3 0/0/0/0 Hepatic encephalopathy 0/1/2 0/8/2 0/7/3 0/0/0 INR, international normalized ratio; NA, not available. Results are presented as median (minimum–maximum) or number. A two-compartment structural model described our data well and the results are shown in Table S1 and Figures S1 and S2 (available as Supplementary data at JAC Online). The power analysis showed that, in our analysis, we had a power of 96.8% and 91.2% to detect a 25% change in clearance due to cirrhosis and severe hepatic impairment, respectively. Clearance of caspofungin in non-cirrhotic patients was 0.52 L/h (95% CI: 0.45–0.59 L/h) and this was found to decrease marginally by 20.8% in cirrhotic patients (95% CI: 9%–32.6%) (P < 0.005). The severity of hepatic dysfunction (21 non-cirrhotic misclassified CP-B patients combined with 10 cirrhotic CP-B patients versus 10 cirrhotic CP-C patients) did not explain the variability in caspofungin clearance. Moreover, the absence of any effect of the severity of hepatic dysfunction is confirmed by a further analysis where clearance was independently investigated in all three groups (non-cirrhotic patients, cirrhotic CP-B patients and CP-C patients). The estimated relative clearances were 100%, 79.7% and 78.8% for non-cirrhotic misclassified CP-B patients, for cirrhotic CP-B patients and for cirrhotic CP-C patients, respectively, with no significant difference between the latter two groups. Figure 1 shows the steady-state AUC0–24 of the Monte Carlo simulation for administration of 50 or 35 mg of caspofungin in presence or absence of cirrhosis for a typical 70 kg person. As observed, dose reduction to 35 mg in cirrhotic patients, compliant with the drug product information, resulted in lower drug exposure than in the approved dose in non-cirrhotic patients or healthy volunteers. Figure 1. View largeDownload slide Box and whisker plot of predicted AUC24 at steady-state with or without cirrhosis and a maintenance dose of 35 or 50 mg for a typical individual of 70 kg. The broken line indicates the typical AUC24 in healthy volunteers at the approved dose. Each box shows the median and the IQR of the predictions and the whiskers extend to the minimum and maximum values. Figure 1. View largeDownload slide Box and whisker plot of predicted AUC24 at steady-state with or without cirrhosis and a maintenance dose of 35 or 50 mg for a typical individual of 70 kg. The broken line indicates the typical AUC24 in healthy volunteers at the approved dose. Each box shows the median and the IQR of the predictions and the whiskers extend to the minimum and maximum values. Discussion To our knowledge, this is the first study to provide caspofungin PK data for CP-C cirrhotic patients. Our findings show that cirrhosis had only a limited impact on clearance of caspofungin, as observed by the reduction of 20.8% (P < 0.005). Moreover, we observed that CP-C does not further decrease clearance of caspofungin compared with CP-B. As further reduction in clearance is likely with worse hepatic function, we postulate that, considering the high power of our analysis to detect a clinically relevant effect, this effect will be small. The impact of cirrhosis is far less pronounced compared with the initial PK study where a 1.8-fold increase in caspofungin AUC was observed in eight patients with CP-B cirrhosis when compared with healthy volunteers.6 This discrepancy might be explained by differences in the design of the PK studies. Our study included a larger number of cirrhotic patients (n = 20). Moreover, we provide PK data of caspofungin of cirrhotic patients in acute decompensation requiring hospitalization, which mimics the clinical context of IFD in cirrhosis. In contrast, Mistry et al.6 performed their PK study in patients with stable cirrhosis for at least 2 months without any decompensation episode. On the other hand, the lack of a healthy control group is a limitation of our study. Other case reports also suggested that the recommended dose reduction of caspofungin in decompensated cirrhotic patients resulted in low exposure and, therefore, the approved dosing regimen should be reconsidered.12,13 Caspofungin is extensively bound to albumin.14,15 Hypoalbuminaemia might lead to changes in caspofungin free fraction. Reducing the dose of caspofungin in non-cirrhotic patients misclassified as CP-B due to isolated hypoalbuminaemia results in significantly lower exposure.4 Hypoalbuminaemia is a part of the liver dysfunction observed in cirrhosis. In our cohort of cirrhotic patients, we cannot dissociate the impact of hypoalbuminaemia from the other sources of impaired hepatic function. We believe that reducing the dose of caspofungin in cirrhotic patients with moderate (CP-B) and severe hepatic impairment (CP-C) results in an unwanted decrease in exposure. As the efficacy of caspofungin is best described by the AUC24 to MIC ratio, reduced exposure may lead to suboptimal clinical outcomes. Specifically in the setting of emerging echinocandin resistance all efforts must be taken to optimize dosing to maximize therapeutic efficacy. We do not recommend dose reduction for caspofungin regardless of the presence and severity of hepatic failure in order to ensure optimal treatment. Funding The work was supported in part by Merck & Co., Inc. Transparency declarations R. J. B. has served as a consultant to Astellas Pharma, Inc., F2G, Gilead Sciences, Merck Sharpe and Dohme Corp. and Pfizer, Inc., and has received unrestricted and research grants from Astellas Pharma, Inc., Gilead Sciences, Merck Sharpe and Dohme Corp. and Pfizer, Inc. All payments were invoiced by the Radboudumc. All other authors: none to declare. Supplementary data Table S1 and Figures S1 and S2 are available as Supplementary data at JAC Online. References 1 Gustot T , Felleiter P , Pickkers P et al. Impact of infection on the prognosis of critically ill cirrhotic patients: results from a large worldwide study . Liver Int 2014 ; 34 : 1496 – 503 . Google Scholar CrossRef Search ADS PubMed 2 Alexopoulou A , Vasilieva L , Agiasotelli D et al. Fungal infections in patients with cirrhosis . J Hepatol 2015 ; 63 : 1043 – 5 . Google Scholar CrossRef Search ADS PubMed 3 Pappas PG , Kauffman CA , Andes DR et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America . Clin Infect Dis 2016 ; 62 : e1 – 50 . Google Scholar CrossRef Search ADS PubMed 4 Martial LC , Brüggemann RJM , Schouten JA et al. Dose reduction of caspofungin in intensive care unit patients with Child Pugh B will result in suboptimal exposure . Clin Pharmacokinet 2016 ; 55 : 723 – 33 . Google Scholar CrossRef Search ADS PubMed 5 Andes D , Diekema DJ , Pfaller MA et al. In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species . Antimicrob Agents Chemother 2010 ; 54 : 2497 – 506 . Google Scholar CrossRef Search ADS PubMed 6 Mistry GC , Migoya E , Deutsch PJ et al. Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations . J Clin Pharmacol 2007 ; 47 : 951 – 61 . Google Scholar CrossRef Search ADS PubMed 7 Muilwijk EW , Schouten JA , van Leeuwen HJ et al. Pharmacokinetics of caspofungin in ICU patients . J Antimicrob Chemother 2014 ; 69 : 3294 – 9 . Google Scholar CrossRef Search ADS PubMed 8 Spriet I , Annaert P , Meersseman P et al. Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation . J Antimicrob Chemother 2009 ; 63 : 767 – 70 . Google Scholar CrossRef Search ADS PubMed 9 Keizer RJ , Karlsson MO , Hooker A. Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose . CPT Pharmacometrics Syst Pharmacol 2013 ; 2 : e50. Google Scholar CrossRef Search ADS PubMed 10 Dosne A-G , Bergstrand M , Harling K et al. Improving the estimation of parameter uncertainty distributions in nonlinear mixed effects models using sampling importance resampling . J Pharmacokinet Pharmacodyn 2016 ; 43 : 583 – 96 . Google Scholar CrossRef Search ADS PubMed 11 Holford NHG , Anderson BJ. 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 12 van der Elst KCM , Veringa A , Zijlstra JG et al. Low caspofungin exposure in patients in intensive care units . Antimicrob Agents Chemother 2017 ; 61 : e01582 – 16 . Google Scholar PubMed 13 Spriet I , Meersseman W , Annaert P et al. Pharmacokinetics of caspofungin in a critically ill patient with liver cirrhosis . Eur J Clin Pharmacol 2011 ; 67 : 753 – 5 . Google Scholar CrossRef Search ADS PubMed 14 Stone JA , Xu X , Winchell GA et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma . Antimicrob Agents Chemother 2004 ; 48 : 815 – 23 . Google Scholar CrossRef Search ADS PubMed 15 Nguyen TH , Hoppe-Tichy T , Geiss HK et al. Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit . J Antimicrob Chemother 2007 ; 60 : 100 – 6 . 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)

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Jun 1, 2018

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