Pharmacokinetic modelling of caspofungin to develop an extended dosing regimen in paediatric patients

Abstract

Background Echinocandins are commonly used in treatment and prophylaxis of invasive fungal diseases. Intravenous daily dosing for prophylaxis in the outpatient setting can however become a hurdle for adequate compliance in the paediatric population. Objectives Simulations were performed to assess extended twice-weekly dosing for antifungal prophylaxis using caspofungin. Methods A population pharmacokinetic model was developed based on previously published data from children aged 3 months to 17 years. Using the final model, Monte Carlo simulations were performed to assess the dose needed for adequate exposure in a twice-weekly setting. Mean weekly AUC0–24 h/MIC together with reported AUC0–24 h from previously reported paediatric trials were used to guide adequate exposure. Results and Conclusions A two-compartment model with linear elimination and allometric scaling using fixed exponents was found most adequate to describe the given paediatric populations. Simulations showed that a 200 mg/m2 twice-weekly regimen with maximal 200 mg total dose should result in exposures matching registered daily dosing as well as commonly used pharmacokinetic/pharmacodynamic targets.

Development and Quality Control of a Population Pharmacokinetic Model Library for Caspofungin

“…The modeling strategies and final PK parameters of the included studies are summarized in Table 2 . Ten studies [ 11 , 12 , 23 , 27 , 28 , 29 , 30 , 32 , 33 , 34 ] used NONMEM software, with first-order conditional estimation with interaction (FOCE-i) being the most used algorithm [ 11 , 12 , 23 , 27 , 28 , 32 , 33 , 34 ]. Most studies employed a two-compartment model to describe caspofungin PKs, although two studies [ 25 , 34 ] utilized a one-compartment model due to sparse sampling schedules that may not accurately represent the characteristics of a two-compartment PK model.…”

“…All studies incorporated between-subject variability (BSV), with a median of 27.5% (range: 11.8–42.3%) in CL across the 13 studies. Residual unexplained variability was described by proportional [ 11 , 23 , 25 , 26 , 27 , 28 , 31 , 32 , 33 , 34 ], additive [ 12 , 30 ], or combined models [ 29 ]. Proportional errors with coefficients of variation ranged from 12.2% to 36% in eleven studies, while three studies [ 12 , 29 , 30 ] included addictive errors ranging from 0.0941 to 0.73 mg/L.…”

“…Proportional errors with coefficients of variation ranged from 12.2% to 36% in eleven studies, while three studies [ 12 , 29 , 30 ] included addictive errors ranging from 0.0941 to 0.73 mg/L. An integration of inter-occasion variability on CL was estimated to be 17.2% and 16.0% in studies by Gastine et al [ 33 ] and Würthwein et al [ 28 ], respectively.…”

New and emerging options for management of invasive fungal diseases in paediatric patients

“…For this purpose, raw data from children aged 3 months to gillosis exist, the proposed regimen also would cover the PK/PD targets proposed for the treatment of invasive candidiasis. 39 Taken together, these studies provide a sound pharmacokinetic and pharmacodynamics rationale for extended dosing regimens of caspofungin and micafungin and their further study in preferentially large and controlled clinical trials.…”

“…Monte Carlo simulations revealed that a 200 mg/m 2 twice‐weekly extended dosing regimen, with a maximum total dose of 200 mg should result in average weekly exposures that match those obtained following the approved once‐daily dosing. While no accepted PK/PD targets for invasive aspergillosis exist, the proposed regimen also would cover the PK/PD targets proposed for the treatment of invasive candidiasis 39 …”