Yun Kim1, Su-jin Rhee1, Kyung-Sang Yu1, In-Jin Jang1, Seung Hwan Lee1
1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
Introduction: Voriconazole is a broad-spectrum antifungal agent for the treatment of invasive aspergillosis. High variable and non-linear pharmacokinetics of voriconazole has been found to be caused by many factors including CYP2C19 polymorphisms, demographics, drug-drug interactions, and liver function. Above all, CYP2C19 phenotype is an important intrinsic determinant of voriconazole exposure. However, the effect of CYP2C19 phenotype on voriconazole exposure was not quantitatively identified.
Objectives: The aims of this study were to develop a population pharmacokinetic model of voriconazole, and to evaluate the demographic, CYP2C19 phenotype, drug-drug interaction, and liver-function related determinants of voriconazole exposure.
Methods: A population pharmacokinetic model was developed using 1579 voriconazole concentrations in 93 healthy male subjects at first. Then, 249 concentrations in 100 patients were used for final model development with the some healthy-driven fixed parameters. Subjects received single and multiple intravenous (IV) and/or oral dosing of voriconazole. The First-Order Conditional Estimation with Interaction estimation method was used with NONMEM (version 7.3). The effects of demographics, liver- and kidney-function related parameters, and CYP2C19 phenotype on the pharmacokinetics of voriconazole were evaluated.
Results: A three-compartment model with an inhibition compartment adequately described the time-concentration profiles of voriconazole. The inhibition compartment reflects the auto-inhibition of voriconazole metabolism. The absorption kinetics of voriconazole was best described by first-order absorption with lag time. The typical values of the model are as follows: clearance (45.3 L/h), volume of distributions (V2, V3 and V4, 35.7, 58.9 and 25.4 L, respectively), inter-compartmental clearances (Q2 and Q3, 10.9 and 54.6 L/h, respectively), first-order absorption rate constant (ka, 1.23 /h) with lag time (0.237 h), and bioavailability (F, 0.876). Clearance was inhibited over time to 16.2 % of its original value dependent on the concentration in an inhibition compartment. Weight was found to be a significant covariate for the CL, Q2, and V3 of voriconazole. CYP2C19 phenotype had a significant effect on the exposure of voriconazole. The extent of the phenotypic effect was derived from healthy volunteers and fixed for the final model development. The CL estimates in CYP2C19 IM and PM decreased 17 % and 53 % compared to that in extensive metabolizer (EM). CL also decreased 47 % in the patients with liver-function test grade (≥3). The remaining CL fraction estimates in CYP2C19 IM and PM decreased both approximately 40 % fold over that in EM.
Conclusions: The pharmacokinetic parameters of voriconazole were well described by the developed population model. This study was first attempt to mechanistically explain the nonlinearity in voriconazole pharmacokinetics using an inhibition compartment model. The model in the contribution of CYP2C19 and liver-function to the pharmacokinetic variability of voriconazole can be served as a tool to predict the systemic exposure of voriconazole, thus providing a rationale for individualized optimal dosing to improve clinical outcome.
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Reference: PAGE 27 (2018) Abstr 8566 [www.page-meeting.org/?abstract=8566]
Poster: Drug/Disease Modelling - Infection