Universität zu Köln

Li, Xia ORCID: 0000-0001-7765-0333, Frechen, Sebastian, Moj, Daniel, Lehr, Thorsten, Taubert, Max ORCID: 0000-0001-8925-7782, Hsin, Chih-hsuan, Mikus, Gerd, Neuvonen, Pertti J., Olkkola, Klaus T., Saari, Teijo, I and Fuhr, Uwe (2020). A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions. Clin. Pharmacokinet., 59 (6). S. 781 - 809. NORTHCOTE: ADIS INT LTD. ISSN 1179-1926

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Abstract

Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim(R). The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C-max), and trough concentrations for multiple dosings (C-trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregateC(max)ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregateC(max)ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to < 5-6 mg/L forC(trough), while 400 mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model. Conclusions Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Li, Xia UNSPECIFIED orcid.org/0000-0001-7765-0333 UNSPECIFIED Frechen, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Moj, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehr, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Taubert, Max UNSPECIFIED orcid.org/0000-0001-8925-7782 UNSPECIFIED Hsin, Chih-hsuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mikus, Gerd UNSPECIFIED UNSPECIFIED UNSPECIFIED Neuvonen, Pertti J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Olkkola, Klaus T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Saari, Teijo, I UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuhr, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-331722
DOI:	10.1007/s40262-019-00856-z
Journal or Publication Title:	Clin. Pharmacokinet.
Volume:	59
Number:	6
Page Range:	S. 781 - 809
Date:	2020
Publisher:	ADIS INT LTD
Place of Publication:	NORTHCOTE
ISSN:	1179-1926
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language STEADY-STATE PHARMACOKINETICS; HUMAN LIVER; ANTIFUNGAL AGENT; SHORT-TERM; SAFETY; METABOLISM; GENOTYPE; GUIDELINES; SPECTRUM; BIOAVAILABILITY Multiple languages Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33172