ArticleClinical pharmacokinetics2026
Assessing the Influence of CYP3A4 Inhibitors on Voriconazole Exposure across CYP2C19 Genotypes: A Physiologically Based Pharmacokinetic Model Analysis.
Article in Clinical pharmacokinetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundVoriconazole (VCZ) is a triazole antifungal agent used to treat invasive infections. It has narrow therapeutic index and exhibits high interindividual variability due to cytochrome P450 (CYP) 3A4 autoinhibition and CYP2C19 polymorphism. As VCZ is a CYP3A4 substrate, it is susceptible to drug-drug interactions (DDIs) with CYP3A4 inhibitors, resulting in increased VCZ exposure. However, due to the differences in CYP2C19 activity, the fraction of VCZ metabolized by CYP3A4 varies across CYP2C19 genotypes. As a result, coadministration of CYP3A4 inhibitors could result in genotype-dependent increases in VCZ exposure, leading to a disproportionate risk for toxicity across genotypes. Despite this, the clinical impact of CYP3A4 inhibition on VCZ exposure across different CYP2C19 genotypes remains poorly characterized.
objectiveThe purpose of this study was to develop a genotype-specific VCZ physiologically based pharmacokinetic (PBPK) model to assess the impact of CYP3A4 inhibition and CYP2C19 polymorphism on VCZ exposure.
methodsA genotype-specific VCZ PBPK model was developed and evaluated in PK-Sim
resultsModel simulations with a strong CYP3A4 inhibitor (clarithromycin) across CYP2C19 genotypes demonstrated greater relative increases in VCZ exposure after a single dose compared with steady state. Following clarithromycin coadministration, a genotype-dependent increase in single-dose VCZ exposure (relative to VCZ alone) was found, with geometric mean fold increases of 1.57, 1.78, 2.31, and 3.24 in extensive, normal, intermediate, and poor metabolizers, respectively. However, steady-state increases in VCZ exposure with clarithromycin were minimal and similar across CYP2C19 genotypes: 1.40-fold in extensive, 1.60-fold in normal, 1.41-fold in intermediate, and 1.26-fold in poor metabolizers. In the absence or presence of clarithromycin, model-predicted single-dose C
conclusionsOverall, this analysis demonstrates the capacity of PBPK modeling to predict DDIs across different genotypes and dosing scenarios. Although the relative increase in steady-state VCZ exposure was predicted to be similar across genotypes, this analysis demonstrated that CYP2C19 intermediate and poor metabolizers are at elevated risk of VCZ toxicity in the presence of strong CYP3A4 inhibition.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.