Premium
Interaction of Dasabuvir With Clopidogrel: Did Predictions by Physiologically Based Pharmacokinetics Modeling Pass the Test?
Author(s) -
Shebley Mohamad
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1196
Subject(s) - physiologically based pharmacokinetic modelling , dasabuvir , clopidogrel , pharmacology , ritonavir , chemistry , ombitasvir , pharmacokinetics , paritaprevir , medicine , aspirin , virology , biochemistry , viral load , human immunodeficiency virus (hiv) , ribavirin , antiretroviral therapy , genotype , gene
To the Editor: A recent drug–drug interaction (DDI) study reported a 3.89–4.67fold increase in exposures of dasabuvir by clopidogrel, and suggested a discrepancy between observed data and previously published physiologically based pharmacokinetic (PBPK) predictions. We have published prospective predictions of dasabuvir and clopidogrel DDI using PBPK, which suggested a 2.8–4.5fold increase at steady state. The PBPK simulation design represented a clinically relevant scenario in which dasabuvir and ritonavir are coadministered with clopidogrel maintenance dosage (75 mg q.d.) at steady state (Figure 1a). The model sensitivity analysis suggested a maximum increase in dasabuvir exposures to 2.6fold for peak plasma concentration (Cmax) and 4.5fold for area under the curve (Figure 1b). Itkonen et al. suggested an apparent underprediction of DDI by the PBPK model. However, when differences between the PBPK simulation and clinical study designs were taken into consideration (Figure 1a,c), the clinical data appear to validate our PBPK predictions. PBPK simulations predicted effects of