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A prerequisite for the prediction of the magnitude of P-glycoprotein (P-gp)-mediated drug–drug interactions between digoxin and P-gp inhibitors (e.g. verapamil and its metabolite norverapamil) or P-gp inducers (e.g. rifampicin) is a predictive pharmacokinetic model for digoxin itself. Thus, relevant in vitro metabolic, transporter and inhibitory data incorporated into permeability-limited models, such as the “advanced dissolution, absorption and metabolism” (ADAM) module and the permeability-limited liver (PerL) module, integrated with a mechanistic physiologically-based pharmacokinetic (PBPK) model such as that of the Simcyp Simulator (version 12.2) are necessary. Simulated concentration–time profiles of digoxin generated using the developed model were consistent with observed data across 31 independent studies [13 intravenous single dose (SD), 12 per oral SD and six multiple dose studies]. The fact that …