Physiologically based pharmacokinetic modelling and in vivo [I]/Ki accurately predict P-glycoprotein-mediated drug-drug interactions with dabigatran etexilate

摘要: Background and purpose In vitro inhibitory potency (Ki)-based predictions of P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) are hampered by the substantial variability in potency. In this study, vivo-based [I]/Ki values were used to predict DDI risks a P-gp substrate dabigatran etexilate (DABE) using physiologically based pharmacokinetic (PBPK) modelling. Experimental approach A baseline PBPK model was established with digoxin, known substrate. The Km (P-gp transport) digoxin adjusted Kmi fit change pharmacokinetics presence inhibitor. Then ‘in vivo’ inhibitor calculated Kmi/Km. Baseline developed for DABE, incorporated into simulate static effect on DABE pharmacokinetics. This approach verified comparing observed simulated five different inhibitors. Key results This accurately predicted effects inhibitors (98–133% 89–104% ratios AUC Cmax respectively). 16 other also confidently simulated. Conclusions implications ‘In modelling, combination, can P-gp-mediated DDIs. described framework provides mechanistic basis proper design clinical studies, as well avoiding unnecessary studies.