This study aimed to construct a physiologically based pharmacokinetic (PBPK) model of rifampicin that can accurately and quantitatively predict complex drug‐drug interactions (DDIs) involving its saturable hepatic uptake and auto‐induction. Using in silico and in vitro parameters, and reported clinical pharmacokinetic data, rifampicin PBPK model was built and relevant parameters for saturable hepatic uptake and UDP‐glucuronosyltransferase (UGT) auto‐induction were optimized by fitting. The parameters for cytochrome P450 (CYP) 3A and CYP2C9 induction by rifampicin were similarly optimized using clinical DDI data with midazolam and tolbutamide as probe substrates, respectively. For validation, our current PBPK model was applied to simulate complex DDIs with glibenclamide (a substrate of CYP3A/2C9 and hepatic organic anion transporting polypeptides (OATPs)). Simulated results were in quite good accordance with the observed data. Altogether, our constructed PBPK model of rifampicin demonstrates the robustness and utility in quantitatively predicting CYP3A/2C9 induction‐mediated and/or OATP inhibition‐mediated DDIs with victim drugs.

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The cause of nonlinear pharmacokinetics (PK) (more than dose-proportional increase in exposure) of a urea derivative under development (compound A: anionic compound [pKa: 4.4]; LogP: 6.5; and plasma protein binding: 99.95%) observed in a clinical trial was investigated. Compound A was metabolized by CYP3A4, UGT1A1, and UGT1A3 with unbound K of 3.3-17.8 μmol/L. OATP1B3-mediated uptake of compound A determined in the presence of human serum albumin (HSA) showed that unbound K and V decreased with increased HSA concentration. A greater decrease in unbound K than in V resulted in increased uptake clearance (V/unbound K) with increased HSA concentration, the so-called albumin-mediated uptake. At 2% HSA concentration, unbound K was 0.00657 μmol/L. A physiologically based PK model assuming saturable hepatic uptake nearly replicated clinical PK of compound A. Unbound K for hepatic uptake estimated from the model was 0.000767 μmol/L, lower than the in vitro unbound K at 2% HSA concentration, whereas decreased K with increased concentration of HSA in vitro indicated lower K at physiological HSA concentration (4%-5%). In addition, unbound K values for metabolizing enzymes were much higher than unbound K for OATP1B3, indicating that the nonlinear PK of compound A is primarily attributed to saturated OATP1B3-mediated hepatic uptake of compound A.

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