Simultaneously predict pharmacokinetic interaction of rifampicin with oral versus intravenous substrates of cytochrome P450 3A/P‑glycoprotein to healthy human using a semi-physiologically based pharmacokinetic model involving both enzyme and transporter turnover.

Abstract

Several reports demonstrated that rifampicin affected pharmacokinetics of victim drugs following oral more than intravenous administration. We aimed to establish a semi-physiologically based pharmacokinetic (semi-PBPK) model involving both enzyme and transporter turnover to simultaneously predict pharmacokinetic interaction of rifampicin with oral versus intravenous substrates of cytochrome P450 (CYP) 3A4/P‑glycoprotein (P-GP) in human. Rifampicin was chosen as the CYP3A /P-GP inducer. Thirteen victim drugs including P-GP substrates (digoxin and talinolol), CYP3A substrates (alfentanil, midazolam, nifedipine, ondansetron and oxycodone), dual substrates of CYP3A/P-GP (quinidine, cyclosporine A, tacrolimus and verapamil) and complex substrates (S-ketamine and tramadol) were chosen to investigate drug-drug interactions (DDIs) with rifampicin. Corresponding parameters were cited from literatures. Before and after multi-dose of oral rifampicin, the pharmacokinetic profiles of victim drugs for oral or intravenous administration to human were predicted using the semi-PBPK model and compared with the observed values. Contribution of both CYP3A and P-GP induction in intestine and liver by rifampicin to pharmacokinetic profiles of victim drugs was investigated. The predicted pharmacokinetic profiles of drugs before and after rifampicin administration accorded with the observations. The predicted pharmacokinetic parameters and DDIs were successful, whose fold-errors were within 2. It was consistent with observations that the DDIs of rifampicin with oral victim drugs were larger than those with intravenous victim drugs. DDIs of rifampicin with CYP3A or P-GP substrates following oral versus intravenous administration to human were successfully predicted using the developed semi-PBPK model.