Summary of the dynamic and the static mechanistic model–based predictions of repaglinide-rifampicin interactions

Dosage RegimenaObserved AUCRPBPK Model PredictionStatic Model Prediction
CLint,h/CL′int,hFg′/FgAUCR[Iu,max,in] (µM) b[Iu,gut] (µM)bR-Value cCLint,h/CL′int,hFg′/FgAUCR
0 hours0.52 (Bidstrup et al., 2004)1.700.400.681.763.753.11.950.300.59
1 hour0.69 (Hatorp et al., 2003)1.830.410.751.763.753.11.950.300.59
12.5 hours0.43 (Niemi et al., 2000)1.150.330.380.2701.30.910.260.24
24 hours0.20 (Bidstrup et al., 2004)0.880.330.290.0201.00.730.260.19
  • AFE, average-fold error model; PPE, percentage prediction error model; Fg′, fraction of drug escaping gut-wall metabolism in the presence of rifampicin; Fg, fraction of drug escaping gut-wall metabolism in the absence of rifampicin; RMSE, root mean square error model.

  • a Time of repaglinide oral dose after the last dose of rifampicin.

  • b For the static model, CYP3A4 induction was assumed constant for 24 hours after the rifampicin treatment and was calculated using 1.76 µM for [Iu,max,in] or 3.75µM for [Iu,gut].

  • c R-value for OATP1B1-mediated interaction (Giacomini et al., 2010; US Food and Drug Administration, 2012) was calculated as 1+(Iu,max,in/Ki).