Effects of Cytochrome P450 3A4 Inhibitors—Ketoconazole and Erythromycin—on Bitopertin Pharmacokinetics and Comparison with Physiologically Based Modelling Predictions

Objective To assess the effect of strong and moderate cytochrome P450 (CYP) 3A4 inhibition on exposure of bitopertin, a glycine reuptake inhibitor primarily metabolized by CYP3A4, and to compare the results with predictions based on physiologically based pharmacokinetic (PBPK) modelling. Methods The effects of ketoconazole and erythromycin were assessed in two male volunteer studies with open-label, two-period, fixed-sequence designs. Twelve subjects were enrolled in each of the studies. In period 1, a single dose of bitopertin was administered; in period 2, 400 mg ketoconazole was administered once daily for 17 days or 500 mg erythromycin was administered twice daily for 21 days. A single dose of bitopertin was coadministered on day 5. Pharmacokinetic parameters were derived by non-compartmental methods. Simulated bitopertin profiles using dynamic PBPK modelling for a typical healthy volunteer in GastroPlus ® were used to predict changes in pharmacokinetic parameters. Results In healthy volunteers, coadministration of ketoconazole increased the bitopertin area under the plasma concentration–time curve (AUC) from 0 to 312 h (AUC 0–312h ) 4.2-fold (90 % confidence interval [CI] 3.5–5.0) and erythromycin increased the AUC from time zero to infinity (AUC 0–inf ) 2.1-fold (90 % CI 1.9–2.3). The peak concentration ( C max ) increased by