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

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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.


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.


In healthy volunteers, coadministration of ketoconazole increased the bitopertin area under the plasma concentration–time curve (AUC) from 0 to 312 h (AUC0–312h) 4.2-fold (90 % confidence interval [CI] 3.5–5.0) and erythromycin increased the AUC from time zero to infinity (AUC0–inf) 2.1-fold (90 % CI 1.9–2.3). The peak concentration (C max) increased by <25 % in both studies. Simulated bitopertin profiles using PBPK modelling showed good agreement with the observed AUC ratios in both studies. The predicted AUC0–inf ratios for the interaction with ketoconazole and erythromycin were 7.7 and 1.9, respectively.


Strong CYP3A4 inhibitors increase AUC0–inf of bitopertin 7- to 8-fold and hence should not be administered concomitantly with bitopertin. Moderate CYP3A4 inhibitors double AUC0–inf.

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All authors were employees of F. Hoffmann-La Roche when this work was carried out. The authors would like to thank Thomas Ramp for in vitro study execution.

Author contributions

Participated in research design: Boetsch, Hofmann, Fowler, Martin-Facklam, Poirier, Hainzl.

Conducted experiments: Boetsch, Fowler, Hofmann, Poirier.

Performed data analysis: Banken, Boetsch, Fowler, Hofmann, Parrott, Poirier.

Wrote or contributed to writing the manuscript: Boetsch, Fowler, Hofmann, Martin-Facklam, Parrott.

Reviewed manuscript drafts and approved final version for submission: Banken, Boetsch, Fowler, Hainzl, Hofmann, Martin-Facklam, Parrott, Poirier.

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Correspondence to Meret Martin-Facklam.

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Boetsch, C., Parrott, N., Fowler, S. et al. Effects of Cytochrome P450 3A4 Inhibitors—Ketoconazole and Erythromycin—on Bitopertin Pharmacokinetics and Comparison with Physiologically Based Modelling Predictions. Clin Pharmacokinet 55, 237–247 (2016).

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