Christophe Boetsch1, Neil Parrott2, Stephen Fowler2, Agnes Poirier2, Dominik Hainzl3, Ludger Banken4, Meret Martin-Facklam5, Carsten Hofmann1. 1. Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Hochstrasse 16, 4070, Basel, Switzerland. 2. Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. 3. Metabolism and Pharmacokinetics, Novartis Institute for BioMedical Research, Cambridge, MA, USA. 4. Biostatistics, Product Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 5. Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Hochstrasse 16, 4070, Basel, Switzerland. meret.martin-facklam@roche.com.
Abstract
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 (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. CONCLUSION: 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.
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 (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. CONCLUSION: 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.
Authors: Kathleen M Giacomini; Shiew-Mei Huang; Donald J Tweedie; Leslie Z Benet; Kim L R Brouwer; Xiaoyan Chu; Amber Dahlin; Raymond Evers; Volker Fischer; Kathleen M Hillgren; Keith A Hoffmaster; Toshihisa Ishikawa; Dietrich Keppler; Richard B Kim; Caroline A Lee; Mikko Niemi; Joseph W Polli; Yuichi Sugiyama; Peter W Swaan; Joseph A Ware; Stephen H Wright; Sook Wah Yee; Maciej J Zamek-Gliszczynski; Lei Zhang Journal: Nat Rev Drug Discov Date: 2010-03 Impact factor: 84.694
Authors: C Merry; M G Barry; F Mulcahy; M Ryan; J Heavey; J F Tjia; S E Gibbons; A M Breckenridge; D J Back Journal: AIDS Date: 1997-03-15 Impact factor: 4.177
Authors: Jenny Y Chien; Aroonrut Lucksiri; Charles S Ernest; J Christopher Gorski; Steven A Wrighton; Stephen D Hall Journal: Drug Metab Dispos Date: 2006-04-12 Impact factor: 3.922
Authors: Mary F Paine; Heather L Hart; Shana S Ludington; Robert L Haining; Allan E Rettie; Darryl C Zeldin Journal: Drug Metab Dispos Date: 2006-02-07 Impact factor: 3.922
Authors: Stephen Fowler; Peter N Morcos; Yumi Cleary; Meret Martin-Facklam; Neil Parrott; Michael Gertz; Li Yu Journal: Curr Pharmacol Rep Date: 2017-02-01