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 (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.


CONCLUSIONS
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.
Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Hochstrasse 16, 4070, Basel, Switzerland.
Christophe
C
Boetsch
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Neil
N
Parrott
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Stephen
S
Fowler
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
Agnes
A
Poirier
Metabolism and Pharmacokinetics, Novartis Institute for BioMedical Research, Cambridge, MA, USA.
Dominik
D
Hainzl
Biostatistics, Product Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Ludger
L
Banken
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.
Meret
M
Martin-Facklam
Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Hochstrasse 16, 4070, Basel, Switzerland.
Carsten
C
Hofmann
D000328:Adult; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D004917:Erythromycin / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics*; D013450:Sulfones / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
C550631:(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone; D065692:Cytochrome P-450 CYP3A Inhibitors; D010879:Piperazines; D013450:Sulfones; D004917:Erythromycin; D007654:Ketoconazole