Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics

Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics Purpose Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects. Methods In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2. In cohort 3, subjects received 10-mg venetoclax doses on day 1 of period 1 and days 1 and 11 of period 2, and 50 mg ritonavir daily on days 1 to 14 of period 2. Results Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration (C ) 2.3- to 2.4-fold max compared to venetoclax alone and the area under the curve (AUC) 6.1- and 8.1-fold, respectively. Daily 50 mg ritonavir resulted in a 2.4- and 7.9-fold increase in venetoclax C and AUC, respectively. Administration of 50 mg ritonavir daily saturated max CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Clinical Pharmacology Springer Journals

Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics

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Publisher
Springer Berlin Heidelberg
Copyright
Copyright © 2018 by Springer-Verlag GmbH Germany, part of Springer Nature
Subject
Biomedicine; Pharmacology/Toxicology
ISSN
0031-6970
eISSN
1432-1041
D.O.I.
10.1007/s00228-017-2403-3
Publisher site
See Article on Publisher Site

Abstract

Purpose Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects. Methods In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2. In cohort 3, subjects received 10-mg venetoclax doses on day 1 of period 1 and days 1 and 11 of period 2, and 50 mg ritonavir daily on days 1 to 14 of period 2. Results Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration (C ) 2.3- to 2.4-fold max compared to venetoclax alone and the area under the curve (AUC) 6.1- and 8.1-fold, respectively. Daily 50 mg ritonavir resulted in a 2.4- and 7.9-fold increase in venetoclax C and AUC, respectively. Administration of 50 mg ritonavir daily saturated max CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50

Journal

European Journal of Clinical PharmacologySpringer Journals

Published: Jan 4, 2018

References

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