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

Overview of attention for article published in European Journal of Clinical Pharmacology, January 2018
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Title
Impact of ritonavir dose and schedule on CYP3A inhibition and venetoclax clinical pharmacokinetics
Published in
European Journal of Clinical Pharmacology, January 2018
DOI 10.1007/s00228-017-2403-3
Pubmed ID
Authors

Kevin J. Freise, Beibei Hu, Ahmed Hamed Salem

Abstract

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. 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. Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration (Cmax) 2.3- to 2.4-fold 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 Cmax and AUC, respectively. Administration of 50 mg ritonavir daily saturated CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50 mg ritonavir was offset by ritonavir CYP3A induction, resulting in a limited net increase in CYP3A inhibition with multiple doses. After completion of the dose ramp-up, venetoclax dose reductions of at least 75% are recommended when administered concomitantly with strong CYP3A inhibitors to maintain venetoclax exposures within the established therapeutic window for CLL treatment.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 3 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 3 100%

Demographic breakdown

Readers by professional status Count As %
Unspecified 1 33%
Student > Master 1 33%
Student > Ph. D. Student 1 33%
Readers by discipline Count As %
Unspecified 1 33%
Pharmacology, Toxicology and Pharmaceutical Science 1 33%
Medicine and Dentistry 1 33%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 September 2018.
All research outputs
#10,325,590
of 13,528,132 outputs
Outputs from European Journal of Clinical Pharmacology
#1,561
of 1,830 outputs
Outputs of similar age
#256,684
of 385,982 outputs
Outputs of similar age from European Journal of Clinical Pharmacology
#19
of 26 outputs
Altmetric has tracked 13,528,132 research outputs across all sources so far. This one is in the 20th percentile – i.e., 20% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,830 research outputs from this source. They receive a mean Attention Score of 4.6. This one is in the 13th percentile – i.e., 13% of its peers scored the same or lower than it.
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We're also able to compare this research output to 26 others from the same source and published within six weeks on either side of this one. This one is in the 19th percentile – i.e., 19% of its contemporaries scored the same or lower than it.