Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials.
Following the decade‐long clinical investigation, venetoclax has accrued pharmacokinetic (PK) data across multiple populations and widely ranging demographics, intrinsic, and extrinsic factors. We leveraged these rich data to systematically characterize venetoclax PK and assess covariate effects wit...
| Published in: | Journal of Clinical Pharmacology Vol. 63; no. 8; pp. 950 - 961 |
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| Main Authors: | , , , , , |
| Format: | research tables/charts Journal Article |
| Published: |
Wiley-Blackwell
Aug2023
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=164877233&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 164877233 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00912700 5WH jtl: Journal of Clinical Pharmacology issn: 00912700 maglogo: Y pubinfo: dt: Aug2023 vid: 63 iid: 8 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 164877233 164877233 164877233 10.1002/jcph.2248 164877233 ppf: 950 ppct: 11 formats: tig: atl: Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials. aug: au: Gong, Jingqi Q. X. Suleiman, Ahmed A. Menon, Rajeev Deng, Rong Mensing, Sven Salem, Ahmed Hamed affil: Clinical Pharmacology, AbbVie Inc., North Chicago Illinois,, USA sug: subj: Antineoplastic Agents Pharmacokinetics Clinical Trials Research Subjects Human Cytochrome P-450 Enzyme System Antagonists and Inhibitors Biological Availability Liver Diseases Asians Models, Biological Funding Source ab: Following the decade‐long clinical investigation, venetoclax has accrued pharmacokinetic (PK) data across multiple populations and widely ranging demographics, intrinsic, and extrinsic factors. We leveraged these rich data to systematically characterize venetoclax PK and assess covariate effects with population PK modeling. Plasma concentration–time data were pooled from 3016 subjects enrolled in 41 phase 1, 2, and 3 clinical studies, including patients from 9 indications and healthy volunteers. A nonlinear mixed‐effect model was developed. Covariates were evaluated with full covariate modeling approach. A 2‐compartment model with 3 transit absorption compartments described the data well. The impact of moderate and strong cytochrome P450 (CYP) 3A inhibition on apparent clearance (CL/F), female sex on apparent volume of distribution, food effect on relative bioavailability, and dose nonlinearity was confirmed. Newly identified covariate effects include 48% lower CL/F in subjects with severe hepatic impairment, 61% higher bioavailability in Asian subjects. When multiple CYP3A inhibitors are taken simultaneously, a 49% decrease in CL/F was estimated with multiple moderate inhibitors, more substantial than the 22% decrease of a single moderate inhibitor. An 85% decrease in CL/F was indicated when at least 1 strong CYP3A inhibitor was taken in combination, comparable to that of a single strong inhibitor. A venetoclax cross‐indication population PK model with improved absorption‐phase characterization was developed. Covariate analyses suggested lower CL/F for subjects with severe hepatic impairment and higher bioavailability in Asian subjects. Further decrease in CL/F was indicated when multiple moderate CYP3A inhibitors are present, compared to a single moderate inhibitor. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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