ArticleJCO precision oncology2025
Physiologically Based Pharmacokinetic Model to Assess the Drug-Drug-Gene Interaction Potential of Belzutifan in Combination With Cyclin-Dependent Kinase 4/6 Inhibitors.
Article in JCO precision oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Not yet cited in PubMed.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase I/IB Trial of Abemaciclib Alone or in Combination With MK-6482 in Advanced Renal Cell Carcinoma
A Multicenter, Open-label, Randomized, Phase 1/2 Study of Belzutifan in Combination With Palbociclib Versus Belzutifan Monotherapy in Participants With Advanced Renal Cell Carcinoma
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Authors and funding
4 authors.
Funding
Abstract
purposeBelzutifan is a novel treatment for von Hippel-Lindau-associated cancers and is being evaluated in clinical trials for the treatment of renal cell carcinoma in combination with the cyclin-dependent kinase 4/6 inhibitors abemaciclib (ClinicalTrials.gov identifier: NCT04627064) and palbociclib (ClinicalTrials.gov identifier: NCT05468697). Belzutifan is metabolized via CYP2C19 and UGT2B17 and is a weak inducer of CYP3A. Induction of CYP3A is predicted to have a greater effect in dual CYP2C19/UGT2B17 poor metabolizers (PMs) relative to normal metabolizers (referred to as extensive metabolizers [EMs] in Simcyp). Our objective was to assess the drug-drug-gene interaction (DDGI) potential of belzutifan when coadministered with the CYP3A substrates abemaciclib and palbociclib in individuals with varying CYP2C19/UGT2B17 phenotypes.
methodsPhysiologically based pharmacokinetic (PBPK) models for belzutifan, abemaciclib, and palbociclib were constructed in Simcyp v.21 and confirmed using data from US Food and Drug Administration reviews and previous publications. Virtual trials evaluating the area under the concentration-time curve from time 0 to infinity (AUC
resultsCompared with dual CYP2C19/UGT2B17 EMs, predicted belzutifan exposure increased approximately 4.4-fold in dual PMs. Belzutifan decreased the AUC
conclusionOur simulations predict that belzutifan decreases the exposure of combination therapies metabolized via CYP3A, with the severity of interaction dependent on CYP2C19 and UGT2B17 phenotypes.
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Registered trials
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