Abstract CT131: Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates
Bibliographic record
Abstract
Abstract Title: Effect of Rivoceranib Administered as 200 mg Once Daily on the Pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 Substrates Background: Rivoceranib is a selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor with potent antitumor activity. The purpose of this study is to evaluate the effect of rivoceranib on the pharmacokinetics of various CYP substrates in healthy subjects following administration of rivoceranib 200 mg once daily (QD), which is similar to the proposed rivoceranib dosing regimen (250 mg QD) in combination with camrelizumab for the treatment of hepatocellular carcinoma. Methods: This open-label, fixed-sequence, crossover drug-drug interaction phase 1 study evaluated the impact of multiple oral doses of rivoceranib at 200 mg QD on the pharmacokinetics of single oral doses of CYP enzyme substrates included in the Cooperstown 5+1 cocktail (midazolam 2 mg [CYP3A4/5 substrate], warfarin 10 mg [CYP2C9 substrate]/vitamin K 10 mg, dextromethorphan 30 mg [CYP2D6 substrate], omeprazole 40 mg [CYP2C19 substrate], and caffeine 200 mg [CYP1A2 substrate]). On Day 1, subjects received a single oral dose of the Cooperstown cocktail. Blood samples were collected predose on Day 1 and up to 120 hours post-dose for pharmacokinetic analyses. On Days 6-15, subjects received rivoceranib at 200 mg QD. On Day 11, a single dose of the Cooperstown Cocktail was co-administered with rivoceranib at 200 mg. Each dose was administered under postprandial conditions except for Day 11 when subjects fasted. Blood samples were collected predose on Day 11 and up to 120 hours post cocktail dosing for pharmacokinetic analyses. Subjects returned on any day between Days 21-25 for safety follow-up. Results: Rivoceranib 200 mg QD increased dextromethorphan AUC0-inf by 144% and Cmax by 70%, increased midazolam AUC0-inf by 65% and Cmax by 16%, increased the warfarin AUC0-inf by 28% and Cmax by 5%, increased omeprazole AUC0-inf by 77% and Cmax by 62%, and decreased caffeine AUC0-inf by 20% and Cmax by 7%. Cooperstown Cocktail alone or coadministration of Cooperstown Cocktail and rivoceranib was generally well tolerated. Conclusions:Rivoceranib at 200 mg QD does not substantially affect the exposure of the substrates of CYP3A4/5, CYP2C9, CYP2C19, and CYP1A2. Recommendation of dose adjustment of these CYP substrates is not needed when administered with rivoceranib at 200 mg QD. Rivoceranib may increase the exposure of the substrate of CYP2D6 by approximately 100%, indicating that a dose adjustment of CYP2D6 substrates and/or close monitoring patients should be considered when administered with rivoceranib 200 mg QD. Citation Format: Seong Jang, Xiaohui (Tracey) Wei, Xianzhang Meng, Joseph Reitano, Vinoo Urity, Cheol Hee Park, Bill Strickland, Grace Lee, David Nguyen. Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT131.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".