ArticleClinical pharmacokinetics2026
Effect of Rivoceranib 200 mg Once Daily on the Pharmacokinetics of a Cocktail Probe Substrate of Cytochrome P450 Enzymes: A Phase I Trial in Healthy Volunteers.
Article in Clinical pharmacokinetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03561298 (An Open-label, Fixed-Sequence Study in Healthy Male Subjects to Assess the Drug Interaction Potential of Multiple Doses of Zanubrutinib With a Drug "Cocktail" Representative for CYP3A4, CYP2C9, CYP2C19, P-gP and BCRP Substrates), which is not on this map. Not yet cited in PubMed.
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An Open-label, Fixed-Sequence Study in Healthy Male Subjects to Assess the Drug Interaction Potential of Multiple Doses of Zanubrutinib With a Drug "Cocktail" Representative for CYP3A4, CYP2C9, CYP2C19, P-gP and BCRP Substrates
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Abstract
BACKGROUND AND
objectiveRivoceranib, a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor with antitumor activity, is metabolized in the liver mostly by cytochrome P450 (CYP)3A4/5. In vitro studies suggest that rivoceranib at clinically relevant concentrations may inhibit metabolism of various CYP substrates. This study evaluated the effects of rivoceranib 200 mg once daily (QD) on the pharmacokinetics of various CYP substrates using the Cooperstown 5+1 cocktail. The dosing regimen of rivoceranib used in this study is similar to the proposed rivoceranib regimen (250 mg QD) in combination with camrelizumab for the treatment of patients with hepatocellular carcinoma.
methodsThis open-label, fixed-sequence, crossover, drug-drug interaction phase I study evaluated the impact of multiple oral doses of rivoceranib 200 mg QD on the single oral dose pharmacokinetics of CYP enzyme substrates administered in the modified Cooperstown 5+1 cocktail (caffeine 200 mg [CYP1A2], warfarin 10 mg [S-warfarin as CYP2C9 substrate] + vitamin K 10 mg, omeprazole 40 mg [CYP2C19], dextromethorphan 30 mg [CYP2D6], and midazolam 2 mg [CYP3A4]) in 18 healthy volunteers. After fasting, volunteers received a single dose of the Cooperstown 5+1 cocktail on day 1 and rivoceranib plus Cooperstown 5+1 cocktail on day 11. After completing a meal, volunteers received a single dose of rivoceranib on days 6-10 and 12-15. Blood samples for pharmcokinetic analyses of substrates were collected pre-dose and up to 120 h post-Cooperstown 5+1 cocktail dosing on days 1 and 11. Volunteers returned once between days 21 and 25 for safety follow-up.
resultsRivoceranib 200 mg QD decreased the cumulative area under the plasma concentration-time curve from time 0 to infinity (AUC
conclusionsRivoceranib 200 mg QD may substantially inhibit the metabolism of CYP2D6 substrates. Therefore, concomitant use of CYP2D6 substrate drugs with rivoceranib should be approached with caution, and dose adjustment of substrates of CYP2D6 may be necessary when co-administration cannot be avoided. Rivoceranib 200 mg QD may also exert weak inhibitory effects on the metabolism of CYP3A, CYP2C9, and CYP2C19 substrates. In such cases, close monitoring for substrate-related adverse reactions is recommended, particularly when toxicity is sensitive to increased exposures of these substrate drugs. CLINICAL
trial registrationClinicalTrials.gov identifier: NCT03561298.
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