Impact of cytochrome P450 3A4 inducer and inhibitor on the pharmacokinetics of trabectedin in patients with advanced malignancies: open-label, multicenter studies.
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Machiels JP, Staddon A, Herremans C, Keung C, Bernard A, Phelps C, Khokhar NZ, Knoblauch R, Parekh TV, Dirix L, Sharma S
Impact of cytochrome P450 3A4 inducer and inhibitor on the pharmacokinetics of trabectedin in patients with advanced malignancies: open-label, multicenter studies.
Cancer Chemother Pharmacol. 2014 Oct;74(4):729-37. doi: 10.1007/s00280-014-2554-1. Epub 2014 Aug 7.
- PubMed ID
- 25100135 [ View in PubMed]
- Abstract
PURPOSE: To evaluate the pharmacokinetics, safety and survival of trabectedin, metabolized primarily by cytochrome P450 (CYP)3A4 enzyme, when coadministered with rifampin (CYP3A4 inducer) or ketoconazole (CYP3A4 inhibitor) in adult patients with advanced solid tumors. METHODS: Two phase 1/2a, 2-way crossover studies were conducted. For rifampin study, 12 patients were randomized (1:1) to sequence of a cycle of trabectedin (1.3 mg/m(2), 3 h, i.v.) coadministered with rifampin (600 mg/day, 6-days), and a cycle of trabectedin monotherapy (1.3 mg/m(2), 3 h, i.v.). In ketoconazole study, eight patients were randomized (1:1) to sequence of a cycle of trabectedin (0.58 mg/m(2), 3 h, i.v.) coadministered with ketoconazole (200 mg, twice-daily, 15-doses), and a cycle of trabectedin monotherapy (1.3 mg/m(2), 3 h, i.v.). RESULTS: The systemic exposure (geometric means) of trabectedin was decreased [22% (C max) and 31% (AUClast)] with rifampin coadministration and increased [22% (C max) and 66% (AUClast)] with ketoconazole coadministration. This correlated with an increased clearance with rifampin (39.6-59.8 L/h) and a decreased clearance with ketoconazole (20.3-12.0 L/h). Consistent with earlier studies, the most common (>/=40%) treatment-emergent adverse events in both studies were nausea, vomiting, diarrhea, hepatic function abnormal, anemia, neutropenia, thrombocytopenia and leukopenia. CONCLUSIONS: Coadministration of rifampin or ketoconazole altered the pharmacokinetics of trabectedin, but no new safety signals were observed. Coadministration of trabectedin with potent CYP3A4 inhibitors or inducers should be avoided if possible. If coadministration of trabectedin with a strong CYP3A4 inhibitor is required, close monitoring for toxicities is recommended, so that appropriate dose reductions can be instituted as warranted.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Trabectedin Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareTrabectedinMethimazole The metabolism of Trabectedin can be decreased when combined with Methimazole. TrabectedinDelavirdine The metabolism of Trabectedin can be decreased when combined with Delavirdine. TrabectedinMidostaurin The metabolism of Trabectedin can be decreased when combined with Midostaurin. TrabectedinRitonavir The metabolism of Trabectedin can be decreased when combined with Ritonavir. TrabectedinVoriconazole The metabolism of Trabectedin can be decreased when combined with Voriconazole.