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Erschienen in:
01.10.2014 | Original Article
Impact of cytochrome P450 3A4 inducer and inhibitor on the pharmacokinetics of trabectedin in patients with advanced malignancies: open-label, multicenter studies
Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2014
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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/m2, 3 h, i.v.) coadministered with rifampin (600 mg/day, 6-days), and a cycle of trabectedin monotherapy (1.3 mg/m2, 3 h, i.v.). In ketoconazole study, eight patients were randomized (1:1) to sequence of a cycle of trabectedin (0.58 mg/m2, 3 h, i.v.) coadministered with ketoconazole (200 mg, twice-daily, 15-doses), and a cycle of trabectedin monotherapy (1.3 mg/m2, 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.