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Effects of ketoconazole on the pharmacokinetics of lenvatinib (E7080) in healthy participants
Author(s) -
Shumaker Robert,
Aluri Jagadeesh,
Fan Jean,
Martinez Gresel,
Thompson Gary A.,
Ren Min
Publication year - 2014
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.140
Subject(s) - lenvatinib , ketoconazole , medicine , pharmacokinetics , cmax , bioequivalence , placebo , adverse effect , pharmacology , confidence interval , crossover study , gastroenterology , area under the curve , cyp3a4 , hepatocellular carcinoma , dermatology , pathology , antifungal , alternative medicine , sorafenib , cytochrome p450 , metabolism
Abstract Background Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p‐glycoprotein. Methods In this Phase I, single‐center, randomized, open‐label, two‐period, crossover study, healthy adults (18–55 years; N = 18) were randomized to one of two sequences (ketoconazole → placebo or vice versa). Ketoconazole (400 mg) or placebo was administered orally once daily for 18 days; a 5 mg dose of lenvatinib was orally administered on Day 5 of each treatment period. Blood samples were collected over 14 days and lenvatinib plasma concentrations measured by high‐performance liquid chromatography/tandem mass spectrometry. Results Systemic exposure to lenvatinib increased slightly (15–19%) with coadministration of ketoconazole. Although the 90% confidence interval (CI) for area under the plasma concentration–time curve (AUC) was within the prespecified bioequivalence interval of 80–125%, C max slightly exceeded the 125% CI bound (134%). No changes in t max , t lag , or t ½ were observed. Thirteen subjects (72%) experienced treatment‐emergent adverse events (11 mild, 2 moderate), most commonly headache (22%) and diarrhea (17%). Conclusions Lenvatinib exposure was slightly increased by ketoconazole; however, the magnitude of the change was relatively small, and likely not clinically meaningful.