Phase 1 study assessing dovitinib (TKI258) on the pharmacokinetics of caffeine, diclofenac, omeprazole, and midazolam in patients with advanced solid tumors.

2581 Background: Dovitinib (TKI258) is an oral tyrosine kinase inhibitor targeting kinases involved in tumor cell proliferation and survival, including FGFR, VEGFR, PDGFR, c-KIT, and FLT3. In vitro, dovitinib induced CYP1A2, CYP2C9, and CYP2C19 activity and increased the mRNA level of CYP3A4. Here, we evaluated the impact of dovitinib on the pharmacokinetics (PK) of caffeine, diclofenac, omeprazole, and midazolam, the probe drugs metabolized by these cytochrome P450 isoforms. Methods: Patients (pts) ≥ 18 years of age with advanced solid tumors were given a cocktail of oral caffeine (100 mg), diclofenac (25 mg), omeprazole (20 mg), and midazolam (2 mg) on days 1 and 13, and dovitinib (500 mg oral once daily, 5 days on/2 days off) starting on day 2. Blood PK samples for each probe were collected predose and for 24 hours after drug cocktail dosing. Area under the curve (AUC) and maximum concentration (Cmax) values were log-transformed and analyzed with a linear mixed-effects model. Following the drug-drug in...