A drug–drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors

Purpose: Dovitinib is an orally available multi tyrosine kinase inhibitor which inhibits VEGFR 1–3, FGFR 1–3, and PDGFR. This study was performed to investigate the potential drug–drug interaction of dovitinib with the CYP1A2 inhibitor fluvoxamine in patients with advanced solid tumors. Methods: Non-smoking patients of ≥ 18 years with advanced solid tumors, excluding breast cancer, were included. Patients were treated with a dose of 300 mg in 5 days on/2 days off schedule. Steady-state pharmacokinetic assessments of dovitinib were performed with or without fluvoxamine. Results: Forty-five patients were enrolled; 24 were evaluable for drug–drug interaction assessment. Median age was 60 years (range 30–85). At steady state the geometric mean for dovitinib (coefficient of variation%) of the area under the plasma concentration–time curve (AUC_0–72h) and maximum concentration (C_max) were 2880 ng/mL h (47%) and 144 ng/mL (41%), respectively. Following administration of dovitinib in combination with fluvoxamine the geometric mean of dovitinib AUC_0–72h and C_max were 8290 ng/mL h (60%) and 259 ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC_0–72h and C_max (dovitinib + fluvoxamine vs. dovitinib alone) were 2.88 [90% confidence interval (CI) 2.58, 3.20] and 1.80 (90% CI 1.66, 1.95). This effect is considered a moderate drug–drug interaction. Conclusions: Fluvoxamine co-administration resulted in a 80% increase in C_max and a 188% increase in AUC_0–72h of dovitinib. Given the increase in exposure to dovitinib observed, patients are at risk of dovitinib related toxicity. Dovitinib should, therefore, not be co-administered with moderate and strong CYP1A2 inhibitors, without dose reduction.