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

• Published in: Cancer chemotherapy and pharmacology 2018, Vol.81 (1), p.73-80
• Main Authors: de Weger, Vincent A., Goel, Sanjay, von Moos, Roger, Schellens, Jan H. M., Mach, Nicholas, Tan, Eugene, Anand, Suraj, Scott, Jeffrey W., Lassen, Ulrik
• Format: Article
• Language: English
• Subjects: Breast cancer; Cancer Research; Coefficient of variation; Confidence intervals; CYP1A2 protein; Cytochrome P450; Drug dosages; Drug interaction; Drug interactions; Enzyme inhibitors; Fibroblast growth factor receptors; Fluvoxamine; Inhibitors; Medicine; Medicine & Public Health; Oncology; Original Article; Patients; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Protein-tyrosine kinase; Smoking; Solid tumors; Steady state; Toxicity; Tumors; Tyrosine; Vascular endothelial growth factor receptors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-017-3469-4

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.