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
Autor: | de Weger, Vincent A, Goel, Sanjay, von Moos, Roger, Schellens, Jan H M, Mach, Nicholas, Tan, Eugene, Anand, Suraj, Scott, Jeffrey W, Lassen, Ulrik N, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
Adult
Male Cancer Research Maximum Tolerated Dose Cytochrome P-450 CYP1A2 Inhibitors medicine.drug_class CYP1A2 Dovitinib Antineoplastic Agents Fluvoxamine Quinolones Pharmacology Toxicology 030226 pharmacology & pharmacy Drug Administration Schedule Tyrosine-kinase inhibitor 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Neoplasms Drug–drug interaction Humans Medicine Drug Interactions Pharmacology (medical) In patient TKI258 Aged Aged 80 and over business.industry Middle Aged Confidence interval Oncology Area Under Curve 030220 oncology & carcinogenesis Toxicity Benzimidazoles Female Geometric mean business Half-Life medicine.drug |
Zdroj: | Cancer Chemotherapy and Pharmacology, 81(1), 73. Springer Verlag |
ISSN: | 0344-5704 |
Popis: | 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. 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. 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 (AUC0–72h) 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 AUC0–72h and C max were 8290 ng/mL h (60%) and 259 ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC0–72h 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. Fluvoxamine co-administration resulted in a 80% increase in C max and a 188% increase in AUC0–72h 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. |
Databáze: | OpenAIRE |
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