Effect of febuxostat on pharmacokinetics of desipramine, a CYP2D6 substrate, in healthy subjects

Abstract

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase (NP-SIXO) being developed for the management of hyperuricemia in patients with gout. Background In-vitro data showed that febuxostat had no significant effect on CYP1A2, CYP2C9, CYP2C19 or CYP3A4 activity (Ki>100 μM), and a weak inhibitory effect on CYP2D6 (Ki=40 μM). Aim The effect of febuxostat on desipramine pharmacokinetics (PK) was evaluated. Methods A phase-1, two-period, crossover, double-blind study was conducted in 18 CYP2D6 extensive-metabolizer subjects. Each subject received a single 25 mg oral dose of desipramine (DES) after multiple oral dosing with febuxostat (FBX) 120 mg or placebo (PLA) once daily. Blood samples were collected to assess the PK of DES and 2-hydroxydesipramine (2-HD). Results The results are shown in the table below. The increase in total exposure to DES and the concomitant decrease in the 2-HD/DES AUC ratio suggest that the metabolism of DES to 2-HD via CYP2D6 was mildly inhibited. However, this effect was not considered to be clinically significant. The incidence of adverse events was similar between treatment regimens with the majority being mild and moderate in severity. Conclusion No dose adjustment is expected for CYP2D6 substrates when co-administered with febuxostat. Clinical Pharmacology & Therapeutics (2005) 77, P43–P43; doi: 10.1016/j.clpt.2004.12.059 Table 1. Mean±SD Plasma PK for DES and 2-HD, Point Estimates (PE) and Confidence Intervals (CI) Parameter DES + FBX DES + PLA PE (90% CI)1 1 Ratio of DES+FBX to DES+PLA 2 AUC Ratio: 2-HD/DES AUC ratio DES Cmax (ng/mL) 9.6 ± 3.5 8.4 ± 3.2 1.16 (1.10–1.23) AUC∞ (ng h/mL) 295 ± 194 263 ± 249 1.22 (1.11–1.35) 2-HD Cmax (ng/mL) 6.2 ± 2.0 6.6 ± 2.3 0.96 (0.90–1.02) AUC∞ (ng h/mL) 163 ± 30 166 ± 62 1.02 (0.93–1.11) AUC Ratio2 0.74 ± 0.40 0.88 ± 0.49 0.83 (0.76–0.91}