title: The effects of febuxostat on the pharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate.
abstract: OBJECTIVE
  To determine the effect of febuxostat on cytochrome P450 2C8 (CYP2C8) activity using rosiglitazone as a CYP2C8 substrate.
  
  
  METHODS
  Healthy subjects received febuxostat 120 mg daily (regimen A) or matching placebo (regimen B) for 9 days along with a single oral dose of rosiglitazone 4 mg on day 5 in a double-blind, randomized, cross-over fashion (≥7 day washout between periods). Plasma samples for analysis of the impact of febuxostat on the pharmacokinetics (PK) of rosiglitazone and its metabolite, N-desmethylrosiglitazone, were collected for 120 h after co-administration.
  
  
  RESULTS
  Of the 39 subjects enrolled, 36 completed the study and were included in the PK analyses. Rosiglitazone PK parameters were comparable between regimens A and B. Median time to maximal plasma concentration, mean maximal plasma concentration (C(max)), area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC(0-tlqc)), AUC from time zero to infinity (AUC(0-∞)), and terminal elimination half-life for regimen A were 0.50 h, 308.6 ng ml⁻¹, 1594.9 ng h ml⁻¹, 1616.0 ng h ml⁻¹ and 4.1 h, respectively, and for regimen B they were 0.50 h, 327.6 ng ml⁻¹, 1564.5 ng h ml⁻¹, 1584.2 ng h ml⁻¹ and 4.0 h, respectively. Point estimates for the ratio of regimen A to regimen B (90% confidence intervals) for rosiglitazone C(max) , AUC(0-tlqc) and AUC(0-∞) central values were 0.94 (0.89-1.00), 1.02 (1.00-1.04) and 1.02 (1.00-1.04), respectively.
  
  
  CONCLUSIONS
  Co-administration of febuxostat had no effect on rosiglitazone or N-desmethylrosiglitazone PK parameters, suggesting that febuxostat can be given safely with drugs metabolized through CYP2C8.
authors.affiliation: Takeda Global Research & Development Center, Inc, One Takeda Parkway, Deerfield, IL 60015, USA. himanshu.naik@takeda.com
authors.forename: Himanshu
authors.initials: H
authors.lastname: Naik
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Wu
authors.forename: Robert
authors.initials: R
authors.lastname: Palmer
authors.forename: Lachy
authors.initials: L
authors.lastname: McLean
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001682:Biological Availability; D001711:Biotransformation; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D004311:Double-Blind Method; D004347:Drug Interactions; D000069465:Febuxostat; D005260:Female; D006074:Gout Suppressants / Q000008:administration & dosage* / Q000009:adverse effects; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D000077154:Rosiglitazone; D013379:Substrate Specificity; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D006074:Gout Suppressants; D007004:Hypoglycemic Agents; C480687:N-desmethylrosiglitazone; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000069465:Febuxostat; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8