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PI‐55
Author(s) -
Khosravan R.,
Wu J.,
JosephRidge N.,
Vernillet L.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.076
Subject(s) - febuxostat , gout , medicine , nonmem , pharmacokinetics , pharmacodynamics , population , uric acid , xanthine oxidase , gastroenterology , creatinine , pharmacology , urology , chemistry , hyperuricemia , biochemistry , environmental health , enzyme
AIMS The objective of this study was to evaluate the population (pop) PK and PD of febuxostat (FBX), a non‐purine selective inhibitor of xanthine oxidase, in gout patients and to identify fixed effect sources of variability. METHODS In a Phase III, double‐blind, 28‐week study (N=1072), a subgroup (115Male/10Female) of gout patients receiving 80, 120, or 240 mg of FBX once daily were evaluated for pop PK‐PD. Steady‐state trough and sparse post dose blood samples were collected from Week 16–24. FBX pop PK and PD[serum uric acid (sUA)] was assessed using NONMEM/XPOSE/SPLUS, including GAM analyses followed by a stepwise selection/elimination process for covariate screening. External validation was done using PK and PD data from a prior Phase II study in gout patients. RESULTS Parameter pop means in the final simultaneous pop PK‐PD model (FO method) were: (See Table)Type PK‐PD Model (2‐compartment with indirect response)PK Cl/F = 4.93 a + 0.0142*CrCl b + 0.0155*WT c − 1.23*FIB d L/h; V c /F = 32.2 L; V p /F = 22.2 L; t lag = 0.23 h; K a = 13.7 e h −1 ; Residual CV = 71% PD K in = 0.0462 + 0.0211*BUA f mg/dL/h; EC 50 = 0.239 g μg/mL; K out = 0.0255 h −1 ; Residual SD = 0.863 mg/dLCV=18; baseline creatinine clearance in mL/min; total body weight in kg; fibrates (no=0, yes=1); CV=176; BUA: baseline sUA in mg/dL; CV=67.The covariate analyses identified CrCl, wt, and fib for Cl/F and bua for k In as statistically significant (p<0.001) covariates. external validation results indicated that the inclusion of the covariates for Cl/F in the final model did not improve the bias/precision of the predicted PK parameters/concentrations. CONCLUSION A simplified version of the final simultaneous PK‐PD model with no covariates for Cl/F is suggested to be as effective in predicting the PK and PD parameters/concentrations in gout patients. Clinical Pharmacology & Therapeutics (2005) 79 , P21–P21; doi: 10.1016/j.clpt.2005.12.076