Effect of hepatic impairment on the pharmacokinetics (PK) of rosiglitazone (RSG)

RSG is an effective glucose lowering agent for type 2 diabetes that is extensively metabolized and highly plasma protein bound. The single dose PK of RSG (8 mg) was studied in patients with hepatic impairment (HP, Child-Pugh Scores 6-11) and in normal subjects (NL). RSG was well tolerated. Plasma concentrations of RSG were quantitated by LC/MS/MS and fraction unbound (fu) was determined by ultrafiltration. Mean (sd) PK data are: NL (n= 17) HP (n= 18) Pt. Est. (95%CI) AUC(0-∞) (ng·h/mL) 2645(677) 3576(1083) 1.34 1 (1.11, 1.62) Cmax (ng/mL) 506(104) 407(119) 0.79 1 (0.68,0.93) fu(%) 0.12(0.03) 0.27(0.12) 0.15*(0.09,0.21) Unbound AUC(0-·) 3.2(1.4) 9.9(5.3) 2.88 1 (2.08,3.99) Unbound Cmax 0.61(0.20) 1.09(0.52) 1.70 1 (1.30,2.22) tratio of geometric means(HP:NL);*difference in means (HP-NL) Lower albumin levels in HP (3.0 vs 4.3 g/dL in NL) were associated with a ∼2-fold higher %fu in HP. The 34% higher total AUC and ∼;3-fold higher unbound AUC in HP reflect both an increase in %fu and a decrease in intrinsic clearance in HP compared to NL. Mean T_1/2 was prolonged in HP (6.0 vs 3.8h in NL). Based on these data, the dose of RSG should be reduced in Type 2 diabetics with moderate to severe hepatic impairment.