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

A. K. Miller, A. L. Inglis, K. Thompson, C. C. Davie, S. Schenker, R. Blum, D. Jorkasky, M. I. Freed

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16 Scopus citations

Abstract

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 T1/2 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.

Original languageEnglish (US)
Pages (from-to)186
Number of pages1
JournalClinical Pharmacology and Therapeutics
Volume65
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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