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Pharmacokinetics of Sirolimus (Rapamycin) in Subjects With Mild to Moderate Hepatic Impairment

From the Departments of Clinical Pharmacology (Dr Zimmerman, Ms Harper, Dr Parker, Mr Matschke) and Mass Spectrometry (Dr Lim), Wyeth Research, Collegeville, Pennsylvania; and SFBC, Miami, Florida (Dr Lasseter, Ms Dilzer).

Eighteen adult subjects with mild to moderate hepatic impairment and 18 healthy control subjects were given a single 15-mg dose of sirolimus by oral solution. Mean whole-blood sirolimus weight-normalized oral-dose clearances (CL/F) were significantly decreased (P = .02) in subjects with mild to moderate hepatic impairment by -31.8% and -36.0%, respectively, compared with controls. There were no significant differences in mean sirolimus C_max and t_max values among groups. The observed decreases in CL/F may be relevant in renal transplant patients with mild to moderate hepatic impairment, based on the close similarity of sirolimus CL/F in controls and previously studied stable renal transplant patients receiving multiple-dose administration of sirolimus and cyclosporine. There was considerable overlap in the CL/F values of hepatic-impaired subjects and controls, suggesting that whole-blood sirolimus trough concentrations in renal transplant patients exhibiting mild to moderate hepatic impairment be initially monitored to assess the need for dose adjustments.

Key Words: Sirolimus • hepatic insufficiency • pharmacokinetics • immunosuppressive agents

Address for reprints: James J. Zimmerman, PhD, Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426.

This article has been cited by other articles:

				J. J. Zimmerman, A. Patat, V. Parks, R. Moirand, and K. Matschke Pharmacokinetics of Sirolimus (Rapamycin) in Subjects With Severe Hepatic Impairment J. Clin. Pharmacol., March 1, 2008; 48(3): 285 - 292. [Abstract] [Full Text] [PDF]