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Pharmacokinetics of Sirolimus (Rapamycin) in Subjects With Severe Hepatic Impairment

From Clinical Pharmacology, Wyeth Research, Collegeville, Pennsylvania (Dr Zimmerman, Mr Matschke); Clinical Research and Development, Wyeth Research, Paris, France (Dr Patat, Ms Parks); and Biotrial, rue Jean-Louis Bertrand, Technopole Atalante Villejean, Rennes, France (Dr Patat, Dr Moirand).

Nine subjects with severe hepatic impairment (Child-Pugh grade C) and 9 healthy matched control subjects were given a single 15-mg dose of sirolimus by oral solution. Increases (P .002) in mean whole-blood sirolimus t (168%), AUC_0- (210%), and MRT_oral (261%), together with a decrease (P = .001) in CL/F (-67%), were observed in subjects with severe hepatic impairment compared with healthy matched controls. Sirolimus pharmacokinetic data in Child-Pugh grade A (n = 13, mild) and B (n = 5, moderate) subjects from a previous identically designed study were available for an inter-study comparison. Overall, mean t, weight-normalized AUC, and MRT_oral increased steadily, whereas mean CL/F decreased steadily, with increasing degrees of hepatic impairment. CL/F showed large intersubject variabilities within subject types and extensive overlap among the subject types. The results of this study suggest that an initial sirolimus dose reduction of approximately 60% is appropriate in patients with acute severe hepatic impairment; this should be followed by further dose adjustment, based on therapeutic drug monitoring, until the trough concentrations have stabilized at sirolimus levels existing prior to the onset of acute liver failure.

Key Words: Sirolimus • hepatic impairment • Child-Pugh grade • pharmacokinetics • immunosuppressive agents

Address for correspondence: Joan Korth-Bradley, Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426; e-mail: korthbj{at}wyeth.com.