Pharmacokinetics of sirolimus (rapamycin) in subjects with mild to moderate hepatic impairment.
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.
Zimmerman
James J
JJ
Department of Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
Lasseter
Kenneth C
KC
Lim
Heng-Keang
HK
Harper
Dawn
D
Dilzer
Stacey C
SC
Parker
Vernon
V
Matschke
Kyle
K
D000328:Adult; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D020123:Sirolimus / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D020123:Sirolimus