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PHARMACOKINETICS AND PHARMACODYNAMICS

A Comparative Study of Sirolimus Tablet Versus Oral Solution for Prophylaxis of Acute Renal Allograft Rejection

Timothy H. Mathew, MBBS, FRACP, Charles Van Buren, MD, Barry D. Kahan, MD, Khalid Butt, MD, Sundaram Hariharan, MD, James J. Zimmerman, PhD for the Rapamune 309 Study Group

From the Queen Elizabeth Hospital, Woodville, Australia (Mr Mathew); the University of Texas School of Medicine, Houston (Dr Van Buren, Dr Kahan); Westchester County Medical Center, Valhalla, New York (Dr Butt); Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin (Dr Hariharan); and Clinical Pharmacology, Wyeth Research, Collegeville, Pennsylvania (Dr Zimmerman).

This multicenter, open-label study compared the efficacy, safety, and pharmacokinetic parameters of sirolimus (rapamycin) tablet and liquid formulations for prevention of efficacy failure. A total of 477 renal allograft recipients were randomly assigned (1:1) to receive either tablet or solution formulations of sirolimus for 12 months, plus cyclosporine (CsA) and steroids. Pharmacokinetic parameters were analyzed based on trough concentrations and 24-hour pharmacokinetic profiles. There were no significant differences in efficacy failure at 3 or 12 months between tablet and solution groups. Graft survival, patient survival, rate of first biopsy-confirmed acute rejection, time to and severity of acute rejection, and laboratory parameters were not significantly different between groups. Mean steady-state sirolimus and CsA pharmacokinetic parameters on days 30 and 90 were not significantly different by formulation, except for longer sirolimus tmax after tablet administration. Multivariate logistic regression analysis indicated that low sirolimus Cmin,TN and more human leukocyte antigen mismatches were predictors of acute rejection. The tablet and solution formulations of sirolimus demonstrated therapeutic equivalence.

Key Words: Sirolimus • pharmacokinetics • pharmacodynamics • immunotherapy • efficacy failure

Address for reprints: James J. Zimmerman, PhD, Clinical Pharmacology Department, A3042, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426.






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