Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience

Abstract

ON APRIL 13, 1993, a phase I trial was initiated to assess the safety and pharmacokinetic behavior of ascending doses of a new immunosuppressant discovered by Sehgal and applied in animal transplant models by Calne et al and Morris et al. Forty stable renal transplant patients who received either the oral liquid formulation of sirolimus (SRL) or placebo, displayed only modest adverse reactions. Drug development proceeded rapidly through a subsequent phase I/II study of de novo drug administration which confirmed the safety and documented the efficacy of a sirolimus-cyclosporine (CsA) combination to reduce the incidence of acute rejection episodes. The first multicenter phase II trial showed that reduced doses of CsA were efficacious in non–African Americans when administered in combination with sirolimus. The pivotal phase III trials performed in the United States (US) and across the world (Global) demonstrated the benefit of a sirolimus-CsAPrednisone (Pred) regimen for acute rejection prophylaxis, leading to approval by the US Food and Drug Administration (FDA). This contribution reviews not only the milestones up to FDA approval, but also our present strategies, as utilized in 1008 renal transplant recipients, to deliver the maximal benefit of sirolimus with minimal CsA exposure, thereby reducing the hazards of chronic immunosuppression.