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The development of sirolimus: The University of Texas-Houston experience.

The transplant team at The University of Texas-Houston has studied sirolimus from preclinical through pivotal Phase III trials to single-center Phase IV trials as we continue to refine algorithms for sirolimus therapy. The sirolimus/CsA combination produces a marked reduction in the occurrence and severity of acute allograft rejection episodes. A recently completed post hoc median effect analysis of drug blood concentrations displayed by patients in the 2 pivotal Phase III trials documented that the combination displays synergistic interactions. Patients in the sirolimus/CsA arms did not display an increased incidence of infectious or malignant complications. However, they did experience a range of nonimmune toxicities, including potentiation of putatively CsA-related adverse reactions, such as renal dysfunction and hypercholesterolemia, which appear to be mitigated by reduction or elimination of CsA. However, thrombocytopenia and to a lesser extent leukopenia and anemia appear to be sirolimus-related side effects. The occurrence and severity of these adverse reactions seem to be avoided or ameliorated in most patients by optimizing sirolimus exposure at concentrations (15 ng/mL or by dose reduction. Sirolimus thus appears to be a potent and unique agent for developing new immunosuppressive strategies in organ transplantation.