title: The development of sirolimus: The University of Texas-Houston experience.
abstract: 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.
authors.affiliation: Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Medical School at Houston, Houston, Texas, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
authors.forename: S M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: K L
authors.initials: KL
authors.lastname: Napoli
authors.forename: S M
authors.initials: SM
authors.lastname: Katz
authors.forename: R J
authors.initials: RJ
authors.lastname: Knight
authors.forename: C
authors.initials: C
authors.lastname: Van Buren
mesh_terms: D000818:Animals; D044383:Black People; D002986:Clinical Trials as Topic; D016572:Cyclosporine / Q000008:administration & dosage; D004353:Drug Evaluation, Preclinical; D004361:Drug Tolerance; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control; D006085:Graft Survival; D006785:Hospitals, University; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology; D015337:Multicenter Studies as Topic; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D015996:Survival Rate; D013781:Texas; D014181:Transplantation Immunology; D001741:Black or African American
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus