Rapamycin: Clinical results and future opportunities

The action of RAPA to inhibit signal transduction induced by most cytokines and growth factors in a variety of mesenchymal cells provides a unique weapon to both disengage the immune response and inhibit non-antigen-dependent injuries. The pharmacokinetics of RAPA reveal low bioavailability, extensive tissue distribution, variable clearance rates, and primary metabolic conversion via cytochrome P450 3A4 isoenzymes. The last property engenders drug-drug interactions; prominent among which are those observed with concomitantly administered CsA. Therapeutic drug monitoring readily compensates for the variability of RAPA disposition, as well as its interaction with CsA. RAPA has been extensively explored in clinical Phase I, II, and III trials both with and without concomitant CsA therapy. The RAPA-CsA combination produces a marked reduction in the occurrence and severity of acute allograft rejection episodes. A post hoc median effect analysis of drug blood concentrations displayed by patients in the two pivotal Phase III trials documented that the combination displays synergistic interactions. Although patients in the RAPA-CsA arms did not display an increased incidence of infectious or malignant complications, they did experience a range of nonimmune toxicities, including potentiation of some CsA-related adverse reactions such as renal dysfunction. These seem to be mitigated by reduction or elimination of CsA. However, other effects seem to be RAPA-related, such as hyperlipidemia and thrombocytopenia, and these seem to be ameliorated in most patients by adjustment of RAPA exposure. RAPA thus proffers a potent and unique platform for new immunosuppressive strategies in organ transplantation.