Pharamacokinetics and tolerability of 40-0-[2-hydroxyethyl]rapamycin in denovo liver transplant recipients

Background. 40-0-[2-Hydroxyrethyl]rapamycin (RAD), a novel macrolide with p otent immunosuppressive and antiproliferative activities, prevents rejectio n in animal allotransplantation models. This phase I trial assessed the eff ects of bile diversion, administration route, and time after transplant on RAD pharmacokinetics after single-dose administration in de novo Liver allo graft recipients. The influence of RAD on cyclosporine (CsA) pharmacokineti cs and the safety of RAD were also evaluated. Methods. Twenty-six de novo Liver allograft recipients were assigned to one of four treatment groups based on the presence or absence of a T tube, adm inistration route (nasogastric or nasoduodenal), and timing of RAD administ ration. Patients received a single 7.5-mg WAD dose on one to three occasion s in addition to CsA (Neoral(R)) and corticosteroids. Steadystate cyclospor ine profiles with and without RAD coadministration were evaluated. Results. Recipients with bile diversion demonstrated lower peak concentrati on (C-max) than those without, but overall drug exposure (AUC) was not alte red. C-max and AUC were not influenced by administration route. A trend tow ards higher C-max on postoperative day 3 than on postoperative day 1 was no ted, although AUC was not altered. Single-dose RAD coadministration did not affect steady-state CsA pharmacokinetics, RAD was well tolerated and cause d few drug-related adverse effects. RAD administration did not increase inf ection rates or produce clinically significant changes in laboratory parame ters. Conclusions. In de novo liver transplant recipients, the overall extent of RAD absorption was not influenced by bile diversion, administration route, or time of administration. CsA pharmacokinetics were not affected by single -dose RAD coadministration. RAD capsules administered in single doses of 7. 5 mg were well tolerated and safe.