title: Pharmacokinetics and tolerability of 40-0-[2-hydroxyethyl]rapamycin in de novo liver transplant recipients.
abstract: BACKGROUND
  40-0-[2-Hydroxyethyl]rapamycin (RAD), a novel macrolide with potent immunosuppressive and antiproliferative activities, prevents rejection in animal allotransplantation models. This phase I trial assessed the effects of bile diversion, administration route, and time after transplant on RAD pharmacokinetics after single-dose administration in de novo liver allograft recipients. The influence of RAD on cyclosporine (CsA) pharmacokinetics 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, administration route (nasogastric or nasoduodenal), and timing of RAD administration. Patients received a single 7.5-mg RAD dose on one to three occasions in addition to CsA (Neoral) and corticosteroids. Steady-state cyclosporine profiles with and without RAD coadministration were evaluated. Results. Recipients with bile diversion demonstrated lower peak concentration (Cmax) than those without, but overall drug exposure (AUC) was not altered. Cmax and AUC were not influenced by administration route. A trend towards higher Cmax on postoperative day 3 than on postoperative day 1 was noted, although AUC was not altered. Single-dose RAD coadministration did not affect steady-state CsA pharmacokinetics. RAD was well tolerated and caused few drug-related adverse effects. RAD administration did not increase infection rates or produce clinically significant changes in laboratory parameters. 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.
authors.affiliation: Toronto General Hospital, Ontario, Canada.
authors.forename: G A
authors.initials: GA
authors.lastname: Levy
authors.forename: D
authors.initials: D
authors.lastname: Grant
authors.forename: K
authors.initials: K
authors.lastname: Paradis
authors.forename: J
authors.initials: J
authors.lastname: Campestrini
authors.forename: T
authors.initials: T
authors.lastname: Smith
authors.forename: J M
authors.initials: JM
authors.lastname: Kovarik
mesh_terms: D000284:Administration, Oral; D002940:Circadian Rhythm; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D016031:Liver Transplantation / Q000276:immunology; D020123:Sirolimus / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus