ArticlesPharmacokinetics and Safety of Single Oral Doses of Sirolimus (Rapamycin) in Healthy Male VolunteersBrattström, Christina* ; Säwe, Juliette† ; Jansson, Bertil‡ ; Lönnebo, Anna‡ ; Nordin, Jan† ; Zimmerman, James J.§ ; Burke, James T.∥; Groth, Carl G.*Author Information *Division of Transplantation Surgery, Department of Surgery and Division of †Clinical Pharmacology, Department of Medical Laboratory Sciences and Technology at Karolinska Institute, Huddinge Hospital, Huddinge, ‡Quintiles AB, Phase I Services, Uppsala, Sweden; §Clin Pharmacokinet Department, Wyeth-Ayerst Research, Philadelphia, Pennsylvania, USA; ∥Clinical Research and Development, Wyeth-Ayerst Research, Paris, France Received August 25, 1999; accepted March 14, 2000. Address correspondence and reprint requests to Christina Brattström, Department of Transplantation Surgery, Huddinge Hospital, S-141 86 Huddinge, Sweden. Therapeutic Drug Monitoring: October 2000 - Volume 22 - Issue 5 - p 537-544 Buy Abstract A phase I study was conducted to determine the pharmacokinetics, safety, and tolerability of sirolimus, a new immunosuppressive drug, in 45 healthy men between 19 and 36 years of age. Nine subjects in each group were randomly assigned to receive single oral doses of either sirolimus (n = 6) or placebo (n = 3) in group I (0.3 mg/m2), group II (1 mg/m2), group III (3 mg/m2), group IV (5 mg/m2) and group V (8 mg/m2). No serious adverse events occurred during the study. Twenty-eight of the 45 volunteers (62%) reported an adverse event; 19 of 30 (63%) were in the sirolimus group and 9 of 15 (60%) were in the placebo group (ns). Asthenia was the most common adverse event, occurring in 7 of 30 (23%) in the sirolimus group compared with 6 of 15 (40%) in the placebo group (ns). Absorption occurred within 1 hour in all volunteers. Whole blood peak concentration and area under the concentration–time curve increased proportionally with dose. Mean (± SD) whole blood terminal disposition half-life (t½), apparent oral dose clearance (Cl/F), and volume of distribution (Vss/F) were 82 ± 12 hours, 278 ± 117 mL/h·kg and 23 ± 10 L/kg, respectively. Distribution of sirolimus into formed blood elements was extensive, with a mean whole blood-to-plasma ratio of 36. Single oral doses of sirolimus (0.3 to 8 mg/m2) solution were well tolerated in healthy male volunteers. © 2000 Lippincott Williams & Wilkins, Inc.