Pharmacokinetics and safety of single oral doses of sirolimus (rapamycin) in healthy male volunteers

Ther Drug Monit. 2000 Oct;22(5):537-44. doi: 10.1097/00007691-200010000-00006.

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 (t1/2), apparent oral dose clearance (Cl/F), and volume of distribution (Vss/F) were 82 +/- 12 hours, 278 +/- 117 mL/h x 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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Area Under Curve
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Humans
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / pharmacokinetics*
  • Male
  • Reference Values
  • Sirolimus / administration & dosage*
  • Sirolimus / adverse effects
  • Sirolimus / blood
  • Sirolimus / pharmacokinetics*

Substances

  • Immunosuppressive Agents
  • Sirolimus