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

A phase I study was conducted to determine the pharmacokinetics, safety, an d tolerability of sirolimus, a new immunosuppressive drug, in 45 healthy me n 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 place bo (n = 3) in group I (0.3 mg/m(2)), group II (1 mg/m(2)), group III (3 mg/ m(2)), group IV (5 mg/m(2)) and group V (8 mg/m(2)). No serious adverse eve nts occurred during the study. Twenty-eight of the 45 volunteers (62%) repo rted 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 adver se 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 i n all volunteers. Whole blood peak concentration and area under the concent ration-lime curve increased proportionally with dose. Mean (+/- SD) whole b lood terminal disposition half-life (t(1/2)), apparent oral dose clearance (Cl/F), and volume of distribution (V-ss/F) were 82 +/- 12 hours, 278 +/- 1 17 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 rat io of 36. Single oral doses of sirolimus (0.3 to 8 mg/m(2)) solution were w ell tolerated in healthy male volunteers.