Pharmacokinetics and Safety of ABT-578, a Sirolimus (Rapamycin) Analogue, after Single Intravenous Bolus Injection in Healthy Male Volunteers.

Objective: ABT-578, a tetrazole analogue of sirolimus (rapamycin), possesses anti-restenosis activity. The aim of this study was to assess the safety and pharmacokinetics of escalating single intravenous (IV) doses of ABT-578 in a phase 1, double-blind, randomised, placebo-controlled study.

Methods: Sixty adult healthy males were divided into five IV-dose groups of 100, 300, 500, 700 and 900mug. Doses were administered as IV bolus over 3 minutes, with eight subjects and four subjects receiving ABT-578 and placebo, respectively, in each dose group. Higher doses were administered after evaluating safety from the preceding lower doses. Blood concentrations of ABT-578 were sampled for 168 hours and measured using LC-MS/MS with a limit of quantification of 0.20 ng/mL.

Results: The pharmacokinetics of ABT-578 were essentially linear across the 100-900microg dose range as illustrated by the dose-proportional increases in concentration at 5 minutes (C(5)) after the end of infusion and area under the concentration-time curve (AUC). The mean half-life ranged between 26.0 and 40.2h over the studied doses and was not significantly different over the 300-900mug dose range. The mean clearance values ranged from 2.90 to 3.55 L/h. Single IV bolus doses up to 900mug of ABT-578 were well tolerated and no clinically significant changes in physical examination results, vital signs or laboratory test results were observed.

Conclusion: It can be concluded that the pharmacokinetics of IV ABT-578 are dose-proportional over the 100-900mug dose range. Single IV bolus doses up to 900mug were well tolerated in healthy male subjects.