Abstract
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 900μg. 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 100–900μg dose range as illustrated by the dose-proportional increases in concentration at 5 minutes (C5) 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 300–900μg dose range. The mean clearance values ranged from 2.90 to 3.55 L/h. Single IV bolus doses up to 900μg 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 100-900μg dose range. Single IV bolus doses up to 900μg were well tolerated in healthy male subjects.
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This work was funded by Abbott Laboratories, Abbott Park, Illinois, USA. The authors were all employees of Abbott during the preparation of this article.
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Palaparthy, R., Pradhan, R., Chan, J. et al. Pharmacokinetics and Safety of ABT-578, a Sirolimus (Rapamycin) Analogue, after Single Intravenous Bolus Injection in Healthy Male Volunteers. Clin. Drug Investig. 25, 491–498 (2005). https://doi.org/10.2165/00044011-200525080-00001
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DOI: https://doi.org/10.2165/00044011-200525080-00001