title: Pharmacokinetics and Safety of ABT-578, a Sirolimus (Rapamycin) Analogue, after Single Intravenous Bolus Injection in Healthy Male Volunteers.
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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacokinetics, Abbott Laboratories, Abbott Park, Illinois, USA.
authors.forename: Rameshraja
authors.initials: R
authors.lastname: Palaparthy
authors.forename: Rajendra
authors.initials: R
authors.lastname: Pradhan
authors.forename: Jenny
authors.initials: J
authors.lastname: Chan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Qin
authors.initials: Q
authors.lastname: Ji
authors.forename: Ramanuj
authors.initials: R
authors.lastname: Achari
authors.forename: Titus
authors.initials: T
authors.lastname: Chira
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Schwartz
authors.forename: Robert
authors.initials: R
authors.lastname: O'dea