Population pharmacokinetic model of sedative doses of GPI15715 and propofol liberated from GPI15715

Abstract

Background GPI15715 (AQUAVAN® Injection, AQ) is a water soluble prodrug of propofol (PR). Pharmacokinetics (PK) of PR liberated from AQ differ from those of PR lipid emulsions. We developed a population PK model of AQ and liberated PR and identified covariates that influenced their PK. Methods In a Phase II colonoscopy sedation study, 5 minutes after fentanyl citrate iv dose (11–201 μg) patients received an AQ iv bolus and up to 4 supplemental iv doses (total dose 495–1675 mg). A total of 597 AQ and 599 PR concentrations from 69 males and 89 females were analyzed using NONMEM. Covariates included age (20–85 yrs, 18 patients≥ 65 yrs), weight (WT 45–140 kg), lean body weight (LBW 37–81 kg), BMI, gender, fentanyl citrate exposure, albumin, creatinine clearance, and lab values. Results Linear 2-comparment models for AQ and PR with a delay compartment between them described the data. CLAQ, V1AQ and CLPR, V1PR increased proportionally with LBW. Model parameters (%SE) under assumption of 100% AQ metabolism to PR were: CLAQ=0.27 L/min (21%), V1AQ=6.4 L (6%), K12AQ=0.023 1/min (56%), K21AQ=0.0032 1/min (52%), KAQ-PR=0.41 1/min (12%), V1PR=1 L (fixed), CLPR=3.7 L/min (18%), K12PR=3.8 1/min (25%), K21PR=0.03 1/min (27%), CLAQLBW=2.5 %/kg (12%), V1AQLBW=1.8 %/kg (21%), CLPRLBW=V1PRLBW=1.6 %/kg (27%). Conclusions Linear population PK model adequately described the data. LBW was a better predictor than WT. Fentanyl citrate did not affect the PK. No clinically significant influence of age was detected. Clinical Pharmacology & Therapeutics (2005) 77, P48–P48; doi: 10.1016/j.clpt.2004.12.076