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A45
October 13, 2007 9:00 AM - 11:00 AM Room Hall D, Area A, |
| Fospropofol Intravenous Injection for Procedural Sedation: A Population Pharmacokinetic Model |
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Ajit Shah, Ph.D., Leonid Gibiansky, Ph.D. MGI Pharma, Bloomington, Minnesota |
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BACKGROUND: AQUAVAN® (fospropofol disodium, FP) Injection is a water-soluble prodrug of propofol (PFP) being developed for sedation during short diagnostic & therapeutic procedures.A randomized,double-blind Phase 3 study evaluated the efficacy & safety of FP 6.5 mg/kg compared to a low dose of 2.0 mg/kg,both following pretreatment with fentanyl, in pts undergoing elective colonoscopy.Another group of pts received Midazolam (MD) as a reference therapy.Based on data obtained in this study,a population PK model of FP & PFP liberated from FP was developed.METHODS:Approximately 300 pts were randomly assigned to FP 2 mg/kg, FP 6.5 mg/kg, or MD 0.02 mg/kg txt groups at a 2:3:1 ratio.Pts weighing <60 kg or >90 kg were administered the FP dose of a 60 kg or 90 kg pt, respectively.Pts≥65 yrs received a 25% dose reduction of FP.For sedation initiation or maintenance, up to 3 supplemental doses were administered at 25% of the initial dose, every 4 min.Plasma samples were collected & analyzed (547 FP &566 PFP concentrations from 153 pts).The FP-PFP population PK model was developed using NONMEM. Influence of weight (range 45-147 kg),body mass index (BMI, range 18-55 kg/m2),age (range 18-85 yrs) & gender (70 M,83 F) was examined.RESULTS:A 5-compartment model adequately described the data.The model consisted of FP compartments 1 and 2, PFP compartments 4 & 5, & compartment 3 describing complete metabolism of FP to PFP with a time delay.For a typical 70 kg (BMI 25) pts administered 6.5 mg/kg, parameter estimates (relative standard errors) were CLFP= 0.30 L/min (3%),VFP=4.2 L(3%),K12= 0.010 min-1(9%), K2=0.019 min-1(27%),K34=0.36 min-1 (27%),CLPFP=2.9 L/min (7%),VPFP=16 L (36%), K45=0.66 min-1(38%), K54=0.048 min-1(13%).Within each dose level, a linear model adequately described PK.Allometric scaling (CL ∼ WT0.75; V ∼ WT; K12, K21, K34, K54, K45 ∼ WT-0.25) described WT dependence for the majority of pts; correction (VFP ∼ BMI-0.41) was required for over- & under-weight pts.No additional covariate trends were identified.Following administration of a 6.5 mg/kg dose, PFP max concentration (Cmax) was achieved at 8 min.Fig 1 shows PFP concentration time profiles for initial & 3 supplemental doses. Approximately 85% of Cmax was achieved by 4 min. If a supplemental dose is administered at 4 min, a 25% higher Cmax would be achieved at 9 min.The second supplemental dose at 8 min would increase Cmax by another 25% at 12 min. Interindividual variability (% coefficient of variation (CV) was relatively small (16% for VFP and 22% for CLFP, CLPFP & VPFP) with the exception of the FP-PFP metabolism rate constant (116% for K34).Residual error by an exponential error with 28% CV & 25% CV for FP and PFP, respectively. CONCLUSIONS:Population PK modeling results confirmed that a 6.5 mg/kg FP dose with 60-90 kg weight bounds provide optimal PFP exposure for sedation to the majority of pts. PK profile justified selected regimen of dose-to-effect titration with 4 min intervals between the doses.Fig1:Population mean plasma propofol (PFP)concentration-time profiles.[figure1] Anesthesiology 2007; 107: A45 |
Figure 1
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