Background: Clinicians have observed longer awakening times for obese compared to normal-weight patients when propofol is dosed as per label guidelines on Total Body Weight (TBW). This may be explained by the non-linear relationship between TBW and CL described by Schuttler et al1. Lean Body Weight (LBW) has been reported to have a linear relationship with drug clearance2 and therefore should be a more appropriate size descriptor for dosing of drugs e.g. propofol.
Aims: (1) To evaluate if a linear LBW covariate model can replace a non-linear multivariate covariate model for propofol clearance1, and (2) to explore how awakening time might vary following different propofol dosing regimens in the obese population.
Methods: For aim (1), a population PK model reported by Schuttler1, where clearance was defined as CL=86.4L.h-1*((TBW/70)0.75) – 2.7*(age-60) was used to simulate one-hundred datasets of 198 subjects each, 7 optimal time-points per subject, with subject weight stratified into 3 groups; 40-60kg, 60-80kg, and 80-100kg. Age, weight, and height for each individual were simulated from a covariate distribution model determined from a medical patient dataset (n = 999). PK parameters were then re-estimated with both Schuttler’s model, and a reduced covariate model where LBW was the single covariate on CL: CL=θ*(LBW/55). The predictive performance of each model was evaluated by calculating the mean error (ME) and root mean square error (RMSE) of individual PK estimates from the “true” simulated values. For aim (2) the reduced LBW model was used to simulate PK profiles for 4000 male subjects (180cm, 30yrs) in 4 weight categories; 70, 100, 130, and 160kg; with a dosing regimen of a 2mg/kg bolus dose followed by a 1h, 6mg/kg/h infusion based on (a) TBW, and (b) LBW. A prior PD model for probability of awakening3 with an EC50 = 1.07ug/ml was used to determine the post-infusion median probability of awakening over time for each weight group.
Results: Re-estimation of individual CL values using the full multivariate and LBW model yielded a ME of -3.94L/h vs -5.03L/h, and RMSE of 8.25L/h vs 8.99L/h, respectively. ME and RMSE of the other PK parameter estimates were also comparable. Between subject variability (as %CV) for each of the parameters was within 10% of the simulation values for both models, with random unexplained variability within 2%. Dosing on TBW resulted in an increased probability of longer time to awakening in the larger weight groups, with the median probability of a subject still being asleep at 30min post-infusion being 68% for 160kg vs. 28% for 70kg. When dosed on LBW, there was no difference between groups (Pasleep(30min) = 14% for all groups).
Conclusions: We have shown that the LBW covariate model has similar predictive properties to a multivariate covariate model used to describe the non-linear increase in CL with TBW. This model may explain the observed differences in patient times to awakening when dosing is based on TBW. A prospective clinical trial will be completed to confirm these results and help develop a safer dosing regimen for the obese population.
References:
Han, P.Y, Duffull, S.B., Kirkpatrick C.M. & Green B. (2007). Dosing in obesity: a simple solution to a big problem. Clin Pharmacol Ther 82(5):505-8