CYP2B6 Genotype Guided Dosing of Propofol Anesthesia in the Elderly Based on Nonparametric Population Pharmacokinetic Modeling and Simulations

Objective: The primary aim of this article is to test the hypothesis that nonparametric pharmacometric modeling will accurately identify CYP2B6 genotype subgroups based on data from a study that reported results based on parametric pharmacokinetics (PK). Methods: Propofol concentration-time data were originally reported in the Kansaku et al., 2011 publication. Nonparametric Nonlinear Mixed Effects Modeling (NLME) was conducted using the PMETRICS R package while population pharmacokinetic model parameters were estimated using a FORTRAN compiler. Finally, model-based dosing simulations were conducted in the MATLAB Simbiology. Results: A total of 51 patients were included in the final PK analysis. A two-compartment gamma multiplicative error model adequately described the propofol concentration-time data. The individual observed versus predicted R2 =0.99 and R-squared=0.93 for the population model predictions. Neither the UGT1A9 nor the CYP2B6 G516T gene variants resulted in statistically significant PK parameter differences while the CYP2B6 A785G gene variants resulted in statistically significant differences for the elimination rate. Model-based dosing-simulations comparing patients with the CYP2B6 AA & AG genotypes to both GG genotypes and patients from a multicenter trial suggest a 50% decrease in propofol infusion dose, to 25mg/ kg/min, be made to result in approximately equivalent drug exposures. Conclusion: Based on the pharmacometric modeling and simulation, if no dosage adjustments are made for the elderly CYP2B6 AA and AG genotypes, a 250% higher propofol blood exposure will be evident within 1-hour from the start of the infusion. Thus, based on the pharmacokinetic model, genotyping elderly patients for the CYP2B6 AA and AG gene variants will decrease the total propofol blood exposure during anesthesia and sedation when an infusion dose adjustment is made to 25mg/kg/min.