Genotype-driven pharmacokinetic simulations of warfarin levels in Puerto Ricans

The inter-individual variability of warfarin dosing has been linked to genetic polymorphisms. This study was aimed at performing genotype-driven pharmacokinetic (PK) simulations to predict warfarin levels in Puerto Ricans.

Analysis of each individual dataset was performed by one-compartmental modeling using WinNonlin®v6.4. The k_e of warfarin given a cytochrome P450 2C9 (CYP2C9) genotype ranged from 0.0189 to 0.0075 h^-1. K_a and V_d parameters were taken from literature. Data from 128 subjects were divided into two groups (i.e., wild-types and carriers) and statistical analyses of PK parameters were performed by unpaired t-tests.

In the carrier group (n=64), 53 subjects were single-carriers and 11 double-carriers (i.e., *2/*2, *2/*3, *2/*5, *3/*5, and *3/*8). The mean peak concentration (Cmax) was higher for wild-type (0.36±0.12 vs. 0.32±0.14 mg/L). Likewise, the average clearance (CL) parameter was faster among non-carriers (0.22±0.03 vs. 0.17±0.05 L/h; p=0.0001), with also lower area under the curve (AUC) when compared to carriers (20.43±6.97 vs. 24.78±11.26 h mg/L; p=0.025). Statistical analysis revealed a significant difference between groups with regard to AUC and CL, but not for Cmax. This can be explained by the variation of k_e across different genotypes.

The results provided useful information for warfarin dosing predictions that take into consideration important individual PK and genotyping data.