Population pharmacokinetics of perhexiline from very sparse, routine monitoring data

Using NONMEM, the population pharmacokinetics of perhexiline were studied i n 88 patients (34 F, 54 M) who were being treated for refractory angina. Th eir mean +/- SD (range) age was 75 +/- 9.9 years (46-92), and the length of perhexiline treatment was 56 +/- 77 weeks (0.3-416). The sampling time aft er a dose was 14.1 +/- 21.4 hours (0.5-200), and the perhexiline plasma con centrations were 0.39 +/- 0.32 mg/L (0.03-1.56). A one-compartment model wi th first-order absorption was fitted to the data using the first-order (FO) approximation. The best model contained 2 subpopulations (obtained via the $MIXTURE subroutine) of 77 subjects (subgroup A) and 11 subjects (subgroup B) that had typical values for clearance (CL/F) of 21.8 L/h and 2.06 L/h, respectively. The volumes of distribution (V/F) were 1470 L and 260 L, resp ectively, which suggested a reduction in presystemic metabolism in subgroup B. The interindividual variability (CV%) was modeled logarithmically and f or CL/F ranged from 69.1% (subgroup A) to 86.3% (subgroup B). The interindi vidual variability in V/F was 111%. The residual variability unexplained by the population model was 28.2%. These results confirm and extend the exist ing pharmacokinetic data on perhexiline, especially the bimodal distributio n of CL/F manifested via an inherited deficiency in hepatic and extrahepati c CYP2D6 activity.