title: Population pharmacokinetics of perhexiline from very sparse, routine monitoring data.
abstract: Using NONMEM, the population pharmacokinetics of perhexiline were studied in 88 patients (34 F, 54 M) who were being treated for refractory angina. Their 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 after a dose was 14.1 +/- 21.4 hours (0.5-200), and the perhexiline plasma concentrations were 0.39 +/- 0.32 mg/L (0.03-1.56). A one-compartment model with 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, respectively, which suggested a reduction in presystemic metabolism in subgroup B. The interindividual variability (CV%) was modeled logarithmically and for CL/F ranged from 69.1% (subgroup A) to 86.3% (subgroup B). The interindividual variability in V/F was 111%. The residual variability unexplained by the population model was 28.2%. These results confirm and extend the existing pharmacokinetic data on perhexiline, especially the bimodal distribution of CL/F manifested via an inherited deficiency in hepatic and extrahepatic CYP2D6 activity.
authors.affiliation: School of Pharmacy and The Australian Center for Pediatric Pharmacokinetics, The University of Queensland, St Lucia, Queensland, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Hussein
authors.forename: B G
authors.initials: BG
authors.lastname: Charles
authors.forename: R G
authors.initials: RG
authors.lastname: Morris
authors.forename: R L
authors.initials: RL
authors.lastname: Rasiah
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010480:Perhexiline / Q000493:pharmacokinetics*; D014665:Vasodilator Agents / Q000493:pharmacokinetics*
chemical_list: D014665:Vasodilator Agents; D019389:Cytochrome P-450 CYP2D6; D010480:Perhexiline