title: Hydralazine dose-response curve analysis.
abstract: A multicenter, parallel, double-blind, 181-patient study compared the safety and antihypertensive efficacy of immediate-release (IR) and extended-release (ER) hydralazine. After 2 to 4 weeks on diuretic, patients were maintained on diuretic and randomized to a hydralazine treatment regimen: IR thrice daily, ER twice daily, or ER once daily. Daily doses of hydralazine were 75, 150, or 300 mg. Although designed as a titration study, important dose-response data were available for analysis with nonlinear mixed effect modeling (NONMEM). Sitting diastolic blood pressure (BP) was selected as the response variable. Several factors were tested for importance, including body weight, time (week) effects, concomitant beta-blocker (BB) therapy, acetylator class, and treatment regimen. All factors were important (p less than 0.05) except treatment regimen (p greater than 0.30). The maximum antihypertensive response (Emax) to hydralazine was 9.4 mm Hg. The daily dose that elicited 50% of the maximum response (D50) was 0.87 mg/kg for slow acetylators and 1.68 mg/kg for fast acetylators. BP fell 0.52 mm Hg per week independent of other effects, and concomitant BB therapy induced a drop of 6.6 mm Hg in addition to hydralazine, diuretic and week effects. NONMEM's use assisted in evaluations and provided information not obtainable through traditional means.
authors.affiliation: Fisons Pharmaceuticals, Rochester, New York 14623.
authors.forename: D A
authors.initials: DA
authors.lastname: Graves
authors.forename: K T
authors.initials: KT
authors.lastname: Muir
authors.forename: W
authors.initials: W
authors.lastname: Richards
authors.forename: B W
authors.initials: BW
authors.lastname: Steiger
authors.forename: I
authors.initials: I
authors.lastname: Chang
authors.forename: B
authors.initials: B
authors.lastname: Patel
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006830:Hydralazine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D006830:Hydralazine