title: Safety and pharmacokinetics of lisdexamfetamine dimesylate in adults with clinically stable schizophrenia: a randomized, double-blind, placebo-controlled trial of ascending multiple doses.
abstract: To assess the safety and pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, this double-blind study enrolled adults with clinically stable schizophrenia who were adherent (≥12 weeks) to antipsychotic pharmacotherapy. The participants received placebo or ascending LDX doses (50, 70, 100, 150, 200, and 250 mg) daily for 5 days at each dose (dose periods, 1-6; days, 1-5). Of the 31 enrolled participants, 27 completed the study (placebo, n = 6; LDX, n = 21). Treatment-emergent adverse events (AEs) were reported by 4 participants receiving placebo and by 23 participants receiving LDX (all doses) with no serious AEs while on active treatment. For all periods, the mean postdose change on day 5 (up to 12 hours postdose) in systolic and diastolic blood pressure and pulse, respectively, ranged from -4.62 to 8.05 mm Hg, -3.67 to 4.43 mm Hg, and -3.57 to 14.43 beats per minute for placebo and -3.83 to 11.25 mm Hg, -1.55 to 5.80 mm Hg, and -0.36 to 21.26 beats per minute for LDX. With ascending LDX dose, the mean (SD) maximum plasma concentration for LDX-derived d-amphetamine ranged from 51.68 (10.28) to 266.27 (56.55) ng/mL. The area under the plasma concentration-time curve for 24 hours ranged from 801.8 (170.2) to 4397.9 (1085.9) ng[BULLET OPERATOR]h/mL. The d-amphetamine maximum plasma concentration and area under the plasma concentration-time curve increased linearly with ascending LDX dose. Antipsychotic agents did not markedly affect d-amphetamine pharmacokinetics. Over a wide range of ascending doses, LDX safety profile in adults with schizophrenia was consistent with previous findings with no unexpected treatment-emergent AEs. Pulse tended to increase with LDX dose; overall, blood pressure did not increase with LDX dose. Consistent with previous studies, pharmacokinetic parameters increased linearly with increasing LDX dose.
authors.affiliation: From the *Shire Development LLC, Wayne, PA; †California Clinical Trials Medical Group, Glendale; and ‡Collaborative Neuroscience Network, Garden Grove, CA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
authors.forename: Bryan
authors.initials: B
authors.lastname: Dirks
authors.forename: Lev
authors.initials: L
authors.lastname: Gertsik
authors.forename: David
authors.initials: D
authors.lastname: Walling
authors.forename: Annette
authors.initials: A
authors.lastname: Stevenson
authors.forename: Mary
authors.initials: M
authors.lastname: Corcoran
authors.forename: Aparna
authors.initials: A
authors.lastname: Raychaudhuri
authors.forename: James
authors.initials: J
authors.lastname: Ermer
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D003913:Dextroamphetamine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000069478:Lisdexamfetamine Dimesylate; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000097:blood* / Q000188:drug therapy*
chemical_list: D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine