title: An open-label investigation of the pharmacokinetic profiles of lisdexamfetamine dimesylate and venlafaxine extended-release, administered alone and in combination, in healthy adults.
abstract: BACKGROUND
  Lisdexamfetamine dimesylate (LDX), a prodrug consisting of d-amphetamine and l-lysine, is being studied in clinical trials of major depressive disorder. Additional drug-drug interaction studies were warranted.
  
  
  OBJECTIVE
  This study aimed to describe the pharmacokinetics and safety of LDX and venlafaxine extended-release (VXR), alone or combined.
  
  
  METHODS
  The study was an open-label, two-arm, single-sequence crossover investigation with randomization to treatment sequence.
  
  
  METHODS
  The study was conducted at two clinical study centres and included healthy adult males and females (18-45 years of age).
  
  
  METHODS
  The study included two single-sequence crossover designs: LDX alone followed by LDX + VXR (Treatment Arm A); and VXR alone followed by VXR + LDX (Treatment Arm B). Drug treatment was initiated on day 1 with once-daily LDX or VXR alone with 15 days' titration to final dose (LDX 30, 50 and 70 mg for 5 days each; VXR 75, 150 and 225 mg for 5 days each). On days 16-30, VXR, titrated to a final dose of 225 mg, or LDX, titrated to a final dose of 70 mg, was coadministered for participants in Treatment Arm A or B, respectively. On days 31-38, VXR doses were tapered.
  
  
  METHODS
  On days 1-2, 15-16 and 30-31, safety evaluations and blood samples were obtained pre-dose through 24 h post-dose for analysis of LDX, d-amphetamine, venlafaxine (VEN), and O-desmethylvenlafaxine (ODV). Combination treatment was considered bioequivalent to single treatment if 90 % confidence intervals (CIs) for geometric mean ratios (GMRs) of analytes fell within the interval 0.80-1.25 based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUCτ). Safety assessments included treatment-emergent adverse events (TEAEs), pulse rate and blood pressure (BP), clinical laboratory assessments, and 12-lead electrocardiograms (ECG).
  
  
  RESULTS
  Among 80 enrolled subjects, 77 were included in pharmacokinetic and safety analyses. Combination LDX + VXR was bioequivalent to LDX alone, based on exposure to d-amphetamine (GMR [95 % CI], Cmax (ng/mL): 0.97 [0.82, 1.14], AUCτ: 0.95 [0.81, 1.12]). Exposure to VEN with LDX + VXR (vs. VXR alone) was increased (Cmax: 1.10 [0.88, 1.38], AUCτ: 1.13 [0.88, 1.45]) and ODV decreased (Cmax: 0.91 [0.77, 1.06], AUCτ: 0.83 [0.71, 0.96]), whereas composite VEN + ODV was bioequivalent to VXR alone (Cmax: 0.96 [0.84, 1.09], AUCτ: 0.98 [0.85, 1.13]). TEAEs with LDX or LDX + VXR were similar. Maximum mean increases from baseline were: pulse rate, +8.73 to 12.76 beats/min with either treatment alone and +17.67 to 20.85 beats/min with LDX + VXR; systolic BP, +4.32 to 6.56 mmHg with either treatment alone and +12.96 to 13.78 mmHg with LDX + VXR; diastolic BP, +5.39 to 5.74 mmHg with either treatment alone and +12.09 to 12.46 mmHg with LDX + VXR. One participant was withdrawn due to a serious TEAE (presyncope). No unexpected, clinically meaningful trends or changes from baseline in mean laboratory or ECG parameters were observed during the trial.
  
  
  CONCLUSIONS
  In healthy adults, combination LDX + VXR (vs. LDX alone) did not alter exposure to d-amphetamine. Although small changes in exposure to VEN (increased) and ODV (decreased) were seen with combination treatment, total VEN + ODV exposure showed no change (vs. VEN alone). LDX + VXR led to increases in BP and pulse rate, supporting existing recommendations for vital sign monitoring when using these medications.
authors.affiliation: Shire Development LLC, 725 Chesterbrook Blvd, Wayne, PA 19087, USA. jaermer@shire.com
authors.forename: James
authors.initials: J
authors.lastname: Ermer
authors.forename: Mary B
authors.initials: MB
authors.lastname: Haffey
authors.forename: Cynthia
authors.initials: C
authors.lastname: Richards
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lasseter
authors.forename: Benno
authors.initials: B
authors.lastname: Roesch
authors.forename: Jaideep
authors.initials: J
authors.lastname: Purkayastha
authors.forename: Mary
authors.initials: M
authors.lastname: Corcoran
authors.forename: Bree
authors.initials: B
authors.lastname: Harlin
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
mesh_terms: D000293:Adolescent; D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003511:Cyclohexanols / Q000008:administration & dosage / Q000627:therapeutic use*; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000069478:Lisdexamfetamine Dimesylate; D008297:Male; D012016:Reference Values; D000069470:Venlafaxine Hydrochloride; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D003511:Cyclohexanols; D000069470:Venlafaxine Hydrochloride; D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine