title: Pharmacokinetics of coadministered guanfacine extended release and lisdexamfetamine dimesylate.
abstract: BACKGROUND
  In clinical practice, α₂-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug-drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated.
  
  
  OBJECTIVE
  The primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination.
  
  
  METHODS
  This was an open-label, randomized, three-period crossover, DDI study.
  
  
  METHODS
  The study was conducted in a single clinical research center.
  
  
  METHODS
  Forty-two healthy adults were randomized in this study.
  
  
  METHODS
  Subjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination.
  
  
  METHODS
  Blood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90% confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) falling within the bioequivalence reference interval (0.80-1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs).
  
  
  RESULTS
  Forty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC0-∞ and Cmax of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90% CI of the geometric mean ratio of AUC∞ for the two treatments was within the bioequivalence criteria, but for Cmax the upper bound of the 90% CI exceeded the standard range for bioequivalence by 7%. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9% of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3%) and headache (7.5, 4.9, and 7.3%) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX.
  
  
  CONCLUSIONS
  In healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.
authors.affiliation: Advanced Biomedical Research, Inc., 241 Main Street, 3rd Floor, Hackensack, NJ 07601, USA. bennoro@cs.com
authors.forename: Benno
authors.initials: B
authors.lastname: Roesch
authors.forename: Mary E
authors.initials: ME
authors.lastname: Corcoran
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fetterolf
authors.forename: Mary
authors.initials: M
authors.lastname: Haffey
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
authors.forename: Peter
authors.initials: P
authors.lastname: Preston
authors.forename: Jaideep
authors.initials: J
authors.lastname: Purkayastha
authors.forename: Phillip
authors.initials: P
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: Ermer
mesh_terms: D000293:Adolescent; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000009:adverse effects; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D016316:Guanfacine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D000069478:Lisdexamfetamine Dimesylate; D008297:Male; D008875:Middle Aged; D013810:Therapeutic Equivalency; D055986:Vital Signs / Q000187:drug effects
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000697:Central Nervous System Stimulants; D016316:Guanfacine; D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine