title: Pharmacokinetics of coadministration of guanfacine extended release and methylphenidate extended release.
abstract: BACKGROUND
  α2-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.
  
  
  OBJECTIVE
  The primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.
  
  
  METHODS
  This was an open-label, randomized, three-period crossover, drug-drug interaction study.
  
  
  METHODS
  The study was conducted at a single clinical research center.
  
  
  METHODS
  Thirty-eight healthy adults were randomized in this study.
  
  
  METHODS
  Subjects were administered single oral doses of GXR (Intuniv(®); Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta(®); McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.
  
  
  METHODS
  Guanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).
  
  
  RESULTS
  Thirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80-1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.
  
  
  CONCLUSIONS
  In this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug-drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH 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
authors.initials: M
authors.lastname: Corcoran
authors.forename: Mary
authors.initials: M
authors.lastname: Haffey
authors.forename: Annette
authors.initials: A
authors.lastname: Stevenson
authors.forename: Phillip
authors.initials: P
authors.lastname: Wang
authors.forename: Jaideep
authors.initials: J
authors.lastname: Purkayastha
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
authors.forename: James
authors.initials: J
authors.lastname: Ermer
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D000328:Adult; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D016316:Guanfacine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000697:Central Nervous System Stimulants; D003692:Delayed-Action Preparations; D008774:Methylphenidate; D016316:Guanfacine