Pharmacokinetics of coadministration of guanfacine extended release and methylphenidate extended release

Drugs R D. 2013 Mar;13(1):53-61. doi: 10.1007/s40268-013-0009-5.


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.

Study design: This was an open-label, randomized, three-period crossover, drug-drug interaction study.

Setting: The study was conducted at a single clinical research center.

Participants: Thirty-eight healthy adults were randomized in this study.

Interventions: 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.

Main outcome measures: 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists / administration & dosage
  • Adrenergic alpha-2 Receptor Agonists / pharmacokinetics
  • Adult
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / pharmacokinetics
  • Cross-Over Studies
  • Delayed-Action Preparations / pharmacokinetics
  • Drug Interactions / physiology
  • Drug Therapy, Combination
  • Female
  • Guanfacine / administration & dosage*
  • Guanfacine / pharmacokinetics*
  • Humans
  • Male
  • Methylphenidate / administration & dosage*
  • Methylphenidate / pharmacokinetics*
  • Young Adult


  • Adrenergic alpha-2 Receptor Agonists
  • Central Nervous System Stimulants
  • Delayed-Action Preparations
  • Methylphenidate
  • Guanfacine