Effects of food on the single-dose pharmacokinetics/pharmacodynamics of tizanidine capsules and tablets in healthy volunteers

Clin Ther. 2006 Sep;28(9):1308-17. doi: 10.1016/j.clinthera.2006.09.014.


Background: A multiparticulate capsule formulation of the alpha2-adrenergic agonist tizanidine has been developed to decrease C(max), AUC, and associated somnolence, while maintaining efficacy.

Objective: The purpose of this study was to compare the pharmacokinetics and impact of somnolence on cognitive function after single doses of the tablet and capsule formulations of tizanidine under fed and fasted conditions in healthy volunteers.

Methods: This Phase I, single-dose, randomized, open-label, 4-way crossover study was conducted at MDS Pharma Services, Belfast, United Kingdom. Healthy male and female adult subjects received tizanidine (8 mg) as tablets and capsules under fasting and nonfasting conditions. Blood samples were collected to determine plasma tizanidine pharmacokinetic profiles, and computerized cognitive function tests were performed that yielded a validated composite score, Power of Attention, an index of sedation.

Results: Ninety-six patients were enrolled in the study (54 men, 42 women; mean [SD] age, 27 [8] years [range, 18-52 years]; mean [SD] body weight, 71.7 [12.4] kg [range, 46-102 kg]). Tizanidine tablets and capsules were found to be bioequivalent after fasting. In the fed state, mean C(max) and AUC(0-t) were substantially decreased, by 33.8% and 15.4%, comparing the capsules and tablets, respectively. The median T(max) increased significantly from 1.41 to 3.0 hours (P < 0.001). Administration of the capsules with food resulted in <20% difference in mean C(max) and AUC(0-t) compared with the fasting state, whereas mean C(max) and AUC(0-t) were 22.6% and 45.2% higher when the tablet formulation was administered with food. The onset of impairment in Power of Attention was significantly delayed from 0.75 to 1.5 hours postdose when capsules were administered with food compared with the other conditions (P < 0.001). The most commonly reported adverse events were asthenia, somnolence, and orthostatic hypotension. A significantly lower adverse event rate was observed in the combined capsules group compared with the tablets, suggesting that differences in tolerability may exist.

Conclusions: The results of this study in healthy volunteers suggest that the capsule and tablet formulations of tizanidine were bioequivalent only in the fasted state. The capsule formulation exhibited a food effect that reduced C(max) and AUC(0-t), and significantly increased T(max), which was associated with a delay in cognitive impairment. The large interpatient variability in plasma profiles most likely dampened the ability to fully elucidate the differences between the 2 formulations.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Capsules
  • Clonidine / administration & dosage
  • Clonidine / analogs & derivatives*
  • Clonidine / pharmacokinetics
  • Cognition / drug effects*
  • Cognition / physiology
  • Cross-Over Studies
  • Disorders of Excessive Somnolence / blood*
  • Disorders of Excessive Somnolence / psychology
  • Female
  • Follow-Up Studies
  • Gas Chromatography-Mass Spectrometry
  • Humans
  • Male
  • Middle Aged
  • Muscle Relaxants, Central / administration & dosage
  • Muscle Relaxants, Central / pharmacokinetics*
  • Reference Values
  • Tablets


  • Capsules
  • Muscle Relaxants, Central
  • Tablets
  • tizanidine
  • Clonidine