Relative bioavailability of tizanidine hydrochloride capsule formulation compared with capsule contents administered in applesauce: A single-dose, open-label, randomized, two-way, crossover study in fasted healthy adult subjects

Abstract Background: The α2-adrenergic agonist tizanidine has been reported to have a narrow therapeutic index. A multiparticulate capsule formulation of tizanidine has been developed in an attempt to improve patient tolerability. Objective: This study assessed bioequivalence between a single, intact, 6-mg capsule of tizanidine and the capsule contents sprinkled in applesauce in fasted healthy subjects. Methods: Healthy male and female subjects aged 18 to 45 years completed 2 treatment periods: one with a tizanidine 6-mg capsule administered intact and the other with capsule contents sprinkled in applesauce. The 2 treatment periods had a 6-day washout period between administrations. Plasma tizanidine concentrations were determined for blood samples collected over 24 hours after administration. All treatment-emergent adverse events were recorded and graded by intensity and relationship to the study drug (not, improbable, possible, probable, definite) by the attending physician based on his or her clinical impression. Results: A total of 19 men and 9 women (mean age, 26 years) completed the trial. Geometric mean natural logarithm-transformed AUC values (AUC 0–∞ [AUC to infinity] and AUC 0–t [AUC to the last measurable time point]) and C max ratios were significantly ( P ≤ 0.035) increased to 1.14 (90% CI, 105.47%–127.01%), 1.16 (90% CI, 106.80%–130.53%), and 1.17 (90% CI, 103.95%–133.66%), respectively, when the contents were sprinkled, with 90% CIs laying outside the 0.80 to 1.25 ratio established by regulatory authorities for bioequivalence. A total of 31 adverse events were reported by 17 of the 28 subjects (61%), including 15 subjects (54%) with the intact capsule reporting 18 events and 11 subjects (39%) with the sprinkled contents reporting 13 events. No serious adverse events or deaths were reported, and no subjects were discontinued due to adverse events. Conclusions: The contents of the tizanidine capsule sprinkled in applesauce were not bioequivalent to the intact 6-mg capsule in these fasted healthy volunteers. Therefore, if switching from the intact capsule to the capsule contents mixed in applesauce, monitoring for adverse events is recommended; in this situation, dose adjustment could be necessary.