Relative bioavailability of tizanidine 4-mg capsule and tablet formulations after a standardized high-fat meal: A single-dose, randomized, open-label, crossover study in healthy subjects

Abstract

Background: An immediate-release, multiparticulate capsule formulation of tizanidine has been developed to modify tizanidine pharmacokinetic characteristics in an attempt to decrease adverse events (AEs) while maintaining effectiveness in the management of spasticity. Objective: This study was designed to compare the pharmacokinetic properties and tolerability of a single dose (4 mg) of an immediate-release, multiparticulate tizanidine capsule versus a commercially available tablet (reference) administered after a standardized high-fat meal. Methods: This single-dose, randomized, open-label, 2-way crossover study in healthy, nonsmoking adult subjects was conducted at MDS Pharma Services, Belfast, United Kingdom. Subjects were randomly assigned to receive the capsule-tablet or tablet-capsule treatment. The 2 treatment periods were separated by a 6-day washout period. All treatments were administered after a standardized high-fat meal. To determine plasma tizanidine pharmacokinetic properties, blood samples were collected over 24 hours after administration. The predetermined bioequivalence range for the test drug (capsule) was 80% to 125% of the reference drug (tablet). Drug tolerability was assessed using routine physical examination, including vital-sign measurements; laboratory analysis (hematology, biochemistry, and urinalysis); 12-lead electrocardiography; direct observation; spontaneous reporting; and non specific questioning. Results: This study included 18 subjects (12 men, 6 women; mean [SD] age, 26 [7] years). The mean height and body weight of the subjects were 176 (8) cm and 70.1 (9.6) kg, respectively. The peak exposure, as measured by mean natural logarithm-transformed C max values, was significantly lower with the capsule compared with the tablet (2.7 vs 4.0 ng/mL; P < 0.019), and mean TmaX was significantly longer (2.6 vs 1.2 hours; P < 0.001). The 90% CIs for the capsule:tablet treatment ratios were 70.55 to 121.94 for AUC 0-lat and 70.12 to 118.75 for AUC 0−∞. The capsule did not achieve the protocol-defined definition of bioequivalence when given after a high-fat meal. All AEs were transient and mild in intensity, with asthenia being the most common event with the capsule and tablet formulations, occurring in 5 (28%) and 8 (44%) subjects, respectively. Conclusions: In this small study in healthy volunteers, after a single oral dose was administered following a high-fat meal, the mean C max was significantly lower and mean T max was significantly longer with the capsule formulation of tizanidine compared with the tablet. The capsule formulation was found not to be bioequivalent to the tablet when given with food. Based on these findings, caution is needed when a patient is switched between the capsule and tablet formulations of tizanidine, or when the timing of administration of either formulation is changed in relation to food ingestion.