Comparative Sirolimus Pharmacokinetics After Single-Dose Administration of Two Prototype 0.5-mg Tablets in Healthy Volunteers.

Availability of a lower dose tablet would add to the dosing flexibility of currently available 1- and 2-mg sirolimus tablets for optimal concentrations and patient compliance. A randomized, 3-period crossover study was conducted in 30 fasting healthy volunteers (29 men, aged 31 ± 8 years, weight 79 ± 12 kg). Subjects were given 5 mg of sirolimus, either as doses of the 0.5-mg nonshellac-core prototype, 0.5-mg shellac-core prototype, or approved 1-mg tablet. Whole blood samples were collected at selected time points for 144 hours after dosing and analyzed using LC/MS/MS assay. Noncompartmental pharmacokinetic analysis was performed, followed by bioequivalence assessment. Twenty-four subjects completed all dosing periods, and no formulation-associated adverse events were reported. Ratios of maximum plasma concentration (Cmax ), area under the concentration-time curve to the last measured concentration (AUCT ), and area under the concentration-time curve from time 0 to infinity (AUC) for the nonshellac-core prototype compared with the 1-mg tablet were within the 80% to 125% range dictated by bioequivalence conventions. Similar results were observed when comparing the ratios of AUCT and AUC for the shellac-core prototype, while 90% confidence interval of the ratio of Cmax values was 105% to 129%. Within the context of clinical equivalence standards established by a phase 3 study comparing liquid to tablet formulations, it was concluded that both prototypes were clinically bioequivalent to the reference formulation.