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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.