Bioequivalence of 1 and 5 mg Tacrolimus Capsules Using a Replicate Study Design

Tacrolimus (FK506, Prograf®) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. A previously conducted, randomized, 24‐subject, crossover bioavailability study of 1 and 5 mg capsules (one period each) failed to demonstrate bioequivalence. A single‐dose, four‐period, four‐sequence, randomized, crossover, replicate study ( N = 32) was therefore used to evaluate the bioequivalence of the marketed 1 and 5 mg capsules in healthy volunteers. Tacrolimus blood concentrations were measured serially over 72 hours using a commercially available ELISA assay. Noncompartmental pharmacokinetic parameters were determined. Ninety percent CIs of log‐transformed parameter ratios were 90.5–101.9, 87.1–101.7, and 89.7–103.8 for C max , AUC 0‐t , and AUC 0‐∞ respectively. Since all values were within 80% to 125%, the capsules are bioequivalent. Based on %CVs, intersubject variability was approximately two to three times greater than intrasubject variability. The safety of single 5 mg oral tacrolimus doses administered to healthy volunteers at 7‐day intervals was also ascertained .