Bioequivalence of 1 and 5 mg tacrolimus capsules using a replicate study design

Tacrolimus (FK506, Prograf(R)) 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), andAUC(0-infinity), 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. Journal of Clinical Pharmacology 1999;39:1032-1037 (C)1999 the American College of Clinical Pharmacology.