Effect of low- and high-fat meals on tacrolimus absorption following 5 mg single oral doses to healthy human subjects

Tacrolimus (FK506, Prograf(R)) is a macrolide lactone antibiotic widely used by the oral route for the prophylaxis of organ rejection in patients who have received allogenic liver or kidney transplants. This study investigated the influence of a high- versus a low-fat meal, relative to the fasting state (three treatments fetal), on the rate and extent of tacrolimus absorption following a single 5 mg oral dose. The protocol employed a three-period, randomized crossover design employing 5 x 1 mg capsules in 35 healthy male nonsmoking, drug-free volunteers, 20 to 45 years of age, who were within 15% of their ideal body weight. Food had a clinically significant effect in reducing relative bioavailability, as well as slowing absorption, but did not affect terminal exponential half-life (similar to 34 hours). Mean maximum tacrolimus blood concentration (G(max)) values were 25.6, 5.88, and 9.03 ng/ml for the fasting, high-fat, and low-fat treatments, respectively; mean area under the blood concentration-time curve (AUC((0-infinity))) values were 272, 181, and 201 (ng/mL)-h, respectively; and mean time of C-max (t(max)) values were 1.37, 6.47 and 3.20 hours, respectively. Differences in parameters between the fasting and each fed treatment were statistically significantly different (p < 0.05). Statistically significant differences also existed in t(max) between the two meals. Results also indicated the safety of single 5 mg oral tacrolimus doses administered to healthy volunteers. (C) 2001 the American College of Clinical Pharmacology.