Effect of Time of Meal Consumption on Bioavailability of a Single Oral 5 mg Tacrolimus Dose

Abstract

Tacrolimus (FK506, Prograf) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. This study investigated the effect of timing of a standardized breakfast meal on both the rate and extent of tacrolimus absorption following a single 5 mg oral dose. The protocol used a randomized, open-label, four-period, four-treatment, four-sequence crossover design in 16 healthy, nonsmoking, drug-free male subjects between the ages of 22 and 45 years who were within 15% of their ideal body weight. The four treatments were the following: (A) fasting for 10 hours, (B) ingestion 1 hour before breakfast, (C) ingestion immediately following consumption of the breakfast, and (D) ingestion 1.5 hours after beginning consumption of the breakfast. The breakfast, which was consumed over 15 minutes, contained 848 kcal, with 30%, 16%, and 54% of calories derived from fat, protein, and carbohydrate, respectively. Tacrolimus absorption in the fasting state provided the greatest relative bioavailability (p < 0.05 compared with all other three treatments). AUC(0-infinity)) averaged 312, 276, 205, and 203 ng x h/mL for treatments A, B, C and D, respectively. In contradistinction to taking the drug 1 hour prior to a meal, which had a relatively minor impact on the relative extent of absorption (approximately 12%) compared to the fasting state, ingestion of tacrolimus immediately after a meal (treatment C) or 1.5 hours subsequent to a meal (treatment D) had a more pronounced influence. Mean AUC(0-infinity) ratios (fasting to either postmeal treatments) were approximately 1.5, indicating that absorption extent was considerably reduced by ingesting tacrolimus capsules immediately after eating or 1.5 hours thereafter. Absorption was also prolonged following drug ingestion after a meal, as indicated by a mean tmax value in the fasting state of 1.84 hours, relative to 3.41 hours (immediately aftermeal, p = 0.0035) and 3.22 hours (1.5 hours postmeal, p = 0.0094). The only discernable difference in parameters between treatments C and D was with Cmax, with values of 7.19 and 9.04 ng/mL, respectively, but was not statistically significantly different (p = 0.231). Based on these results and those from a prior study, it is recommended that under therapeutic conditions, oral tacrolimus be administered in a consistent manner, both with respect to the type of meal as well as timing of ingestion relative to consumption of the meal.

Large Within-Day Variation in Cyclosporine Absorption

“…Applying Occam's razor, there seems to be no reason to hypothesize any mechanism beyond that associated with food effects to explain a.m.-p.m. differences in exposure to CsA. Our results are consistent with some reports in the literature for tacrolimus as well (14,16,20,21). Min et al (14) found morning-evening differences in absorption of tacrolimus that were comparable to those of our study; however, they did not investigate the effect of food per se.…”

Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Twice Daily Versus Once Daily Dosing

“…There were no differences in characteristics between the groups. [12][13][14][15][16][17][18][19][20][21][22][23][24] BID: twice daily administration; QD: once daily administration in the morning. Mean ± SD.…”

“…(15-40%) and AUC (2-12%) have been reported in a fasting state vs. a nonfasting state (15)(16)(17). Furthermore, the time of tacrolimus administration with respect to a meal has been reported to effect bioavailability of tacrolimus (15,16). It is possible that in Phase I of the trial the evening dose of tacrolimus had altered bioavailability because food was allowed from 2.5 to 3 h prior to the evening dose, whereas for the morning dose patients were asked to fast for 10 h prior to administration.…”

“…An increase in C max . (15-40%) and AUC (2-12%) have been reported in a fasting state vs. a nonfasting state (15)(16)(17). Furthermore, the time of tacrolimus administration with respect to a meal has been reported to effect bioavailability of tacrolimus (15,16).…”

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“…Food intake may be a relevant determinant, whereas genetic factors seem less important. [4][5][6][7] Whatever the cause of the IPV in tacrolimus pharmacokinetics may be, patients with a high variability have a tacrolimus exposure more often outside the target range. Such patients may be at risk for underimmunosuppression and rejection, as well as overexposure and toxicity.…”