A modified-release version of tacrolimus, LCP-tacrolimus (LCPT; Envarsus XR, Veloxis Pharmaceuticals), has been licensed in the United States for prophylaxis of organ rejection in de novo kidney transplant patients. As tacrolimus has a narrow therapeutic window, the impact of circadian patterns on LCPT drug exposure, including food and chronopharmacokinetic effects, needs to be elucidated to optimize dosing.
Two randomized, crossover, Phase 1 studies were conducted in healthy volunteers. The first assessed the effect of morning versus evening dosing on the pharmacokinetic profile of LCPT 2 mg; the second assessed the effect of food on the pharmacokinetic profile of LCPT 5 mg. In both, blood samples were drawn from participants for up to 144 h after administration of a single LCPT dose.
No significant differences were observed between evening and morning dosing in peak blood concentration (4.4 vs. 4.0 ng/mL; p=0.27), area under the time-concentration curve (AUC) from time 0 to time of the last concentration (89.1 vs. 102.6 ng/mL; p=0.20), AUC from time 0 to infinity (99.7 vs. 114.3 ng·h/mL; p=0.18), AUC from 0 to 24 h post-dose (AUC0-24; 49.4 vs. 51.6 ng·h/mL; p=0.56), time to reach maximum blood concentration (median, 6.0 vs. 6.0 h; p=0.91), total clearance (arithmetic mean = 21.5 vs. 19.5 L/h; p=0.50), or terminal half-life (arithmetic mean = 26.8 vs. 28.1 h; p=0.26). After a high-calorie meal in the morning, the AUC0-24 reduced by 54% (ratio of geometric means = 45.6%; p<0.0001) and peak blood concentration reduced by 22% (ratio of geometric means = 78.4%; p=0.0006). However, the terminal half-life did not differ between fasted and fed states (33.3 vs. 34.8 h; p=0.16), implying that these differences occurred due to altered bioavailability rather than modified clearance.
For LCPT, no chronopharmacokinetic effects were observed, whereas food significantly reduced the 24-h exposure and the peak blood concentration.