Chronopharmacokinetics and Food Effects of Single-Dose LCP-Tacrolimus in Healthy Volunteers

Abstract

Background: A modified-release version of tacrolimus, LCP-tacrolimus (LCPT; Envarsus XR, Veloxis Pharmaceuticals, Cary, NC), 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. Methods: 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 hours after administration of a single LCPT dose. Results: No significant differences were observed between evening and morning dosing in peak blood concentration (4.4 versus 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 versus 102.6 ng/mL; P = 0.20), AUC from time 0 to infinity (99.7 versus 114.3 ng·h/mL; P = 0.18), AUC from 0 to 24 hours post-dose (AUC0–24; 49.4 versus 51.6 ng·h/mL; P = 0.56), time to reach maximum blood concentration (median, 6.0 versus 6.0 hours; P = 0.91), total clearance (arithmetic mean = 21.5 versus 19.5 L/h; P = 0.50), or terminal half-life (arithmetic mean = 26.8 versus 28.1 hours; 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 versus 34.8 hours; P = 0.16), implying that these differences occurred because of altered bioavailability rather than modified clearance. Conclusions: For LCPT, no chronopharmacokinetic effects were observed, whereas food significantly reduced the 24-h exposure and the peak blood concentration.

Tacrolimus Area Under the Concentration Versus Time Curve Monitoring, Using Home-Based Volumetric Absorptive Capillary Microsampling

“…Tacrolimus circadian variation is a controversial, as some publications suggest reported variation is only a result of study design and the time interval between food and tacrolimus dosing (242,256). In Paper II we observed circadian variation of tacrolimus pharmacokinetic in the fasting state, with a slower absorption rate and lower systemic exposure after the evening dose.…”

“…In the real-life non-fasting setting, circadian variation was not present, and the pharmacokinetic profiles both after morning and evening administration produced relatively flat pharmacokinetic profiles. and C max (242). This proves that also for other tacrolimus formulations, real-life behavior of the patients is important to account for when monitoring tacrolimus to optimize the dosing and especially if aiming towards an AUC-target.…”

Differential Effect of a Continental Breakfast on Tacrolimus Formulations With Different Release Characteristics

“…The effect of our continental breakfast on PR-Tac exposure was considerably less than the AUC reduction to 45% as reported after a high-fat meal. 5 C max and t max were affected only after IR-Tac. Thus, if tacrolimus is administered with food (which would be off-label for IR-Tac in some countries and for PR-Tac), intrapatient variability is expected to be smaller with PR-Tac.…”

“…3,4 Nevertheless, administration after a high-fat meal leads to substantially reduced tacrolimus exposure. 5 The effect of a (presumably more common) continental breakfast is unknown. Presumably, a common practice is drug administration 1 hour before breakfast (a recommended option for IR-Tac), especially in working patients.…”

“…3,4 Nevertheless, administration after a high-fat meal reduced its bioavailability by ≈ 55%. 5 Thus, administration on an empty stomach is recommended in the European Summary of Product Characteristics and on the FDA drug label.…”