Chronopharmacokinetics and Food Effects of Single-Dose LCP-Tacrolimus in Healthy Volunteers. Issue 5 (19th October 2020)

• Record Type: Journal Article
• Authors: Alloway, Rita R.; Trofe-Clark, Jennifer; Brennan, Daniel C.; Kerr, Janice; Cohen, Elizabeth A.; Meier-Kriesche, Ulf; Stevens, Daniel R.; Moten, Misbah A.; Momper, Jeremiah D.
• Is Part Of: Therapeutic drug monitoring. Volume 42:Issue 5(2020:Oct.)
• Page Start: 679
• Page End: 685
• Publication Date: 2020-10-19
• Subjects: tacrolimus -- chronopharmacokinetic -- dosing -- pharmacokinetics -- transplantation; Pharmacokinetics -- Periodicals; Patient monitoring -- Periodicals; Drugs -- Analysis -- Periodicals; Body fluids -- Analysis -- Periodicals; Drug Therapy -- Periodicals; Monitoring, Physiologic -- Periodicals; Pharmacology -- Periodicals; 615.7
• DOI: 10.1097/FTD.0000000000000773
• Languages: English
• ISSNs: 0163-4356

Abstract

Abstract : Supplemental Digital Content is Available in the Text. 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.