A single‐center, open‐label, randomized cross‐over study to evaluate the pharmacokinetics and bioavailability of once‐daily prolonged‐release formulations of tacrolimus in de novo liver transplant recipients

• Published in: Immunity, Inflammation and Disease Vol. 9; no. 4; pp. 1771 - 1780
• Main Authors: Herden, Uta, Sterneck, Martina, Buchholz, Bettina M., Achilles, Eike G., Ott, Armin, Fischer, Lutz
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-12-2021; John Wiley and Sons Inc; Wiley
• Subjects: Adult; Bioavailability; Biological Availability; Clinical medicine; Cross-Over Studies; Drug Administration Schedule; Drug dosages; Humans; Immunosuppressive Agents; Liver Transplantation; Liver transplants; Mass spectrometry; Metabolism; Original; Patients; Pharmacokinetics; prolonged‐release formulations; Scientific imaging; Tacrolimus; Therapeutic drug monitoring; Variance analysis; Germany; pharmacokinetics; prolonged-release formulations; tacrolimus; liver transplantation
• ISSN: 2050-4527; 2050-4527
• DOI: 10.1002/iid3.537

Background
The narrow therapeutic window of tacrolimus (Tac) requires intense drug monitoring to achieve adequate efficacy while minimizing dose‐related toxicities. Once‐daily formulations of Tac (LCP‐Tac and PR‐Tac) have been recently designed for higher bioavailability and a more consistent exposure over time, as opposed to the twice‐daily, administered immediate‐release formulation of Tac (IR‐Tac).
Methods
This single‐center, open‐label, randomized cross‐over pharmacokinetic (PK) study compares extended‐release LCP‐Tac with the prolonged‐release formulation of tacrolimus (PR‐Tac) in adult de novo liver transplant recipients. Eligible patients were screened and randomized 1:1 to the two treatment arms up to 30 days after liver transplantation. Patients were administered either LCP‐Tac or PR‐Tac for 14 days followed by another 14‐day time interval of the other once‐daily Tac medication. A 24hr‐PK profile was obtained at the end of each time interval.
Results
Nine patients (45%) completed the study resulting in a total of 18 Tac PK profiles. Overall, the profile of the mean concentrations indicated a flattened kinetic of LCP‐Tac compared to PR‐Tac, especially in the first 3 h after drug intake. The average cumulative dose per day to achieve equivalent trough levels was approximately 25% lower for LCP‐Tac (8.7 mg) than for PR‐Tac (11.7 mg). LCP‐Tac resulted in a longer tmax and fewer peak‐to‐trough fluctuations compared to PR‐Tac.
Conclusion
Despite methodological weaknesses that limit the conclusions, we have found a more consistent drug exposure for LCP‐Tac in de novo LT recipients. LCP‐Tac demonstrated a greater bioavailability compared to PR‐Tac.
This is a single‐center, open‐label, randomized cross‐over pharmacokinetic (PK) study, designed to compare LCP‐Tac with the established once‐daily prolonged‐release formulation of tacrolimus (PR‐Tac) in adult de novo liver transplant recipients. As a result, we have more consistent drug exposure for Envarsus® and, in particular, a lower medication requirement to achieve equivalent trough levels.