Circadian and time-dependent variability in tacrolimus pharmacokinetics

Area of Science:

• Pharmacology
• Transplantation Medicine
• Clinical Pharmacy

Background:

• Tacrolimus (TAC) is a critical-dose immunosuppressant vital for kidney transplant recipients.
• Understanding TAC pharmacokinetics (PK) is crucial for maintaining therapeutic efficacy and minimizing toxicity.
• Circadian rhythms and time-dependent changes can significantly influence drug absorption and metabolism.

Purpose of the Study:

• To investigate circadian and time-dependent alterations in tacrolimus pharmacokinetics within the first year post-kidney transplantation.
• To assess the impact of dosing time (a.m. vs. p.m.) on TAC absorption and exposure.
• To evaluate the evolution of TAC PK parameters over 12 months and their inter- and intra-individual variability.

Main Methods:

• Pharmacokinetic studies in 26 kidney transplant recipients at day 7 post-transplant, with morning and evening TAC doses.
• Serial PK sampling over 12 hours post-administration.
• Additional PK assessments at 6 and 12 months post-transplant in a subset of patients.
• Analysis of dose-normalized AUC, Cmax, and Tmax, alongside intra- and inter-individual variability.

Main Results:

• Tacrolimus administration in the evening (p.m.) resulted in higher Cmax and AUC, and lower Tmax compared to morning (a.m.) doses, indicating circadian variation.
• Dose-normalized TAC exposure (AUC, Cmax) increased significantly from day 7 to 6 months post-transplant, suggesting improved absorption over time.
• High intra-individual variability in TAC exposure was observed throughout the first year, yet good correlations between a.m. and p.m. trough levels (C0) and AUC were maintained.

Conclusions:

• Tacrolimus pharmacokinetics exhibit circadian rhythmicity, with delayed and slower absorption during nighttime dosing.
• Absorption of tacrolimus improves within the first six months after kidney transplantation.
• Despite circadian variations, trough-level monitoring of tacrolimus remains a reliable strategy for optimizing immunosuppression in kidney transplant recipients.