Does Age Influence Immunosuppressant Drug Pharmacokinetics in Kidney Transplant Recipients?

Abstract

Background: The pharmacokinetics of immunosuppressant drugs may change with advancing age, potentially affecting patient outcomes.

Objective: To characterise the effects of age on the pharmacokinetic and exposure parameters of tacrolimus, mycophenolate, and prednisolone.

Methods: Pharmacokinetic profiling, involving whole blood tacrolimus, total and free plasma mycophenolic acid (MPA), total plasma mycophenolic acid glucuronide (MPAG), and total and free plasma prednisolone, was performed in an older and younger adult cohort. Thirteen samples were drawn on a single occasion, pre-oral dose and then at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, and 12 h post-dose. Non-compartmental analysis was conducted using the PKNCA package, and pharmacokinetic and exposure parameters were compared between age groups using a Mann-Whitney test. A regression analysis was conducted for free MPA and MPAG using significant variables of interest.

Results: This exploratory study included 21 older and 18 younger adults. Dose-adjusted tacrolimus, total MPA and free prednisolone pharmacokinetic parameters were not different between age groups; however, for free MPA and MPAG, older recipients had significantly greater minimum and maximum concentrations, trough concentrations, and half-life. There was a two-fold increase in free MPA exposure in older adults (median dose-adjusted AUC_0-12: 1284 vs. 684 μg h/L, p < 0.0001); MPAG exposure similarly increased. Age was significantly associated with free MPA and MPAG exposure, and free MPA exposure was associated with haematocrit (p < 0.05).

Conclusion: Differences in MPA were found with advancing age and may be due to altered kidney function, haematocrit, plasma protein binding and/or drug absorption. Future research should explore specific covariate contributions to this further.