Hidden Interaction: Dulaglutide Significantly Alters Immunosuppressant Pharmacokinetics After Kidney Transplantation

Introduction: Glucagon-like peptide-1 receptor agonists (GLP1RA) are recommended as the first-line therapy for diabetes also after kidney transplantation (KT). It is crucial to characterise the impact of these agents on the pharmacokinetics (PK) of tacrolimus (TAC) and mycophenolate mofetil and given its narrow therapeutic window, the large interpatient variability, its interaction with other drugs and its impact on allograft outcomes. This prospective cohort study was designed to evaluate changes in TAC/MMF exposure in kidney transplant recipients who were initially treated with dulaglutide and then discontinued the treatment.
Methods: This is a prospective PK study evaluating changes in TAC (LCP-TAC) and MMF exposure in KT recipients when combined with dulaglutide and after its discontinuation. Intensive PK sampling was performed twice: once during treatment (area under the curve: AUC1) and again one month after dulaglutide discontinuation (AUC2). Blood samples were collected from patients at pre-dose and at 0.5, 1, 1.5, 2, 4, 6, 8 and 12 hours after taking the immunosuppressant. Differences between PK parameters were analysed and normalised by dose.
Results: Fourteen KT recipients were included. Most of them were male (64.3%), with a mean age of 59.1 ± 3.8 years. Despite dulaglutide use not affecting TAC PK in terms of Tmax, its use was associated with significantly lower Cmin, Cmax and AUC0–24h compared with exposure after dulaglutide discontinuation (54.02 ng·h/mL ± 8.16 vs 82.15 ± 9.76, p<0.001) (Table 1). Regarding MMF, GLP1RA use produced a modification to the typical AUC0-12 morphology, showing modified absorption with a delayed Tmax of 3.54h ± 0.66 vs. 1.19h ± 0.27 (p < 0.001), as well as significantly lower Cmax and AUC0–12h compared with exposure after dulaglutide discontinuation (0.044 ng·h/mL ± 0.004 vs. 0.79 ± 0.01, p<0.05) (Table 1).

Conclusions: The PK profile of MMF/TAC shows lower AUC when dulaglutide is used in KT recipients. Caution must be taken when initiating GLP1RA in transplant recipients, with an increase in the dose of immunosuppressants being necessary in order to avoid allograft rejection.