Concomitant calcium supplementation does not compromise immunosuppressive dosing in kidney transplant recipients

Polypharmacy following kidney transplantation entails a risk of both drug-drug interactions (DDIs) and reduced patient adherence. Co-administration of calcium supplementation and mycophenolate mofetil (MMF) has previously been shown to influence pharmacokinetics (PK) of MMF. In current DDI databases, there is a recommendation for 2- to 3-h time-shifted administration. Whether a similar interaction potentially exists for tacrolimus has not been evaluated. We aimed to investigate the potential PK DDI between co-administrated calcium/vitamin D supplementation and the immunosuppressive drugs MMF and tacrolimus, using volumetric absorptive microsampling (VAMS).

Twenty-five kidney transplant recipients on stable MMF, tacrolimus and prednisolone treatment provided two 12-h PK investigations of simultaneous assessment of both mycophenolic acid (MPA) and tacrolimus concentrations. One PK investigation with and one without concomitant treatment with a calcium/vitamin D supplement. Capillary blood samples using VAMS were utilized to obtain samples in a patient friendly manner. Clinically relevant interactions were assessed by the with/without ratio of AUC_0-12 and C_max in accordance with EMA bioequivalence guidelines.

The MPA AUC_0-12 ratio was 0.94 (90% confidence interval [CI], 0.83-1.07) and the C_max ratio was 0.79 (90% CI, 0.65-0.97). For tacrolimus, the AUC_0-12 and C_max ratios were 1.00 (90% CI, 0.92-1.09) and 0.96 (90% CI, 0.87-1.07), respectively.

In kidney transplant recipients there is no clinically relevant PK DDI caused by concomitant administration of calcium/vitamin D supplementation with MMF and tacrolimus. Based on these observations, recommendation of time-shifted administration of calcium supplements and immunosuppressive drugs seems unnecessary.