A Phase 1, open-label, crossover study evaluating the effect of a single dose of sodium zirconium cyclosilicate on the pharmacokinetics of tacrolimus and cyclosporin.

Abstract

Sodium zirconium cyclosilicate (SZC) is an oral, highly selective potassium binder approved for the treatment of hyperkalaemia in adults. SZC may change the absorption of co-administered drugs that exhibit pH-dependent bioavailability. This study evaluated whether the pharmacokinetic (PK) profiles of tacrolimus and cyclosporin were altered by concomitant SZC administration in healthy participants. This was an open-label, randomised sequence, two-cohort crossover, single-centre study. Healthy adults were assigned to one of two cohorts: Cohort 1 (tacrolimus) received a single dose of tacrolimus 5mg and tacrolimus 5mg+SZC 15g in a random order; Cohort 2 (cyclosporin) received a single dose of cyclosporin 100mg and cyclosporin 100mg+SZC 15g in a random order. Primary PK endpoints were maximum observed blood concentration (Cmax) and area under the concentration-time curve (AUC) from time zero to infinity (AUCinf). Differences in mean Cmax and AUCinf were analysed using a mixed effects model. Thirty participants in Cohort 1 and 29 in Cohort 2 completed the study. Tacrolimus exposure was lower with tacrolimus+SZC versus tacrolimus alone: Cmax geometric mean ratio (GMR) 71.10% [90% confidence interval (CI) 65.44-77.24], AUCinf 62.91% (55.64-71.13). Cyclosporin exposure was similar with cyclosporin+SZC compared with cyclosporin alone: Cmax GMR 102.9% (90% CI 96.11-110.10), AUCinf 97.23% (92.93-101.70). Tacrolimus exposure was lower when co-administered with SZC 15g and should be administered ≥2h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.