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.