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

Mats Någård; Nurul Choudhury; Ayman Al-Shurbaji; Vera Lisovskaja; Neil Mackillop

doi:10.1093/ckj/sfac205

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

Clin Kidney J. 2022 Sep 13;16(1):151-158. doi: 10.1093/ckj/sfac205. eCollection 2023 Jan.

Authors

Mats Någård¹, Nurul Choudhury², Ayman Al-Shurbaji³, Vera Lisovskaja⁴, Neil Mackillop⁵

Affiliations

¹ Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, Research and Development, AstraZeneca, Gaithersburg, MD, USA.
² Department of Patient Safety, Research and Development, AstraZeneca, Gothenburg, Sweden.
³ BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden.
⁴ Department of Biostatistics, Research and Development, AstraZeneca, Gothenburg, Sweden.
⁵ Late Clinical Development, Cardiovascular, Renal and Metabolism, AstraZeneca, Cambridge, UK.

Abstract

Background: 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.

Methods: 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 5 mg and tacrolimus 5 mg + SZC 15 g in a random order; Cohort 2 (cyclosporin) received a single dose of cyclosporin 100 mg and cyclosporin 100 mg + SZC 15 g in a random order. Primary PK endpoints were maximum observed blood concentration (C_max) and area under the concentration-time curve (AUC) from time zero to infinity (AUC_inf). Differences in mean C_max and AUC_inf were analysed using a mixed effects model.

Results: Thirty participants in Cohort 1 and 29 in Cohort 2 completed the study. Tacrolimus exposure was lower with tacrolimus + SZC versus tacrolimus alone: C_max geometric mean ratio (GMR) 71.10% [90% confidence interval (CI) 65.44-77.24], AUC_inf 62.91% (55.64-71.13). Cyclosporin exposure was similar with cyclosporin + SZC compared with cyclosporin alone: C_max GMR 102.9% (90% CI 96.11-110.10), AUC_inf 97.23% (92.93-101.70).

Conclusions: Tacrolimus exposure was lower when co-administered with SZC 15 g and should be administered ≥2 h before or after SZC. The PK profile of cyclosporin was not affected by SZC co-administration.

Keywords: cyclosporin; pharmacokinetics; sodium zirconium cyclosilicate; tacrolimus.