Study to Assess the Effect of Sodium Zirconium Cyclosilicate on the Pharmacokinetics of Tacrolimus and Cyclosporin in Healthy Subjects

Study Overview
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Brief Summary
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This study will be an open-label, randomised sequence, 2-period, 2-cohort, 2-treatment in each cohort, cross-over study in healthy subjects (males and females of non-childbearing potential), performed at a single study centre.

Detailed Description
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The study will comprise: A screening period of maximum 28 days; Two treatment periods: Treatment Period 1 starts with admission to the Clinical Unit on Day -1, followed by dosing on Day 1 with the assigned treatment (A, B, C, or D) as per assigned cohort and treatment sequence, followed by a washout period of at least 14 days. Treatment Period 2 starts with admission to Clinical Unit on Day -1, followed by dosing on Day 1 with cross-over treatment as per assigned cohort, followed by a follow-up period of 7 to 10 days. A follow-up visit/early termination visit at 7 to 10 days after the last investigation medicinal product (IMP) administration. Subjects will be assigned to either Cohort 1 (tacrolimus) or to Cohort 2 (cyclosporin). Each cohort will have 2 treatment periods. Subjects in each cohort will be randomly assigned to one of 2 treatment sequences (AB|BA or CD|DC) where, Treatment A: Tacrolimus Treatment B: Tacrolimus + SZC Treatment C: Cyclosporin Treatment D: Cyclosporin + SZC

Official Title
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A Two-Cohort, Randomised Sequence, Cross-over, Open-label Study to Assess the Effect of a Single Dose of Sodium Zirconium Cyclosilicate (SZC) on the Pharmacokinetics of Tacrolimus and Cyclosporin in Healthy Subjects

Conditions
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Hyperkalaemia

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Cyclosporin
* Drug: Sodium Zirconium Cyclosilicate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Healthy male and female subjects aged 18 to 50 years (both inclusive) Exclusion Criteria: History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study. History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. Any clinically important abnormalities in rhythm, conduction or morphology of the 12-lead safety electrocardiogram (ECG), at screening visit and/or admission to the Clinical Unit. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to SZC, tacrolimus, or cyclosporin. Subjects who have previously received SZC.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects in Cohort 1 will be randomised in a 1:1 ratio to receive one of the 2 treatment sequences and then cross-over to the other: tacrolimus alone (treatment A) followed by the combination treatment of tacrolimus and SZC (treatment B) or vice versa. | Drug: Tacrolimus<br>* Each subject in this cohort will receive a single dose of oral capsules of tacrolimus on 2 occasions, once alone and once in combination with oral suspension of SZC. Drug administrations will occur after a 12 hour overnight fast.<br>Drug: Sodium Zirconium Cyclosilicate<br>* Each subject will receive single oral doses of SZC with tacrolimus (cohort 1) or cyclosporin (cohort 2) under fasted conditions. The doses will be administered after an overnight fast of at least 12 hours.<br>|
| Experimental: Cohort 2<br>Subjects in Cohort 2 will be randomised in a 1:1 ratio to receive one of the 2 treatment sequences and then cross-over to the other: cyclosporin alone (treatment C) followed by the combination treatment of cyclosporin and SZC (treatment D) or vice versa. | Drug: Cyclosporin<br>* Each subject will receive a single dose of oral capsules of cyclosporin on 2 occasions, once alone and once in combination with oral suspension of SZC. Drug administrations will occur after a 12 hour overnight fast.<br>Drug: Sodium Zirconium Cyclosilicate<br>* Each subject will receive single oral doses of SZC with tacrolimus (cohort 1) or cyclosporin (cohort 2) under fasted conditions. The doses will be administered after an overnight fast of at least 12 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) | Effect of co-administered SZC on the Cmax of tacrolimus and cyclosporin in healthy subjects will be determined. | Treatment Periods 1 and 2: Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours post-dose | 
| Area under concentration-time curve from time zero to infinity (AUCinf) | Effect of co-administered SZC on the AUCinf of tacrolimus and cyclosporin in healthy subjects will be determined. | Treatment Periods 1 and 2: Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve from time zero to time of last quantifiable concentration (AUClast) | Effect of co-administered SZC on the AUClast of tacrolimus and cyclosporin in healthy subjects will be determined. | Treatment Periods 1 and 2: Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours post-dose | 
| Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) | Effect of co-administered SZC on the t½λz of tacrolimus and cyclosporin in healthy subjects will be determined. | Treatment Periods 1 and 2: Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours post-dose | 
| Time to reach maximum observed concentration following drug administration (tmax) | Effect of co-administered SZC on the tmax of tacrolimus and cyclosporin in healthy subjects will be determined. | Treatment Periods 1 and 2: Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours post-dose | 
| Number of subjects with adverse events (AEs) and serious AEs | Safety and tolerability of co-administration of SZC and tacrolimus/cyclosporin as compared to tacrolimus/cyclosporin alone will be assessed. | From screening (Days -28 to -2) to Follow-up/Early Termination Visit (7-10 days after last IMP administration) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Sodium Zirconium Cyclosilicate, Tacrolimus, Cyclosporin, Drug-drug interaction study