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

• ClinicalTrials.gov Identifier: NCT04788641
• Recruitment Status: Completed
• First Posted: March 9, 2021
• Last Update Posted: May 10, 2022
• Sponsor: AstraZeneca
• Collaborator: Parexel
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hyperkalaemia	Drug: Tacrolimus; Drug: Cyclosporin; Drug: Sodium Zirconium Cyclosilicate	Phase 1

Detailed Description:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 30, 2021
• Actual Primary Completion Date: September 16, 2021
• Actual Study Completion Date: September 16, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; 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; 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.; Drug: Sodium Zirconium Cyclosilicate; 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.
Experimental: Cohort 2; 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; 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.; Drug: Sodium Zirconium Cyclosilicate; 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.

Outcome Measures

Primary Outcome Measures :

1. Maximum observed concentration (Cmax) [ Time Frame: 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 ]
   Effect of co-administered SZC on the Cmax of tacrolimus and cyclosporin in healthy subjects will be determined.
2. Area under concentration-time curve from time zero to infinity (AUCinf) [ Time Frame: 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 ]
   Effect of co-administered SZC on the AUCinf of tacrolimus and cyclosporin in healthy subjects will be determined.

Secondary Outcome Measures :

1. Area under the concentration-time curve from time zero to time of last quantifiable concentration (AUClast) [ Time Frame: 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 ]
   Effect of co-administered SZC on the AUClast of tacrolimus and cyclosporin in healthy subjects will be determined.
2. Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) [ Time Frame: 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 ]
   Effect of co-administered SZC on the t½λz of tacrolimus and cyclosporin in healthy subjects will be determined.
3. Time to reach maximum observed concentration following drug administration (tmax) [ Time Frame: 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 ]
   Effect of co-administered SZC on the tmax of tacrolimus and cyclosporin in healthy subjects will be determined.
4. Number of subjects with adverse events (AEs) and serious AEs [ Time Frame: From screening (Days -28 to -2) to Follow-up/Early Termination Visit (7-10 days after last IMP administration) ]
   Safety and tolerability of co-administration of SZC and tacrolimus/cyclosporin as compared to tacrolimus/cyclosporin alone will be assessed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

Germany

Research Site

Berlin, Germany, 14050

Sponsors and Collaborators

AstraZeneca

Parexel

Investigators

• Principal Investigator: Thomas Koernicke, Dr; Parexel Early Phase Clinical Unit Berlin

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04788641
• Other Study ID Numbers: D9480C00012
• First Posted: March 9, 2021
• Last Update Posted: May 10, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:

Pharmacokinetics; Sodium Zirconium Cyclosilicate; Tacrolimus; Cyclosporin; Drug-drug interaction study

Additional relevant MeSH terms:

Hyperkalemia; Water-Electrolyte Imbalance; Metabolic Diseases; Cyclosporine; Tacrolimus; Cyclosporins; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Antirheumatic Agents