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

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

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.

Study Overview

• Status: Completed
• Conditions: Hyperkalaemia
• Intervention / Treatment: Drug: Tacrolimus; Drug: Sodium Zirconium Cyclosilicate; Drug: Cyclosporin

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 Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 46 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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: 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.; 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.

What is the study measuring?

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 participants was determined.	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 of tacrolimus or cyclosporin
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 participants was determined.	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 of tacrolimus or cyclosporin

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 participants was determined.	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 of tacrolimus or cyclosporin
Time to Reach Maximum Observed Concentration Following Drug Administration (Tmax)	Effect of co-administered SZC on the tmax of tacrolimus and cyclosporin in healthy participants was determined.	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 of tacrolimus or cyclosporin
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 participants was determined.	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 of tacrolimus or cyclosporin
Number of Participants With Adverse Events (AEs) and Serious AEs	Safety and tolerability of co-administration of SZC and tacrolimus/cyclosporin as compared to tacrolimus/cyclosporin alone was assessed.	From the time of IMP administration (Day 1) to Follow-up/Early Termination Visit (7-10 days after last IMP administration) [up to 4 weeks]

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel
• Investigators: Principal Investigator: Thomas Koernicke, Dr, Parexel Early Phase Clinical Unit Berlin

Publications and helpful links

Helpful Links

• Protocol
• CSR Synopsis

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2021
• Primary Completion (Actual): September 16, 2021
• Study Completion (Actual): September 16, 2021

Study Registration Dates

• First Submitted: March 5, 2021
• First Submitted That Met QC Criteria: March 5, 2021
• First Posted (Actual): March 9, 2021

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Tacrolimus; Drug-drug interaction study; Cyclosporin; Sodium Zirconium Cyclosilicate
• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyperkalemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Tacrolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: D9480C00012; 2020-000515-68 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing 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.
• IPD Sharing 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No