Pharmacokinetics of Verinurad and Allopurinol in Combination With Cyclosporine and Rifampicin in Healthy Volunteers

NCT04532918 | Completed Phase 1 Results FDA Drug

• 1 other identifier: D5495C00013
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

This Phase 1 study aims to quantify the effects of cyclosporine, a broad transporter inhibitor, and rifampicin, an OATP1B1/3 inhibitor, on verinurad pharmacokinetics (PK). The study is conducted in accordance with Food and Drug Administration guidance on Clinical Drug Interaction Studies, 2020. Verinurad will be developed as a fixed combination since it will always be administered together with allopurinol.

Conditions

Chronic Kidney Disease

Keywords

Pharmacokinetics; Cyclosporine; Rifampicin; Drug-Drug interaction; Organic anion transporting polypeptide (OATP1B) 1

Outcome Measures

Primary Outcomes (3)

• Geometric Mean Ratio of Maximum Observed Plasma Peak Concentration (Cmax) for Verinurad

  Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad. Verinurad Cmax ratio of geometric mean of test treatment (verinurad+allopurinol with \[cyclosporine or rifampicin\], relative to reference treatment (verinurad+allopurinol alone) in each treatment period.

  Days 1 to 5 (pre-dose and post-dose)

• Geometric Mean Ratio of Area Under Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) for Verinurad

  Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad. Verinurad AUCinf ratio of geometric means of test treatment, relative to reference treatment in each treatment period.

  Days 1 to 5 (pre-dose and post-dose)

• Geometric Mean Ratio of Area Under the Plasma Concentration-time Curve From Zero to Time of Last Quantifiable Concentration (AUClast) for Verinurad

  Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad. Verinurad AUClast ratio of geometric means of test treatment, relative to reference treatment in each treatment period.

  Days 1 to 5 (pre-dose and post-dose)

Secondary Outcomes (18)

• Geometric Mean Ratio of Cmax for Verinurad Metabolites: M1 and M8

  Days 1 to 5 (pre-dose and post-dose)

• Geometric Mean Ratio of AUCinf for Verinurad Metabolites: M1 and M8

  Days 1 to 5 (pre-dose and post-dose)

• Geometric Mean Ratio of AUClast for Verinurad Metabolites: M1 and M8

  Days 1 to 5 (pre-dose and post-dose)

• Geometric Mean Ratio of Cmax for Allopurinol and Oxypurinol

  Days 1 to 5 (pre-dose and post-dose)

• Geometric Mean Ratio of AUCinf for Allopurinol and Oxypurinol

  Days 1 to 5 (pre-dose and post-dose)

Study Arms (3)

Verinurad + allopurinol

EXPERIMENTAL

The subjects will receive single oral dose of verinurad 7.5 mg and allopurinol 300 mg under fasted condition.

Drug: Verinurad; Drug: Allopurinol

Verinurad + allopurinol + cyclosporine

EXPERIMENTAL

The subjects will receive single oral dose of verinurad 7.5 mg, allopurinol 300 mg and cyclosporine 600 mg under fasted condition.

Drug: Verinurad; Drug: Allopurinol; Drug: Cyclosporine

Verinurad + allopurinol + rifampicin

EXPERIMENTAL

The subjects will receive single oral dose of verinurad 7.5 mg, allopurinol 300 mg and rifampicin 600 mg under fasted condition.

Drug: Verinurad; Drug: Allopurinol; Drug: Rifampicin

Interventions

Verinurad DRUG

The subjects will receive single oral dose of extended release capsule verinurad 7.5 mg on Day 1 of each treatment period under fasted condition.

Verinurad + allopurinol; Verinurad + allopurinol + cyclosporine; Verinurad + allopurinol + rifampicin

Allopurinol DRUG

The subjects will receive single oral dose of tablet allopurinol 300 mg on Day 1 of each treatment period under fasted condition.

Verinurad + allopurinol; Verinurad + allopurinol + cyclosporine; Verinurad + allopurinol + rifampicin

Cyclosporine DRUG

The subjects will receive single oral dose of soft capsule cyclosporine 600 mg on Day 1 of treatment period 2 under fasted condition.

Also known as: Sandimmun Optoral

Verinurad + allopurinol + cyclosporine

Rifampicin DRUG

The subjects will receive single oral dose of film coated tablets rifampicin 600 mg on Day 1 of treatment period 3 under fasted condition.

Also known as: Eremfat

Verinurad + allopurinol + rifampicin

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent form prior to any study specific procedures.
• Healthy male or female subjects aged 18 - 55 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
• Females must be either (1) Of non-childbearing potential, confirmed at Screening by fulfilling one of the following criteria (i) Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and Follicle-stimulating hormone (FSH) levels in the post-menopausal range (FSH \>40 IU/mL).
• (ii) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
• Male subjects must adhere to the contraception methods.
• Have a body mass index between 18 and 30 kg/m2 (inclusive) and weigh at least 50 kg and no more than 100 kg (inclusive).
• Must be able to swallow multiple capsules/tablets.

You may not qualify if:

• 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.
• Subject has a positive test result for severe acute respiratory syndrome coronavirus 2 before dosing in Treatment Period 1.
• Has clinical signs and symptoms consistent with coronavirus disease 2019 (COVID-19) infection, eg fever, dry cough, dyspnea, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission.
• History of severe COVID-19 (extracorporeal membrane oxygenation, mechanically ventilated).
• 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 significant illness, medical/surgical procedure, or trauma within 4 weeks prior to the first administration of verinurad.
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, at Screening (Visit 1) and on first admission (Day -1 in Treatment Period 1) as judged by the Investigator, including:
• Alanine aminotransferase \>1.5 × Upper limit of normal (ULN) Aspartate aminotransferase \>1.5 × ULN Bilirubin (total) \>1.5 × ULN Gamma glutamyl transpeptidase \>1.5 × ULN If any of these tests are out of range, the test can be repeated once at the Screening Visit at the discretion of the Investigator.
• Any clinically significant abnormal findings in vital signs at Screening Visit and/or on admission (Day -1 in Treatment Period 1) to the Clinical Unit, including, but not limited to, any of the following:
• Systolic blood pressure \<90 mmHg or \>140 mmHg and/or diastolic blood pressure \<50 mmHg or \>90 mmHg sustained for more than 10 minutes while resting in a supine position
• Heart rate (resting, supine) \<50 or \>90 bpm
• Any clinically significant abnormalities on 12-lead electrocardiogram at Screening Visit, as judged by the Investigator, including, but not limited to any of the following:
• QTcF \> 450 ms or \< 340 ms or family history of long QT syndrome,
• Any significant arrhythmia,
• Conduction abnormalities,

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Berlin, 14050, Germany

Location

Related Links

• CSP and SAP redacted

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Interventions

verinurad; Allopurinol; Cyclosporine; Rifampin

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca Clinical Study Information Center

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Thomas Kӧrnicke, MD

  Parexel Early Phase Clinical Unit Berlin

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Fixed-sequence

Study Record Dates

• First Submitted: August 4, 2020
• First Posted: August 31, 2020
• Study Start: September 10, 2020
• Primary Completion: November 23, 2020
• Study Completion: November 23, 2020
• Last Updated: March 27, 2023
• Results First Posted: March 27, 2023

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will share
• 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 de-identified 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.

Locations

DE (1)