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

An Open-label, 3-Treatment, 3-Period, Fixed Sequence Study in Healthy Subjects to Assess the Pharmacokinetics of Verinurad and Allopurinol When Administered Alone, and in Combination With Single Doses of Cyclosporine or Rifampicin

Sponsors

Lead Sponsor: AstraZeneca

Collaborator: Parexel

Source AstraZeneca
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.

Detailed Description

This Phase 1 study will be an open-label, 3-period, 3-treatment, fixed-sequence study in healthy subjects (males and females of non-childbearing potential), performed at a single Clinical Unit. The study will comprise of the following periods (visits): - A Screening Period (Visit 1); - A fixed sequence of 3 Treatment Periods during which subjects will be resident at the Clinical Unit from one day prior to administration of verinurad+allopurinol (Day -1) of Treatment Period 1 until the morning of Day 5 of the Treatment Period 2, and similarly for Treatment Period 3. There will be a washout period between Treatment Periods 2 and 3 dosing. The 3 Treatment Periods, include the washout period (Visits 2 to 3); - A Follow-up Visit, after the last administration of verinurad+allopurinol (Visit 4).

Overall Status Active, not recruiting
Start Date September 10, 2020
Completion Date November 13, 2020
Primary Completion Date November 13, 2020
Phase Phase 1
Study Type Interventional
Primary Outcome
Measure Time Frame
Geometric mean ratio of maximum observed plasma peak concentration (Cmax) for verinurad Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of area under plasma concentration-time curve from time zero to infinity (AUCinf) for verinurad Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of area under the plasma concentration-time curve from zero to time of last quantifiable concentration (AUClast) for verinurad Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Secondary Outcome
Measure Time Frame
Geometric mean ratio of Cmax for verinurad metabolite: M1 Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of Cmax for verinurad metabolite: M8 Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of AUCinf for verinurad metabolite: M1 Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of AUCinf for verinurad metabolite: M8 Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of AUClast for verinurad metabolite: M1 Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of AUClast for verinurad metabolite: M8 Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of Cmax for allopurinol Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of AUCinf for allopurinol Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of AUClast for allopurinol Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of Cmax for oxypurinol Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of AUCinf for oxypurinol Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Geometric mean ratio of AUClast for oxypurinol Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Cmax Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
AUCinf Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
AUClast Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Area under the concentration-time curve from time zero to 24 hours post-dose [AUC(0-24)] Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Time to reach peak or maximum observed concentration following drug (tmax) Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Terminal elimination rate constant (λz) Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Apparent total body clearance of drug from plasma after extravascular administration (CL/F) Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Mean Residence Time of the unchanged drug in the systemic circulation (MRTinf) Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Volume of distribution (apparent) at steady state following extravascular administration (Vss/F) Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Metabolite:Parent (MP) ratio of Cmax Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
MP ratio of AUCinf Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
MP ratio of AUClast Days 1 to 5: 30 minutes pre-dose and up to 96 hours post-dose
Number of subjects with abnormal blood pressure (BP) For approximately 9 weeks (from screening to follow-up)
Number of subjects with abnormal pulse rate For approximately 9 weeks (from screening to follow-up)
Number of subjects with abnormal temperature For approximately 9 weeks (from screening to follow-up)
Number of subjects with abnormal 12-lead electrocardiogram (ECG) At screening and post-treatment follow-up visit (7-14 day after last dose of verinurad)
Number of subjects with abnormal physical examination For approximately 9 weeks (from screening to follow-up)
Number of subjects with abnormal hematology parameters At screening, Day -1, Day 3 (Treatment Periods 1, 2 and 3) and post-treatment follow-up (7-14 days after last dose of verinurad)
Number of subjects with abnormal clinical chemistry parameters At screening, Day -1 (Treatment Periods 1 and 3), Day 1, Day 2 and Day 3 (Treament Period 1), and post-treatment follow-up (7-14 days after last dose of verinurad)
Number of subjects with abnormal urinalysis parameters At screening, Day -1 (Treatment Periods 1 and 3), Day 1, Day 2 and Day 3 (Treament Period 1), and post-treatment follow-up (7-14 days after last dose of verinurad)
Number of subjects with adverse events (AEs) and serious AEs For approximately 9 weeks (from screening to follow-up)
Enrollment 14
Condition
Intervention

Intervention Type: Drug

Intervention Name: Verinurad

Description: 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.

Intervention Type: Drug

Intervention Name: Allopurinol

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

Intervention Type: Drug

Intervention Name: Cyclosporine

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

Arm Group Label: Verinurad + allopurinol + cyclosporine

Other Name: Sandimmun Optoral

Intervention Type: Drug

Intervention Name: Rifampicin

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

Arm Group Label: Verinurad + allopurinol + rifampicin

Other Name: Eremfat

Eligibility

Criteria:

Inclusion Criteria: - 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. 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. - 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: 1. 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 2. 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: 1. QTcF > 450 ms or < 340 ms or family history of long QT syndrome, 2. Any significant arrhythmia, 3. Conduction abnormalities, 4. Clinically significant PR(PQ) interval prolongation (> 240 ms); intermittent second or third degree atrioventricular (AV) block, or AV dissociation, 5. Complete bundle branch block and/or QRS duration > 120 ms. - Any positive result at Screening Visit for serum hepatitis B surface antigen or anti-hepatitis B core antibody, hepatitis C antibody, and human immunodeficiency virus antibody. - Suspicion or known Gilbert's and/or Lesch-Nyhan syndrome - History of hypersensitivity to drugs with a similar chemical structure or class to verinurad, allopurinol, cyclosporine or rifampicin or excipients. - Subjects who wear soft contact lenses (due to possible staining from rifampicin), unless the subject is prepared to refrain from wearing soft lenses throughout Treatment Period 3 until after the last PK sample collection. - Women of childbearing potential. - Carrier of the Human leukocyte antigen B*58:01 allele. - Has received another new chemical or biological entity (defined as a compound which has not been approved for marketing in the US or EU) within 30 days or within 5 half-lives (whichever is longer) of the first administration of verinurad in this study. - Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening. - 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 Novel uric acid transporter 1 transporter inhibitor & xanthine oxidase inhibitor. - Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening. - Positive screen for drugs of abuse, cotinine or alcohol at Screening or on each admission to the Clinical Unit. - Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of verinurad. - Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life. - Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the Investigator. Excessive intake of alcohol defined as the regular consumption of more than 24 g of alcohol per day for men or 12 g of alcohol per day for women. - Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as judged by the Investigator. Excessive intake of caffeine defined as the regular consumption of more than 600 mg of caffeine per day or would likely be unable to refrain from the use of caffeine-containing beverages during in-house stay at the investigational site. - Involvement of any AstraZeneca, Parexel or Clinical Unit employee or their close relatives. - Judgment by the Investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements. - Subjects who are vegans or have medical dietary restrictions. - Subjects who cannot communicate reliably with the Investigator and/or are not able to read, speak and understand the German language. - Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Gender: All

Minimum Age: 18 Years

Maximum Age: 55 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Thomas Kӧrnicke, MD Principal Investigator Parexel Early Phase Clinical Unit Berlin
Location
Facility: Research Site
Location Countries

Germany

Verification Date

October 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Label: Verinurad + allopurinol

Type: Experimental

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

Label: Verinurad + allopurinol + cyclosporine

Type: Experimental

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

Label: Verinurad + allopurinol + rifampicin

Type: Experimental

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

Patient Data Yes
Study Design Info

Allocation: Non-Randomized

Intervention Model: Crossover Assignment

Intervention Model Description: Fixed-sequence

Primary Purpose: Other

Masking: None (Open Label)

Source: ClinicalTrials.gov