Pharmacokinetics of Verinurad and Allopurinol in Combination With Cyclosporine and Rifampicin in Healthy Volunteers
Condition: Chronic Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic
Intervention: Verinurad; Allopurinol; Cyclosporine; Rifampicin
Intervention 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.; The subjects will receive single oral dose of tablet allopurinol 300 mg on Day 1 of each treatment period under fasted condition.; The subjects will receive single oral dose of soft capsule cyclosporine 600 mg on Day 1 of treatment period 2 under fasted condition.; The subjects will receive single oral dose of film coated tablets rifampicin 600 mg on Day 1 of treatment period 3 under fasted condition.
Intervention MeSH terms: Cyclosporine; Rifampin; Allopurinol; Verinurad; Cyclosporins
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Intervention model description: Fixed-sequence
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Pharmacokinetics; Cyclosporine; Rifampicin; Drug-Drug interaction; Organic anion transporting polypeptide (OATP1B) 1

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.
    

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.