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.
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).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
14
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.
Research Site
Berlin, Germany
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.
Time frame: 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.
Time frame: 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.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Geometric Mean Ratio of Cmax for Verinurad Metabolites: M1 and M8
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad metabolites M1 and M8. Cmax ratio of geometric means of test treatment, relative to reference treatment in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Geometric Mean Ratio of AUCinf for Verinurad Metabolites: M1 and M8
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad metabolites M1 and M8. AUCinf ratio of geometric means of test treatment, relative to reference treatment in each treatment period.
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The subjects will receive single oral dose of film coated tablets rifampicin 600 mg on Day 1 of treatment period 3 under fasted condition.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Geometric Mean Ratio of AUClast for Verinurad Metabolites: M1 and M8
Evaluation of a single dose of cyclosporine or rifampicin on the PK of verinurad metabolites M1 and M8. AUClast ratio of geometric means of test treatment, relative to reference treatment in each treatment period is reported.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Geometric Mean Ratio of Cmax for Allopurinol and Oxypurinol
Evaluation of a single dose of cyclosporine or rifampicin on the PK of allopurinol and oxypurinol. Cmax ratio of geometric means of test geometric means of test treatment, relative to reference treatment in each treatment period is reported.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Geometric Mean Ratio of AUCinf for Allopurinol and Oxypurinol
Evaluation of a single dose of cyclosporine or rifampicin on the PK of allopurinol and oxypurinol. AUCinf ratio of geometric means of test geometric means of test treatment, relative to reference treatment in each treatment period is reported.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Geometric Mean Ratio of AUClast for Allopurinol and Oxypurinol
Evaluation of a single dose of cyclosporine or rifampicin on the PK of allopurinol and oxypurinol. AUClast ratio of geometric means of test geometric means of test treatment, relative to reference treatment in each treatment period is reported.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Area Under Plasma Concentration-time Curve From Zero to 24 Hours Post-dose AUC(0-24) of Verinurad, M1, M8, Allopurinol and Oxypurinol
AUC(0-24) of verinurad, M1, M8, allopurinol and oxypurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Time to Reach Peak or Maximum Plasma Concentration (Tmax) for Verinurad, M1, M8, Allopurinol and Oxypurinol
tmax of verinurad, M1, M8, allopurinol and oxypurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration Time Curve (t½λz) of Verinurad, M1, M8, Allopurinol and Oxypurinol
t½λz of verinurad, M1, M8, allopurinol and oxypurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Terminal Elimination Rate Constant (λz) of Verinurad, M1, M8, Allopurinol and Oxypurinol
λz of verinurad, M1, M8, allopurinol and oxypurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (CL/F) for Verinurad and Allopurinol
CL/F for verinurad and allopurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Mean Residence Time of the Unchanged Drug in the Systemic Circulation (MRTinf) for Verinurad and Allopurinol
MRTinf for verinurad and allopurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Vss/F) of Verinurad and Allopurinol
Vss/F of verinurad and allopurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Volume of Distribution (Apparent) at Steady State Following Extravascular Administration (Based on the Terminal Phase) (Vz/F) of Verinurad and Allopurinol
Vz/F of verinurad and allopurinol when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Metabolite:Parent (MP) Cmax Ratios for M1 and M8: Verinurad
Metabolite:parent (MP) Cmax ratios for M1 and M8: verinurad when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Metabolite:Parent (MP) AUCinf Ratios for M1 and M8: Verinurad
Metabolite:parent (MP) AUCinf ratios for M1 and M8: verinurad when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Metabolite:Parent (MP) AUClast Ratios for M1 and M8: Verinurad
Metabolite:parent (MP) AUClast ratios for M1 and M8: verinurad when verinurad+allopurinol administered alone or in combination with cyclosporine or rifampicin in each treatment period.
Time frame: Days 1 to 5 (pre-dose and post-dose)
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
Assessment the safety and tolerability of verinurad and allopurinol in combination with cyclosporine or rifampicin
Time frame: From screening (Day -28 to -2) until Follow-up or Early Termination (7-14 days after last verinurad dose)