Clinical trial NCT05045313: A Study to Evaluate the Drug-drug Interactions (DDIs) of DBPR108 With Warfarin Sodium, Digoxin, Probenecid in Healthy Subjects
Official title: A Three-part, Single-center, Open-label, Phase I Clinical Study to Evaluate the Drug-drug Interactions (DDIs) Between DBPR108 and Warfarin Sodium/Digoxin/Probenecid in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Lead sponsor: CSPC ZhongQi Pharmaceutical Technology Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2021-09-16
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a three-part, single-center, open-label phase I clinical study to characterize the DDIs potential of DBPR108 with Warfarin sodium, Digoxin, or Probenecid in healthy subjects. This study also aims to evaluate the safety and tolerability of DBPR108 in the presence of Warfarin sodium, Digoxin, or Probenecid.

Detailed description: DBPR108 is a potent dipeptidylpeptidase-4 inhibitor. This study will be run in three parts to characterize the DDIs potential of DBPR108 with the expected concomitant drugs (Warfarin sodium, Digoxin, Probenecid) in Healthy Subjects. Each part of this study consists of a screening period (Day -14 to Day -1), a baseline period (Day -1), a treatment period, and a follow-up visit period. Approximately 14 subjects will be enrolled in each part of this study.

Eligibility criteria: Inclusion Criteria:

1. Voluntarily sign the informed consent form, understand the trial procedures, and be willing to comply with all trial procedures and restrictions;
2. 18 to 45 years (inclusive), male and female;
3. Male subjects weight ≥50.0 kg and female subjects weight ≥45.0 kg. Body mass index (BMI): 18-28 kg/m\^2 (inclusive) (BMI= weight (kg)/height\^2 (m\^2)；
4. Subjects (including their partners) are willing to use effective contraceptives from screening to the 6 months after the last dose administration;
5. Subjects judged to be in good health by the investigator, based on the physical examination, vital signs examination, 12-lead electrocardiogram (ECG) examination and laboratory examination etc;

Exclusion Criteria:

1. Subjects who have a history of allergic conditions (such as asthma, urticaria), or have a history of allergy to any of the study drugs or other similarly structured drugs;
2. Subjects with a history of severe diseases, such as cardiovascular, respiratory, liver, gastrointestinal, endocrine, hematological, psychiatric/neurological systems diseases within 1 year prior to screening;
3. Subjects with a history of hypoglycemia or abnormal blood glucose at screening: fasting blood glucose \<70 mg/dL (3.9 mmol/L) or \>110 mg/dL (6.1 mmol/L);
4. Subjects who have previously undergone surgery that may affect the absorption, distribution, metabolism, or excretion of the drug (e.g., subtotal gastrectomy), or who have a scheduled surgical plan during the study period;
5. Use of any prescription drug, over-the-counter drug, or herbal medicine within 2 weeks prior to screening;
6. Have been vaccinated within 4 weeks prior to screening or who have a scheduled vaccinated plan during the study period;
7. History of drug abuse, or positive urine drug screen at screening;
8. Smoking more than 5 cigarettes per day within 3 months prior to screening，or who cannot stop using any tobacco products during the study period；
9. Average daily intake of alcohol is more than 28 g alcohol (male) or 14 g (female) (14 g ≈ 497 mL beer, or 44 mL spirits with low alcohol content, or 145 mL wine) within the 3 months prior to screening, or taking any product containing alcohol within 48 h before dosing, or a positive ethanol breath test at screening;
10. Consumption of grapefruit juice, methylxanthine-rich food or beverage (such as coffee, tea, cola, chocolate, energy drinks) within 48 h before the administration, or those who have had strenuous exercise, or have other factors affecting drug absorption, distribution, metabolism, excretion, etc;
11. Participation in another clinical trial within 3 months before screening (whichever is administrated)；
12. Blood donation (or blood loss) ≥400 mL, or receiving whole blood transfusions or erythrocyte suspension transfusions within 3 months prior to the screening;
13. Any positive test result of hepatitis B surface antigen, hepatitis C virus antibody, anti-human immunodeficiency virus antibody or anti-Treponema pallidum specific antibody;
14. Pregnant/lactating woman, or has a positive pregnancy test at screening;
15. Not suitable for this study as judged by the investigator;
16. Supplementary exclusion criteria for the first part of the study: subjects with bleeding tendency, or PT and INR test results judged by the investigator to be not suitable for participating in the study;
17. Supplementary exclusion criteria for the third part of the study: the estimated glomerular filtration rate (eGFR) calculated by the modification of diet in renal diseases (MDRD) equation at screening with clinical significance as judged by the investigator, or subjects with nephrolithiasis or have a history of nephrolithiasis.

Primary outcomes:
measure: Part one: Peak plasma concentration (Cmax) of S-warfarin and R-warfarin
timeFrame: Day 1 to Day 8, and Day 19 to Day 26
measure: Part one: Area under the plasma concentration versus time curve (AUC) of S-warfarin and R-warfarin
timeFrame: Day 1 to Day 8, and Day 19 to Day 26
measure: Part one: Peak plasma concentration (Cmax) of DBPR108
timeFrame: Day 17 to Day 20
measure: Part one: Area under the plasma concentration versus time curve (AUC) of DBPR108
timeFrame: Day 17 to Day 20
measure: Part two: Peak plasma concentration (Cmax) of Digoxin
timeFrame: Day 1 to Day 6, and Day 10 to Day 15
measure: Part two: Area under the plasma concentration versus time curve (AUC) of Digoxin
timeFrame: Day 1 to Day 6, and Day 10 to Day 15
measure: Part two: Peak plasma concentration (Cmax) of DBPR108
timeFrame: Day 8 to Day 11
measure: Part two: Area under the plasma concentration versus time curve (AUC) of DBPR108
timeFrame: Day 8 to Day 11
measure: Part three: Peak plasma concentration (Cmax) of DBPR108
timeFrame: Day 1 to Day 3, and Day 7 to Day 9
measure: Part three: Area under the plasma concentration versus time curve (AUC) of DBPR108
timeFrame: Day 1 to Day 3, and Day 7 to Day 9
Secondary outcomes:
measure: Part one: Time to achieve maximum plasma concentration (Tmax) of S-warfarin and R-warfarin
timeFrame: Day 1 to Day 8, and Day 19 to Day 26
measure: Part one: Half-life(t1/2) of S-warfarin and R-warfarin
timeFrame: Day 1 to Day 8, and Day 19 to Day 26
measure: Part one: Apparent volume of Distribution(Vz/F) of S-warfarin and R-warfarin
timeFrame: Day 1 to Day 8, and Day 19 to Day 26
measure: Part one: Apparent clearance(CL/F) of S-warfarin and R-warfarin
timeFrame: Day 1 to Day 8, and Day 19 to Day 26
measure: Part one: Time to achieve maximum plasma concentration (Tmax) of DBPR108
timeFrame: Day 17 to Day 20
measure: Part one: Half-life(t1/2) of DBPR108
timeFrame: Day 17 to Day 20
measure: Part one: Apparent volume of Distribution(Vz/F) of DBPR108
timeFrame: Day 17 to Day 20
measure: Part one: Apparent clearance(CL/F) of DBPR108
timeFrame: Day 17 to Day 20
measure: Part one: the pharmacodynamic parameters-Prothrombin time(PT)
timeFrame: Day 1 to Day 8, and Day 19 to Day 26
measure: Part one: the pharmacodynamic parameters-International normalized ratio(INR)
timeFrame: Day 1 to Day 8, and Day 19 to Day 26
measure: Part two: Time to achieve maximum plasma concentration (Tmax) of Digoxin
timeFrame: Day 1 to Day 6, and Day 10 to Day 15
measure: Part two: Half-life(t1/2) of Digoxin
timeFrame: Day 1 to Day 6, and Day 10 to Day 15
measure: Part two: Apparent volume of Distribution(Vz/F) of Digoxin
timeFrame: Day 1 to Day 6, and Day 10 to Day 15
measure: Part two: Apparent clearance(CL/F) of Digoxin
timeFrame: Day 1 to Day 6, and Day 10 to Day 15
measure: Part two: Time to achieve maximum plasma concentration (Tmax) of DBPR108
timeFrame: Day 8 to Day 11
measure: Part two: Half-life(t1/2) of DBPR108
timeFrame: Day 8 to Day 11
measure: Part two: Apparent volume of Distribution(Vz/F) of DBPR108
timeFrame: Day 8 to Day 11
measure: Part two: Apparent clearance(CL/F) of DBPR108
timeFrame: Day 8 to Day 11
measure: Part three: Time to achieve maximum plasma concentration (Tmax) of DBPR108
timeFrame: Day 1 to Day 3, and Day 7 to Day 9
measure: Part three: Half-life(t1/2) of DBPR108
timeFrame: Day 1 to Day 3, and Day 7 to Day 9
measure: Part three: Apparent volume of Distribution(Vz/F) of DBPR108
timeFrame: Day 1 to Day 3, and Day 7 to Day 9
measure: Part three: Apparent clearance(CL/F) of DBPR108
timeFrame: Day 1 to Day 3, and Day 7 to Day 9
measure: Part three:Cumulative amount of drug excreted in urine(Ae) of DBPR108
timeFrame: Day 1 to Day 3, and Day 7 to Day 9
measure: Part three: Cumulative fraction of the dose excreted(fe) of DBPR108
timeFrame: Day 1 to Day 3, and Day 7 to Day 9
measure: Part three: Renal Clearance(CLR) of DBPR108
timeFrame: Day 1 to Day 3, and Day 7 to Day 9
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in 12-lead electrocardiogram (ECG) examination will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in 12-lead electrocardiogram (ECG) examination will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in physical examination will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in vital signs examination will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in vital signs examination will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in vital signs examination will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in routine blood test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in routine blood test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in routine blood test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in routine blood test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in routine urine test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in routine urine test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in coagulation function test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in coagulation function test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
measure: Clinically significant changes from baseline in coagulation function test will be recorded as AEs at each visit time point.
timeFrame: Up to Day 33 from screening for part one, up to Day 22 from screening for part two, and up to Day 16 from screening for part three.
Other outcomes:
Locations:
city: Suzhou
country: China
facility: First Affiliated Hospital of Soochow University
Study officials:
References: