A Study to Evaluate the Drug-drug Interactions (DDIs) of DBPR108 With Warfarin Sodium, Digoxin, Probenecid in Healthy Subjects

Healthy Subjects Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05045313
• Other study ID #: HA1118-CSP-012
• Status: Completed
• Phase: Phase 1
• Start date: October 20, 2021
• Est. completion date: December 1, 2021

Study information

• Verified date: August 2021
• Source: CSPC ZhongQi Pharmaceutical Technology Co., Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: December 1, 2021
• Est. primary completion date: December 1, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• Healthy Subjects

Intervention

Drug:
• Warfarin sodium tablets
Drug: Warfarin sodium, tablet, oral
• Digoxin tablet
Drug: Digoxin, tablet, oral
• Probenecid tablets
Drug: Probenecid, tablet, oral
• DBPR108 tablets
Drug: DBPR108, tablet, oral

Locations

Country	Name	City	State
China	First Affiliated Hospital of Soochow University	Suzhou

Sponsors (1)

Lead Sponsor	Collaborator
CSPC ZhongQi Pharmaceutical Technology Co., Ltd.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part one: Peak plasma concentration (Cmax) of S-warfarin and R-warfarin		Day 1 to Day 8, and Day 19 to Day 26
Primary	Part one: Area under the plasma concentration versus time curve (AUC) of S-warfarin and R-warfarin		Day 1 to Day 8, and Day 19 to Day 26
Primary	Part one: Peak plasma concentration (Cmax) of DBPR108		Day 17 to Day 20
Primary	Part one: Area under the plasma concentration versus time curve (AUC) of DBPR108		Day 17 to Day 20
Primary	Part two: Peak plasma concentration (Cmax) of Digoxin		Day 1 to Day 6, and Day 10 to Day 15
Primary	Part two: Area under the plasma concentration versus time curve (AUC) of Digoxin		Day 1 to Day 6, and Day 10 to Day 15
Primary	Part two: Peak plasma concentration (Cmax) of DBPR108		Day 8 to Day 11
Primary	Part two: Area under the plasma concentration versus time curve (AUC) of DBPR108		Day 8 to Day 11
Primary	Part three: Peak plasma concentration (Cmax) of DBPR108		Day 1 to Day 3, and Day 7 to Day 9
Primary	Part three: Area under the plasma concentration versus time curve (AUC) of DBPR108		Day 1 to Day 3, and Day 7 to Day 9
Secondary	Part one: Time to achieve maximum plasma concentration (Tmax) of S-warfarin and R-warfarin		Day 1 to Day 8, and Day 19 to Day 26
Secondary	Part one: Half-life(t1/2) of S-warfarin and R-warfarin		Day 1 to Day 8, and Day 19 to Day 26
Secondary	Part one: Apparent volume of Distribution(Vz/F) of S-warfarin and R-warfarin		Day 1 to Day 8, and Day 19 to Day 26
Secondary	Part one: Apparent clearance(CL/F) of S-warfarin and R-warfarin		Day 1 to Day 8, and Day 19 to Day 26
Secondary	Part one: Time to achieve maximum plasma concentration (Tmax) of DBPR108		Day 17 to Day 20
Secondary	Part one: Half-life(t1/2) of DBPR108		Day 17 to Day 20
Secondary	Part one: Apparent volume of Distribution(Vz/F) of DBPR108		Day 17 to Day 20
Secondary	Part one: Apparent clearance(CL/F) of DBPR108		Day 17 to Day 20
Secondary	Part one: the pharmacodynamic parameters-Prothrombin time(PT)		Day 1 to Day 8, and Day 19 to Day 26
Secondary	Part one: the pharmacodynamic parameters-International normalized ratio(INR)		Day 1 to Day 8, and Day 19 to Day 26
Secondary	Part two: Time to achieve maximum plasma concentration (Tmax) of Digoxin		Day 1 to Day 6, and Day 10 to Day 15
Secondary	Part two: Half-life(t1/2) of Digoxin		Day 1 to Day 6, and Day 10 to Day 15
Secondary	Part two: Apparent volume of Distribution(Vz/F) of Digoxin		Day 1 to Day 6, and Day 10 to Day 15
Secondary	Part two: Apparent clearance(CL/F) of Digoxin		Day 1 to Day 6, and Day 10 to Day 15
Secondary	Part two: Time to achieve maximum plasma concentration (Tmax) of DBPR108		Day 8 to Day 11
Secondary	Part two: Half-life(t1/2) of DBPR108		Day 8 to Day 11
Secondary	Part two: Apparent volume of Distribution(Vz/F) of DBPR108		Day 8 to Day 11
Secondary	Part two: Apparent clearance(CL/F) of DBPR108		Day 8 to Day 11
Secondary	Part three: Time to achieve maximum plasma concentration (Tmax) of DBPR108		Day 1 to Day 3, and Day 7 to Day 9
Secondary	Part three: Half-life(t1/2) of DBPR108		Day 1 to Day 3, and Day 7 to Day 9
Secondary	Part three: Apparent volume of Distribution(Vz/F) of DBPR108		Day 1 to Day 3, and Day 7 to Day 9
Secondary	Part three: Apparent clearance(CL/F) of DBPR108		Day 1 to Day 3, and Day 7 to Day 9
Secondary	Part three:Cumulative amount of drug excreted in urine(Ae) of DBPR108		Day 1 to Day 3, and Day 7 to Day 9
Secondary	Part three: Cumulative fraction of the dose excreted(fe) of DBPR108		Day 1 to Day 3, and Day 7 to Day 9
Secondary	Part three: Renal Clearance(CLR) of DBPR108		Day 1 to Day 3, and Day 7 to Day 9
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	Number of participants with treatment-related adverse events will be assessed by CTCAE v5.0. The AEs will be summarized according to the system organ class (SOC) and preferred term (PT), including the number and percentage of participants who had AEs.	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.
Secondary	Clinically significant changes from baseline in 12-lead electrocardiogram (ECG) examination will be recorded as AEs at each visit time point.	ECG monitoring includes heart rate in bpm.	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.
Secondary	Clinically significant changes from baseline in 12-lead electrocardiogram (ECG) examination will be recorded as AEs at each visit time point.	ECG monitoring includes P-R, QT and QTc intervals in ms.	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.
Secondary	Clinically significant changes from baseline in physical examination will be recorded as AEs at each visit time point.	Physical examination includes general conditions, skin, mucous membranes, head, neck, chest, abdomen, spine, limbs, nervous system, and lymphatic system.	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.
Secondary	Clinically significant changes from baseline in vital signs examination will be recorded as AEs at each visit time point.	Vital signs monitoring includes body temperature in degrees Celsius.	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.
Secondary	Clinically significant changes from baseline in vital signs examination will be recorded as AEs at each visit time point.	Vital signs monitoring includes respiratory rate and pulse in times per minute.	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.
Secondary	Clinically significant changes from baseline in vital signs examination will be recorded as AEs at each visit time point.	Vital signs monitoring includes systolic blood pressure and diastolic blood pressure in mmHg.	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.
Secondary	Clinically significant changes from baseline in routine blood test will be recorded as AEs at each visit time point.	Routine blood test includes red blood cell count in 10^12/L.	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.
Secondary	Clinically significant changes from baseline in routine blood test will be recorded as AEs at each visit time point.	Routine blood test includes hemoglobin in g/L.	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.
Secondary	Clinically significant changes from baseline in routine blood test will be recorded as AEs at each visit time point.	Routine blood test includes hematocrit in L/L.	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.
Secondary	Clinically significant changes from baseline in routine blood test will be recorded as AEs at each visit time point.	Routine blood test includes white blood cell count, platelet, neutrophilic granulocyte count, lymphocyte count and monocyte count in 10^9 /L.	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.
Secondary	Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.	Blood biochemistry test includes total protein and albumin in g/L.	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.
Secondary	Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.	Blood biochemistry test includes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and glutamyltranspeptidase in U/L.	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.
Secondary	Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.	Blood biochemistry test includes total bilirubin and serum creatinine in umol/L.	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.
Secondary	Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.	Blood biochemistry test includes urea in mmol/L.	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.
Secondary	Clinically significant changes from baseline in routine urine test will be recorded as AEs at each visit time point.	Routine urine test includes urobilinogen, glucose and protein in mg/dL.	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.
Secondary	Clinically significant changes from baseline in routine urine test will be recorded as AEs at each visit time point.	Routine urine test includes pH.	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.
Secondary	Clinically significant changes from baseline in coagulation function test will be recorded as AEs at each visit time point.	Coagulation action test includes fibrinogen in g/L.	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.
Secondary	Clinically significant changes from baseline in coagulation function test will be recorded as AEs at each visit time point.	Coagulation action test includes prothrombin time, thrombin time and activated partial thromboplatin time in seconds.	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.
Secondary	Clinically significant changes from baseline in coagulation function test will be recorded as AEs at each visit time point.	Coagulation action test includes international normalized ratio.	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.