A Clinical Study to Evaluate the Pharmacokinetics of Microdose Midazolam, Dabigatran, Pitavastatin, Atorvastatin and Rosuvastatin in Healthy Volunteers and Renal Impairment Patients

NCT ID: NCT05747768

Last Updated: 2023-02-28

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-07-15
• Study Completion Date: 2024-12-31

Brief Summary

1. To explore the functional changes of P-gp, CYP3A4, OATP1B and BCRP in Chinese people with renal impairment;

2. To explore the effect of dialysis on the functional changes of P-gp, CYP3A4, OATP1B and BCRP in patients with end-stage renal disease;

3. Validation of urotoxic molecules as possible biomarkers that can assess intestinal P-gp function.

Conditions

Chronic Kidney Disease

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Healthy Volunteers

Healthy volunteer received drug combinations（10 µg midazolam, 375 µg dabigatran etexilate, 10 µg pitavastatin, 50 µg rosuvastatin, and 100 µg atorvastatin） on an empty stomach

Group Type: EXPERIMENTAL

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin

Intervention Type: DRUG

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin were provided by the Department of Pharmacy, Peking University Third Hospital, and were dissolved and mixed with normal saline respectively, and the mixing process needed to be fully stirred. Then, according to the concentration of the drug mixed solution, the corresponding volume of mixed solution was given to achieve the dosage of 10 μg midazolam, 375 μg dabigatran etexilate, 10 μg pitavastatin, 50 μg rosuvastatin and 100 μg atorvastatin. In order to avoid the food effect, the test drugs were administered on an empty stomach on the administration day in this experiment.

Patients with mild-to-moderate renal impairment

Patients with mild-to-moderate renal impairment received drug combinations（10 µg midazolam, 375 µg dabigatran etexilate, 10 µg pitavastatin, 50 µg rosuvastatin, and 100 µg atorvastatin） on an empty stomach

Group Type: EXPERIMENTAL

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin

Intervention Type: DRUG

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin were provided by the Department of Pharmacy, Peking University Third Hospital, and were dissolved and mixed with normal saline respectively, and the mixing process needed to be fully stirred. Then, according to the concentration of the drug mixed solution, the corresponding volume of mixed solution was given to achieve the dosage of 10 μg midazolam, 375 μg dabigatran etexilate, 10 μg pitavastatin, 50 μg rosuvastatin and 100 μg atorvastatin. In order to avoid the food effect, the test drugs were administered on an empty stomach on the administration day in this experiment.

Patients with moderate to severe renal impairment

Patients with moderate to severe renal impairment received drug combinations（10 µg midazolam, 375 µg dabigatran etexilate, 10 µg pitavastatin, 50 µg rosuvastatin, and 100 µg atorvastatin） on an empty stomach

Group Type: EXPERIMENTAL

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin

Intervention Type: DRUG

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin were provided by the Department of Pharmacy, Peking University Third Hospital, and were dissolved and mixed with normal saline respectively, and the mixing process needed to be fully stirred. Then, according to the concentration of the drug mixed solution, the corresponding volume of mixed solution was given to achieve the dosage of 10 μg midazolam, 375 μg dabigatran etexilate, 10 μg pitavastatin, 50 μg rosuvastatin and 100 μg atorvastatin. In order to avoid the food effect, the test drugs were administered on an empty stomach on the administration day in this experiment.

Patients with severe renal impairment

Patients with severe renal impairment received drug combinations（10 µg midazolam, 375 µg dabigatran etexilate, 10 µg pitavastatin, 50 µg rosuvastatin, and 100 µg atorvastatin） on an empty stomach

Group Type: EXPERIMENTAL

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin

Intervention Type: DRUG

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin were provided by the Department of Pharmacy, Peking University Third Hospital, and were dissolved and mixed with normal saline respectively, and the mixing process needed to be fully stirred. Then, according to the concentration of the drug mixed solution, the corresponding volume of mixed solution was given to achieve the dosage of 10 μg midazolam, 375 μg dabigatran etexilate, 10 μg pitavastatin, 50 μg rosuvastatin and 100 μg atorvastatin. In order to avoid the food effect, the test drugs were administered on an empty stomach on the administration day in this experiment.

Patients with end-stage renal disease

Patients with end-stage renal disease received drug combinations（10 µg midazolam, 375 µg dabigatran etexilate, 10 µg pitavastatin, 50 µg rosuvastatin, and 100 µg atorvastatin） on an empty stomach

Group Type: EXPERIMENTAL

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin

Intervention Type: DRUG

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin were provided by the Department of Pharmacy, Peking University Third Hospital, and were dissolved and mixed with normal saline respectively, and the mixing process needed to be fully stirred. Then, according to the concentration of the drug mixed solution, the corresponding volume of mixed solution was given to achieve the dosage of 10 μg midazolam, 375 μg dabigatran etexilate, 10 μg pitavastatin, 50 μg rosuvastatin and 100 μg atorvastatin. In order to avoid the food effect, the test drugs were administered on an empty stomach on the administration day in this experiment.

Interventions

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin

Midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin were provided by the Department of Pharmacy, Peking University Third Hospital, and were dissolved and mixed with normal saline respectively, and the mixing process needed to be fully stirred. Then, according to the concentration of the drug mixed solution, the corresponding volume of mixed solution was given to achieve the dosage of 10 μg midazolam, 375 μg dabigatran etexilate, 10 μg pitavastatin, 50 μg rosuvastatin and 100 μg atorvastatin. In order to avoid the food effect, the test drugs were administered on an empty stomach on the administration day in this experiment.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

All participants:

1. male or female , Chinese (individuals have Chinese descent) subjects, Age between 18-65 (include) with the ability of cognizance;

2. body mass index (BMI) of 18.5 to 24 kg/m2 for all participants ; body weight for male >50 kg; a total body weight for female >45 kg;

3. female must be non-pregnant, non-breast feeding and if she is reproductive potential: must agree to use (and/have their partner use) effective methods of birth control beginning at screening ,throughout the study and until 6 months after last dosing of study drug;

4. is a non-smoker or moderate smoker (≤20 cigarettes/day or the equivalent);

5. signed the Inform Consent Form , fully understood the trial conduction and comply with the requirement of the research;

Participants with mild to moderate , moderate to severe , severe renal impairment or end stage renal disease:

1. has a clinical diagnosis of renal impairment and meets the protocol-specified renal impairment function qualifications at screening;

2. with the classification of KDIGO (Kidney Disease Improving Global Outcomes ), the mild to moderate renal impairment patients have eGFR between 45 to 90(include) mL/min/1.73m2 based on MDRD (Modification of Diet in Renal Disease Study) equation, without dialysis before;

3. with the classification of KDIGO (Kidney Disease Improving Global Outcomes ), the moderate to severe renal impairment patients have eGFR between 30 to 44(include) mL/min/1.73m2 based on MDRD(Modification of Diet in Renal Disease Study) equation, without dialysis before;

4. with the classification of KDIGO (Kidney Disease Improving Global Outcomes ), The moderate to severe renal impairment patients have eGFR between 15 to 29(include) mL/min/1.73m2 based on MDRD(Modification of Diet in Renal Disease Study) equation, without dialysis before;

5. with the classification of KDIGO (Kidney Disease Improving Global Outcomes ), The end stage renal disease patients have eGFR below 15 (include) mL/min/1.73m2 based on MDRD(Modification of Diet in Renal Disease Study) equation, with dialysis therapy;

6. participants with mild to moderate , moderate to severe , severe renal impairment or end stage renal disease: With stable renal function lasted for three months before first oral dose ; the shrinkage of eGFR be within 30%;

Healthy participants ,besides:

1. has baseline eGFR ≥ 90 mL/min based on MDRD (Modification of Diet in Renal Disease Study) equation;

2. is judged to be in good health based on medical history, physical examination, vital signs and laboratory safety tests, without clinically significant laboratory abnormalities.

Exclusion Criteria

1. is mentally or legally incapacitated at the time of the screening visit or expected during the conduct of the study;

2. history of stroke, chronic seizures, or major neurological disorders;

3. history of malignant neoplastic disease;

4. history or presence of alcoholism or drug abuse within the past 6 months;

5. history of hypersensitive reaction or allergic to study drug (including midazolam, dabigatran Etexilate, pitavastatin, atorvastatin, rosuvastatin), only if with researchers permission;

6. blood donation within the past 4 weeks or lost more than 500 mL blood before screening;

7. apheresis within the past 8 weeks before screening;

8. take weak/moderate inhibiters or inducers of CYP3A/BCRP/OATP1B/P-gp within 14 days before screening, including but not limited to: clarithromycin, boceprevir, cobicistatdanoprevir, grapefruit juice, indinavir, ketoconazole, telaprevir, paritaprevir, Telithromycin, troleandomycin, voriconazole, nafazodone, Idelalisib, nelfinavir, fluconazole, aprepitant, ciprofloxacin, conivaptan , crizotinib, cyclosporin A, diltiazem, fluvoxamine, imatinib, tofisopam, atazanavir, erythromycingemfibrozilsimepreviramiodarone, carvedilol, itraconazole, lapatinib, lopinavir, ritonavir, propafenone, quinidine, ranolazine, saquinavir, telaprevir, verapamil, tipranavir, curcumin, Eltrombopag, phenytoin, rifampicin, apalutamide, carbamazepine, St. John's Wort, mitotan, enzalutamide, bosentan, efavirenz, primidone, phenobarbital;

9. intolerance of venous blood collection;

10. history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, immunological, respiratory, or genitourinary abnormalities or diseases, include cancer, traumatic brain injury, persistent viral infection, rheumatoid arthritis, inflammatory bowel disease, NAFLD, Liver cirrhosis, HIV, Hyperthyreosis, Cushing syndrome, Parkinson or has a history of Parkinson in his family;

11. history of myocardial infarction, cerebral stroke, cerebral infarction within 3 months;

12. history of gastrointestinal diseases: irritable bowel syndrome, enteric bacterial overgrowth syndrome, gastroesophageal reflux disease, Gallstones, coeliac disease, Crohn disease, Ulcerative Colitis, active peptic ulcers;

13. subjects who test positive at screening for human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B surface antigen (HbsAg), and syphilis;

1. history of renal transplant or nephrectomy;

2. presence of uncontrolled type 2 diabetes mellitus (T2DM), a history of type 1 diabetes or ketoacidosis;

3. participants with rapid fluctuation of renal function according to previous laboratory examination; or have been diagnosed of renal stenosis. The definition of rapid fluctuation of renal function refers to the fluctuation of eGFR greater than 30% within 3 months after the examination. If no historical measurements are available, two examinations will be used to demonstrate stability: fluctuation of eGFR less than 30% between two consecutive examinations within 3 months before screening;

1.presence of hypoglycemia, glucose intolerance,uncontrolled type 2 diabetes mellitus (T2DM) or ketoacidosis.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Peking University Third Hospital

OTHER

Sponsor Role: lead

Responsible Party

Dongyang Liu

Researcher

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Peking University Third Hospital

Beijing, , China

Site Status: RECRUITING

Countries

China

Central Contacts

Dongyang Liu

Role: CONTACT

Phone: (86)010-82266658

Email: liudongyang@vip.sina.com

Hao Liang

Role: CONTACT

Phone: 13426217031

Email: lianghao86@126.com

Facility Contacts

Dongyang Liu

Role: primary

Other Identifiers

DCTC-IIR202229

Identifier Type: -

Identifier Source: org_study_id