A Study to Assess the Effects of Savolitinib on the Pharmacokinetics of Digoxin, Rosuvastatin, Metformin, and Furosemide in Healthy Male Subjects

NCT ID: NCT05768360

Last Updated: 2023-07-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-04-25
• Study Completion Date: 2023-06-24

Brief Summary

This study will assess the effects of savolitinib on the pharmacokinetics (PK) of substrates of human transporters digoxin (P-gp), rosuvastatin (OATP1B1/3), metformin (OCT2, MATE1/2K), and furosemide (OAT1/3) in healthy male subjects, performed at a single clinical unit.

Detailed Description

This study will be performed at a single clinical unit.

Subjects will be admitted to the clinical unit on Day -1 of Period 1 and Period 2. Subjects will have a washout period of 14 days between Period 1 and Period 2.

Period 1: Subjects will recieve a single dose of a drug cocktail of 4 medications (digoxin Dose B, furosemide Dose C, metformin hydrochloride Dose D, and rosuvastatin Dose E).

Period 2: Participants will receive savolitinib (Dose A) in combination with the drug cocktail of 4 medications as received in Period 1.

The study will consist of 4 visits:

Visit 1 (Enrollment): Following full written informed consent, subjects will be screened for eligibility.

Visit 2 (Period 1: Treatment and Sample Collection Period): Each subject will be admitted to the clinical unit on Day -1 of Period 1, single dose of drug cocktail is administered on Day 1, and remain in clinical unit until Day 5 assessments. A washout period of 14 days is followed.

Visit 3 (Period 2: Treatment and Sample Collection Period): Each subject will be admitted to the clinical unit on Day -1 of Period 2, single dose of savolitinib and drug cocktail is administered, and remain in clinical unit until Day 5 assessments.

Visit 4 (Follow-up): Subjects will attend the clinical unit for a final Follow-up Visit 5 to 7 days post Day 5 in Period 2.

Each subject will be involved in the study for 9 weeks including screening to final follow up.

Conditions

Healthy Male Subjects

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Drug cocktail/Savolitinib + Drug cocktail

Subjects will receive two different interventions in two periods (Periods 1 and 2). In Period 1, the subjects will receive a single-dose of Drug cocktail components (digoxin Dose B, furosemide Dose C, metformin hydrochloride Dose D, and rosuvastatin Dose E). During Period 2, the subjects will receive savolitinib dose A in combination with the Drug cocktail components.

Group Type: EXPERIMENTAL

Savolitinib

Intervention Type: DRUG

The subjects will receive single dose of oral film-coated tablet of Savolitinib A dose on Day 1 of Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Digoxin

Intervention Type: DRUG

The subjects will receive single dose of oral uncoated tablet of Digoxin Dose B on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Metformin Hydrochloride

Intervention Type: DRUG

The subjects will receive single dose of oral film-coated tablet of Metformin Hydrochloride Dose D on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Rosuvastatin

Intervention Type: DRUG

The subjects will receive single dose of oral film-coated tablet of Rosuvastatin Dose E on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Furosemide

Intervention Type: DRUG

The subjects will receive single dose of oral solution of Furosemide Dose C on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Interventions

Savolitinib

The subjects will receive single dose of oral film-coated tablet of Savolitinib A dose on Day 1 of Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Intervention Type: DRUG

Digoxin

The subjects will receive single dose of oral uncoated tablet of Digoxin Dose B on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Intervention Type: DRUG

Metformin Hydrochloride

The subjects will receive single dose of oral film-coated tablet of Metformin Hydrochloride Dose D on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Intervention Type: DRUG

Rosuvastatin

The subjects will receive single dose of oral film-coated tablet of Rosuvastatin Dose E on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Intervention Type: DRUG

Furosemide

The subjects will receive single dose of oral solution of Furosemide Dose C on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Male subjects must use barrier contraception (condoms) during sexual intercourse with a female partner of childbearing potential during the study and for 6 months after the last dose of the IMPs investigational medical products (IMPs).

2. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.

3. Regular bowel movements (ie, on average production of at least 1 stool per day).

Exclusion Criteria

1. History of any clinically significant disease or disorder

2. History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.

3. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results.

4. Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) at screening and/or first admission to the clinical unit, as judged by the investigator.

5. QTcF >450 ms or QT ≥500 ms or other ECG abnormality making interpretation more difficult, as judged by the investigator, or a history of additional risk factors for Torsades de Points (eg heart failure, hypokalemia, family history of long QT syndrome), which in the opinion of the investigator may put the subject at risk.

6. Any positive result on screening for serum hepatitis B surface antigen OR anti-HBc antibody, indicative of active hepatitis B (ie, subjects with positive anti-HBc antibody result are acceptable if anti HBc IgM antibodies are negative), hepatitis C antibody, and HIV antibody.

7. History of latent or chronic infections (eg, tuberculosis, recurrent sinusitis, genital herpes, urinary tract infections) or at risk of infection.

8. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months (12 weeks) or within 5 half-lives of the drug, whichever is longer, of Visit 2 (Day -1 of Period 1) in this study or participation in a method development study (no drug) 1 month prior to Visit 2. The period of exclusion ends 3 months after the final dose or after 5 elimination half-lives of the drug or 1 month after the last visit, whichever is the longer.

9. 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 savolitinib, or drug cocktail medications or their excipients.

10. Subject has clinical signs and symptoms consistent with Coronavirus disease (COVID-19), 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 unless confirmed by a negative severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test (SARS-CoV-2 PCR test).

11. Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

12. Positive screen for drugs of abuse or cotinine at screening or on each admission to the clinical unit or positive screen for alcohol on each admission to the clinical unit.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Parexel

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Research Site

Berlin, , Germany

Countries

Germany

Other Identifiers

2022-003785-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D5084C00014

Identifier Type: -

Identifier Source: org_study_id