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

Healthy Male Subjects Clinical Trial

Official title:

A Phase I, Fixed-sequence, Open-label Study to Assess the Effects of Savolitinib on the Pharmacokinetics of Substrates of Human Transporters Digoxin (P-gp), Rosuvastatin (OATP1B1/3), Metformin (OCT2, MATE1/2K), and Furosemide (OAT1/3) in Healthy Male Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05768360
• Other study ID #: D5084C00014
• Secondary ID: 2022-003785-21
• Status: Completed
• Phase: Phase 1
• Start date: April 25, 2023
• Est. completion date: June 24, 2023

Study information

• Verified date: July 2023
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: June 24, 2023
• Est. primary completion date: June 24, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Healthy Male Subjects

Intervention

Drug:
• 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.
• 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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Germany	Research Site	Berlin

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma Area Under Concentration-time Curve from zero to infinity (AUCinf) of the drug cocktail components	To evaluate AUCinf of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2)	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Primary	Plasma Area under the concentration-curve from zero to the last quantifiable concentration (AUClast) of the drug cocktail components	To evaluate AUClast of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2)	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Primary	Plasma partial area under the concentration-time curve from time 0 to time t post-dose (AUC(0-t)) of the drug cocktail components	To evaluate (AUC(0-t)) of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Primary	Maximum observed plasma drug concentration (Cmax) of drug cocktail components	To evaluate Cmax of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Primary	The ratio of plasma AUCinf (R AUCinf) of the drug cocktail components in the presence and absence of savolitinib	To evaluate AUCinf ratio of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Primary	The ratio of plasma AUC(0-t) (R AUC(0-t)) of the drug cocktail components in the presence and absence of savolitinib	To evaluate AUC(0-t) ratio of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Primary	The ratio of plasma Cmax (R Cmax) of drug cocktail components in the presence and absence of savolitinib	To evaluate Cmax ratio of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Number of participants with adverse events	To assess safety and tolerability of savolitinib following oral dosing.	Day 1 in Periods 1 (Week 1) and 2 (Week 4) to Day 7 (follow-up after last Pharmacokinetic (PK) sample)
Secondary	Area under plasma concentration-time curve from zero to infinity (AUCinf) of savolitinib and its metabolites (M2 and M3)	To assess AUCinf of savolitinib and its metabolites (M2 and M3).	Day 1 and Day 2 in Period 2 (Week 4)
Secondary	Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUCinflast) of savolitinib and its metabolites (M2 and M3)	To assess AUClast of savolitinib and its metabolites (M2 and M3)	Day 1 and Day 2 in Period 2 (Week 4)
Secondary	Partial area under the concentration-time curve from time 0 to time t post-dose (AUC(0-t)) of savolitinib and its metabolites (M2 and M3)	To assess AUC(0-t) of savolitinib and its metabolites (M2 and M3).	Day 1 and Day 2 in Period 2 (Week 4)
Secondary	Maximum observed plasma (peak) drug concentration (Cmax) of savolitinib and its metabolites (M2 and M3) of savolitinib and its metabolites (M2 and M3)	To assess Cmax of savolitinib and its metabolites (M2 and M3).	Day 1 and Day 2 in Period 2 (Week 4)
Secondary	Observed lowest concentration before the next dose is administered (Ctrough) of savolitinib and its metabolites (M2 and M3)	To assess Ctrough of savolitinib and its metabolites (M2 and M3).	Day 1 and Day 2 in Period 2 (Week 4)
Secondary	Terminal elimination half-life (t½?z) of savolitinib and its metabolites (M2 and M3)	To assess t½?z of savolitinib and its metabolites (M2 and M3).	Day 1 and Day 2 in Period 2 (Week 4)
Secondary	Time to reach maximum observed concentration (tmax) of savolitinib and its metabolites (M2 and M3)	To assess tmax of savolitinib and its metabolites (M2 and M3).	Day 1 and Day 2 in Period 2 (Week 4)
Secondary	Apparent volume of distribution based on the terminal phase (Vz/F) of savolitinib and its metabolites (M2 and M3)	To assess Vz/F of savolitinib and its metabolites (M2 and M3).	Day 1 and Day 2 in Period 2 (Week 4)
Secondary	Apparent total body clearance (CL/F) of savolitinib and its metabolites (M2 and M3)	To assess CL/F of savolitinib and its metabolites (M2 and M3).	Day 1 and Day 2 in Period 2 (Week 4)
Secondary	Maximum observed plasma (peak) drug concentration (Cmax) of cocktail parent components	To assess the Cmax of the drug cocktail parent components.	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Time to reach maximum observed plasma concentration (Tmax) of the cocktail parent components	To assess the PK parameter tmax of the drug cocktail parent components	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Plasma terminal elimination half-life (t½?z) of cocktail parent components	To assess the PK parameter t½?z of the drug cocktail parent components.	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Plasma terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (?z) of cocktail parent components	To assess the PK parameter ?z of the drug cocktail parent components.	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Plasma Apparent total body clearance (CL/F) of cocktail parent components	To assess the PK parameter CL/F of the drug cocktail parent components.	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Plasma Apparent volume of distribution based on the terminal phase (Vz/F) of cocktail parent components	To assess the PK parameter Vz/F of the drug cocktail parent components.	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Renal clearance (CLR) of cocktail parent components	To assess the urine PK parameter CLR of the drug cocktail parent components.	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Cumulative amount of unchanged drug excreted into urine (Ae) of cocktail parent components	To assess the urine PK parameter Ae of the drug cocktail parent components.	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Cumulative amount of unchanged drug excreted into the urine from time 0 to time t (Ae(0-t)) of cocktail parent components	To assess Ae(0-t) of the drug cocktail parent components	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Percentage of dose excreted unchanged in urine from time 0 to t (fe(0-t)) of cocktail parent components	To assess fe(0-t) of the drug cocktail parent components.	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary	Cumulative amount of unchanged drug excreted into urine (CumAe) of the cocktail parent components	To assess CumAe of the drug cocktail parent components	Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)