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

NCT05768360 | Completed Phase 1

• 2 other identifiers: D5084C000142022-003785-21
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Male Subjects

Keywords

Drug-Drug Interaction; Substrate of human drug transporters; Fixed-sequence; Drug cocktail

Outcome Measures

Primary Outcomes (7)

• 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)

• 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)

• 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)

• 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)

• 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)

• 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)

• 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 Outcomes (21)

• Number of participants with adverse events

  Day 1 in Periods 1 (Week 1) and 2 (Week 4) to Day 7 (follow-up after last Pharmacokinetic (PK) sample)

• Area under plasma concentration-time curve from zero to infinity (AUCinf) of savolitinib and its metabolites (M2 and M3)

  Day 1 and Day 2 in Period 2 (Week 4)

• Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUCinflast) of savolitinib and its metabolites (M2 and M3)

  Day 1 and Day 2 in Period 2 (Week 4)

• 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)

  Day 1 and Day 2 in Period 2 (Week 4)

• Maximum observed plasma (peak) drug concentration (Cmax) of savolitinib and its metabolites (M2 and M3) of savolitinib and its metabolites (M2 and M3)

  Day 1 and Day 2 in Period 2 (Week 4)

Study Arms (1)

Drug cocktail/Savolitinib + Drug cocktail

EXPERIMENTAL

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.

Drug: Savolitinib; Drug: Digoxin; Drug: Metformin Hydrochloride; Drug: Rosuvastatin; Drug: Furosemide

Interventions

Savolitinib 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.

Drug cocktail/Savolitinib + Drug cocktail

Digoxin 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.

Drug cocktail/Savolitinib + Drug cocktail

Metformin Hydrochloride 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.

Drug cocktail/Savolitinib + Drug cocktail

Rosuvastatin 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.

Drug cocktail/Savolitinib + Drug cocktail

Furosemide 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.

Drug cocktail/Savolitinib + Drug cocktail

Eligibility Criteria

• Age: 18 Years - 55 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• History of any clinically significant disease or disorder
• History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results.
• Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) at screening and/or first admission to the clinical unit, as judged by the investigator.
• 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.
• 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.
• History of latent or chronic infections (eg, tuberculosis, recurrent sinusitis, genital herpes, urinary tract infections) or at risk of infection.
• 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.
• 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).
• Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
• 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.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Berlin, 14050, Germany

Location

MeSH Terms

Interventions

1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; Digoxin; Metformin; Rosuvastatin Calcium; Furosemide

Intervention Hierarchy (Ancestors)

Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates; Biguanides; Guanidines; Amidines; Organic Chemicals; Sulfonamides; Amides; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Sulfanilamides; Aniline Compounds; Amines

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 3, 2023
• First Posted: March 14, 2023
• Study Start: April 25, 2023
• Primary Completion: June 24, 2023
• Study Completion: June 24, 2023
• Last Updated: July 13, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

DE (1)