Clinical trial NCT05768360: A Study to Assess the Effects of Savolitinib on the Pharmacokinetics of Digoxin, Rosuvastatin, Metformin, and Furosemide in Healthy Male Subjects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Male Subjects
Keywords: Drug-Drug Interaction
Substrate of human drug transporters
Fixed-sequence
Drug cocktail
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2023-03-14
Enrollment: 6
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.

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.

Primary outcomes:
measure: Plasma Area Under Concentration-time Curve from zero to infinity (AUCinf) of the drug cocktail components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Plasma Area under the concentration-curve from zero to the last quantifiable concentration (AUClast) of the drug cocktail components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Plasma partial area under the concentration-time curve from time 0 to time t post-dose (AUC(0-t)) of the drug cocktail components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Maximum observed plasma drug concentration (Cmax) of drug cocktail components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: The ratio of plasma AUCinf (R AUCinf) of the drug cocktail components in the presence and absence of savolitinib
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: The ratio of plasma AUC(0-t) (R AUC(0-t)) of the drug cocktail components in the presence and absence of savolitinib
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: The ratio of plasma Cmax (R Cmax) of drug cocktail components in the presence and absence of savolitinib
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Secondary outcomes:
measure: Number of participants with adverse events
timeFrame: Day 1 in Periods 1 (Week 1) and 2 (Week 4) to Day 7 (follow-up after last Pharmacokinetic (PK) sample)
measure: Area under plasma concentration-time curve from zero to infinity (AUCinf) of savolitinib and its metabolites (M2 and M3)
timeFrame: Day 1 and Day 2 in Period 2 (Week 4)
measure: Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUCinflast) of savolitinib and its metabolites (M2 and M3)
timeFrame: Day 1 and Day 2 in Period 2 (Week 4)
measure: 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)
timeFrame: Day 1 and Day 2 in Period 2 (Week 4)
measure: Maximum observed plasma (peak) drug concentration (Cmax) of savolitinib and its metabolites (M2 and M3) of savolitinib and its metabolites (M2 and M3)
timeFrame: Day 1 and Day 2 in Period 2 (Week 4)
measure: Observed lowest concentration before the next dose is administered (Ctrough) of savolitinib and its metabolites (M2 and M3)
timeFrame: Day 1 and Day 2 in Period 2 (Week 4)
measure: Terminal elimination half-life (t½λz) of savolitinib and its metabolites (M2 and M3)
timeFrame: Day 1 and Day 2 in Period 2 (Week 4)
measure: Time to reach maximum observed concentration (tmax) of savolitinib and its metabolites (M2 and M3)
timeFrame: Day 1 and Day 2 in Period 2 (Week 4)
measure: Apparent volume of distribution based on the terminal phase (Vz/F) of savolitinib and its metabolites (M2 and M3)
timeFrame: Day 1 and Day 2 in Period 2 (Week 4)
measure: Apparent total body clearance (CL/F) of savolitinib and its metabolites (M2 and M3)
timeFrame: Day 1 and Day 2 in Period 2 (Week 4)
measure: Maximum observed plasma (peak) drug concentration (Cmax) of cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Time to reach maximum observed plasma concentration (Tmax) of the cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Plasma terminal elimination half-life (t½λz) of cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Plasma terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) of cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Plasma Apparent total body clearance (CL/F) of cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Plasma Apparent volume of distribution based on the terminal phase (Vz/F) of cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Renal clearance (CLR) of cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Cumulative amount of unchanged drug excreted into urine (Ae) of cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Cumulative amount of unchanged drug excreted into the urine from time 0 to time t (Ae(0-t)) of cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Percentage of dose excreted unchanged in urine from time 0 to t (fe(0-t)) of cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
measure: Cumulative amount of unchanged drug excreted into urine (CumAe) of the cocktail parent components
timeFrame: Day 1 to Day 5 in Periods 1 (Week 1) and 2 (Week 4)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Research Site
Study officials:
References: