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

Study identifier:D5084C00014

ClinicalTrials.gov identifier:NCT05768360

EudraCT identifier:2022-003785-21

CTIS identifier:N/A

Study Complete

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

Medical condition

Healthy male subjects

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Savolitinib, Digoxin, Metformin Hydrochloride, Rosuvastatin, Furosemide

Sex

Male

Actual Enrollment

Study type

Interventional

Age

18 Years - 55 Years

Date

Study Start Date: 25 Apr 2023

Primary Completion Date: 24 Jun 2023

Study Completion Date: 24 Jun 2023

Study design

Allocation: N/A
Endpoint Classification: -
Intervention Model: Sequential Assignment
Masking: -
Primary Purpose: Other

Verification:

Verified 01 Jan 2025 by AstraZeneca

Collaborators

PAREXEL

Inclusion and exclusion 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.

Location

Research Site

Berlin, Germany, 14050

Arms	Assigned Interventions
Experimental: 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.	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. 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. 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. 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.

Arms

Assigned Interventions

Experimental: 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.

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.

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.

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.

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.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study was conducted from 25 April 2023 (first subject first visit) to 24 June 2023 (last subject last visit) at Parexel Early Phase Clinical Unit in Berlin.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
During the screening period (4 weeks), eligible participants signed the informed consent. All the study assessments were performed as per the schedule of assessment.

Reporting Groups

	Description
Overall	Participants received single dose of only Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 and savolintinb along with the Drug Cocktail in Period 2 of the study

Participant Flow: Overall Study

	Overall
STARTED	23
COMPLETED	23
NOT COMPLETED	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Overall	Participants received single dose of only Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 and savolintinb along with the Drug Cocktail in Period 2 of the study

Baseline Measures

	Overall
Number of Participants [units: Participants]	23
Sex: Female, Male [units: Participants]
Female	0
Male	23
Ethnicity [units: Participants] Not Hispanic or Latino	23
Age Continuous [units: years] Mean ± Standard Deviation	40.5 ± 10.9
Race/Ethnicity, Customized [units: Participants]
White	20
Other	3

Outcome Measures

1. Primary Outcome Measure: Area under plasma concentration-time curve from zero to infinity (AUCinf) [ Time Frame: Day 1 to Day 5 for Period 1 and 2 ]

Measure Type	Primary
Measure Name	Area under plasma concentration-time curve from zero to infinity (AUCinf)
Measure Description	The AUCinf for each drug component of the drug cocktail administered alone in Period 1 and when administered in combination with savolitinib in Period 2 were evaluated.
Time Frame	Day 1 to Day 5 for Period 1 and 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of interventional medicinal products (IMP) and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of interventional medicinal products (IMP) and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Area under plasma concentration-time curve from zero to infinity (AUCinf) [units: Hournanogram/milliliter (hng/mL)] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	17.20 (22.38%)	16.53 (19.88%)
Metformin	6352 (17.85%)	9080 (17.17%)
Rosuvastatin	34.67 (51.09%)	43.25 (50.16%)
Furosemide	215.4 (23.45%)	223.7 (26.70%)

Statistical Analysis 1 for Area under plasma concentration-time curve from zero to infinity (AUCinf)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	0.9608
90% Confidence Interval	( 0.8880 to 1.0395 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of AUCinf of digoxin when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Area under plasma concentration-time curve from zero to infinity (AUCinf)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.4296
90% Confidence Interval	( 1.3531 to 1.5103 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of AUCinf of metformin when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Area under plasma concentration-time curve from zero to infinity (AUCinf)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.2476
90% Confidence Interval	( 1.1560 to 1.3464 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of AUCinf of rosuvastatin when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Area under plasma concentration-time curve from zero to infinity (AUCinf)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.0386
90% Confidence Interval	( 0.9884 to 1.0914 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of AUCinf of furosemide when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) [ Time Frame: Day 1 to Day 5 for Period 1 and 2 ]

Measure Type	Primary
Measure Name	Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast)
Measure Description	The PK parameter AUClast for each drug component of the drug cocktail administered alone in Period 1 and when administered in combination with savolitinib in Period 2 were evaluated.
Time Frame	Day 1 to Day 5 for Period 1 and 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	11.94 (22.28%)	11.79 (21.76%)
Metformin	6269 (18.06%)	8992 (17.37%)
Rosuvastatin	33.00 (53.46%)	41.68 (52.55%)
Furosemide	209.5 (23.93%)	218.8 (27.42%)

Statistical Analysis 1 for Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	0.9878
90% Confidence Interval	( 0.9150 to 1.0665 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of AUClast of digoxin when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.4343
90% Confidence Interval	( 1.3569 to 1.5162 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of AUClast of metformin when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.2632
90% Confidence Interval	( 1.1661 to 1.3682 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of AUClast of rosuvastatin when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.0443
90% Confidence Interval	( 0.9929 to 1.0985 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of AUClast of furosemide when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: Maximum observed plasma drug concentration (Cmax) [ Time Frame: Day 1 to Day 5 for Period 1 and 2 ]

Measure Type	Primary
Measure Name	Maximum observed plasma drug concentration (Cmax)
Measure Description	The PK parameter Cmax for each drug component of the drug cocktail administered alone in Period 1 and when administered in combination with savolitinib in Period 2 were evaluated.
Time Frame	Day 1 to Day 5 for Period 1 and 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Maximum observed plasma drug concentration (Cmax) [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	0.7809 (34.67%)	0.9571 (40.35%)
Metformin	865.6 (15.18%)	1369 (16.79%)
Rosuvastatin	2.930 (63.52%)	3.809 (59.20%)
Furosemide	46.65 (25.98%)	46.96 (29.52%)

Statistical Analysis 1 for Maximum observed plasma drug concentration (Cmax)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.2257
90% Confidence Interval	( 1.0691 to 1.4053 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of Cmax of digoxin when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Maximum observed plasma drug concentration (Cmax)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.5821
90% Confidence Interval	( 1.4932 to 1.6762 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of Cmax of metformin when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Maximum observed plasma drug concentration (Cmax)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.2999
90% Confidence Interval	( 1.1842 to 1.4269 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of Cmax of rosuvastatin when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Maximum observed plasma drug concentration (Cmax)

Groups^[1]	All groups
Method^[3]	Mixed Models Analysis
Other^[5]	1.0067
90% Confidence Interval	( 0.9469 to 1.0703 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The statistical comparison of Cmax of furosemide when administered alone versus in combination with savolitinib was evaluated. Results based on mixed model analysis of log transformed PK parameter with treatment fitted as a fixed effect and participants fitted as a random effect.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Primary Outcome Measure: Partial area under plasma concentration-time curve from 0 to 24 hours post dose (AUC0-24) [ Time Frame: Day 1 to Day 5 in Period 1 and 2 ]

Measure Type	Primary
Measure Name	Partial area under plasma concentration-time curve from 0 to 24 hours post dose (AUC0-24)
Measure Description	The AUC0-24 for each drug component of the drug cocktail administered alone in Period 1 and when administered in combination with savolitinib in Period 2 were evaluated.
Time Frame	Day 1 to Day 5 in Period 1 and 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Partial area under plasma concentration-time curve from 0 to 24 hours post dose (AUC0-24) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	5.351 (18.00%)	5.963 (16.53%)
Metformin	6006 (17.73%)	8645 (17.62%)
Rosuvastatin	27.86 (55.40%)	35.41 (54.75%)
Furosemide	214.0 (23.20%)	222.8 (26.78%)

No statistical analysis provided for Partial area under plasma concentration-time curve from 0 to 24 hours post dose (AUC0-24)

5. Primary Outcome Measure: The ratio of plasma AUCinf (R AUCinf) of the drug cocktail components in presence of savolitinib [ Time Frame: Day 1 to Day 5 in Period 2 ]

Measure Type	Primary
Measure Name	The ratio of plasma AUCinf (R AUCinf) of the drug cocktail components in presence of savolitinib
Measure Description	The AUCinf ratio for each drug component of the drug cocktail administered in combination with savolitinib in Period 2 was evaluated.
Time Frame	Day 1 to Day 5 in Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23
The ratio of plasma AUCinf (R AUCinf) of the drug cocktail components in presence of savolitinib [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	0.9608 (22.26%)
Metformin	1.430 (15.45%)
Rosuvastatin	1.248 (21.53%)
Furosemide	1.039 (13.92%)

No statistical analysis provided for The ratio of plasma AUCinf (R AUCinf) of the drug cocktail components in presence of savolitinib

6. Primary Outcome Measure: The ratio of plasma Cmax (RCmax) of the drug cocktail components in presence of savolitinib [ Time Frame: Day 1 to Day 5 in Period 2 ]

Measure Type	Primary
Measure Name	The ratio of plasma Cmax (RCmax) of the drug cocktail components in presence of savolitinib
Measure Description	The Cmax ratio for each drug component of the drug cocktail administered in combination with savolitinib in Period 2 were evaluated.
Time Frame	Day 1 to Day 5 in Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23
The ratio of plasma Cmax (RCmax) of the drug cocktail components in presence of savolitinib [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	1.226 (39.62%)
Metformin	1.582 (16.25%)
Rosuvastatin	1.300 (26.48%)
Furosemide	1.007 (17.23%)

No statistical analysis provided for The ratio of plasma Cmax (RCmax) of the drug cocktail components in presence of savolitinib

7. Primary Outcome Measure: The ratio of plasma AUClast of the drug cocktail components in presence of savolitinib [ Time Frame: Day 1 to 5 in Period 2 ]

Measure Type	Primary
Measure Name	The ratio of plasma AUClast of the drug cocktail components in presence of savolitinib
Measure Description	The AUClast ratio for each drug component of the drug cocktail administered in combination with savolitinib in Period 2 was evaluated.
Time Frame	Day 1 to 5 in Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23
The ratio of plasma AUClast of the drug cocktail components in presence of savolitinib [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	0.9878 (21.65%)
Metformin	1.434 (15.59%)
Rosuvastatin	1.263 (22.60%)
Furosemide	1.044 (14.19%)

No statistical analysis provided for The ratio of plasma AUClast of the drug cocktail components in presence of savolitinib

8. Secondary Outcome Measure: Number of participants with Adverse events (AE) [ Time Frame: From Screening (Day-28 to Day -2) to Follow-up [7 days post last Pharmacokinetic (PK) sample upto 9 weeks] ]

Measure Type	Secondary
Measure Name	Number of participants with Adverse events (AE)
Measure Description	The safety and tolerability of savolitinib after administration orally was evaluated. IMP=Investigational medicinal product
Time Frame	From Screening (Day-28 to Day -2) to Follow-up [7 days post last Pharmacokinetic (PK) sample upto 9 weeks]
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set included all participants who received at least 1 dose of the IMP during the treatment periods, by actual treatment received, and for whom any safety post-dose data were available.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Number of participants with Adverse events (AE) [units: Participants]
Any AE	7	8
Any serious adverse events (SAE)	0	0
Any SAE with outcome of death	0	0
Any SAE with outcome of death, possibly related to IMP	0	0
Any AE leading to discontinuation of IMP	0	0
Any AE possibly related to IMP	3	5
Any SAE possibly related to IMP	0	0

No statistical analysis provided for Number of participants with Adverse events (AE)

9. Secondary Outcome Measure: Area under plasma concentration-time curve from zero to infinity (AUCinf) of savolitinib and its metabolites (M2 and M3) [ Time Frame: Day 1 and Day 2 in Period 2 ]

Measure Type	Secondary
Measure Name	Area under plasma concentration-time curve from zero to infinity (AUCinf) of savolitinib and its metabolites (M2 and M3)
Measure Description	The AUCinf of savolitinib and its metabolites M2 and M3 were evaluated.
Time Frame	Day 1 and Day 2 in Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23
Area under plasma concentration-time curve from zero to infinity (AUCinf) of savolitinib and its metabolites (M2 and M3) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Savolitinib	12520 (27.51%)
Savolitinib Metabolite 2	4098 (15.56%)
Savolitinib Metabolite 3	1418 (34.14%)

No statistical analysis provided for Area under plasma concentration-time curve from zero to infinity (AUCinf) of savolitinib and its metabolites (M2 and M3)

10. Secondary Outcome Measure: Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of savolitinib and its metabolites (M2 and M3) [ Time Frame: Day 1 and Day 2 in Period 2 ]

Measure Type	Secondary
Measure Name	Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of savolitinib and its metabolites (M2 and M3)
Measure Description	The AUClast of savolitinib and its metabolite M2 and M3 were evaluated.
Time Frame	Day 1 and Day 2 in Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23
Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of savolitinib and its metabolites (M2 and M3) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Savolitinib	12480 (27.39%)
Savolitinib Metabolite 2	4054 (15.63%)
Savolitinib Metabolite 3	1389 (34.41%)

No statistical analysis provided for Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of savolitinib and its metabolites (M2 and M3)

11. Secondary Outcome Measure: Partial area under the concentration-time curve from time 0 to 24 hours post-dose [AUC(0-24)] of savolitinib and its metabolites (M2 and M3) [ Time Frame: Day 1 and Day 2 of Period 2 ]

Measure Type	Secondary
Measure Name	Partial area under the concentration-time curve from time 0 to 24 hours post-dose [AUC(0-24)] of savolitinib and its metabolites (M2 and M3)
Measure Description	The AUC(0-24h) of Savolitinib and its metabolites M2 and M3 were evaluated.
Time Frame	Day 1 and Day 2 of Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23
Partial area under the concentration-time curve from time 0 to 24 hours post-dose [AUC(0-24)] of savolitinib and its metabolites (M2 and M3) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Savolitinib	12410 (27.25%)
Savolitinib Metabolite 2	4004 (15.59%)
Savolitinib Metabolite 3	1365 (34.39%)

No statistical analysis provided for Partial area under the concentration-time curve from time 0 to 24 hours post-dose [AUC(0-24)] of savolitinib and its metabolites (M2 and M3)

12. Secondary Outcome Measure: Maximum observed plasma (peak) drug concentration (Cmax) of savolitinib and its metabolites (M2 and M3) [ Time Frame: Day 1 and Day 2 of Period 2 ]

Measure Type	Secondary
Measure Name	Maximum observed plasma (peak) drug concentration (Cmax) of savolitinib and its metabolites (M2 and M3)
Measure Description	The Cmax of savolitinib and its metabolites M2 and M3 were evaluated.
Time Frame	Day 1 and Day 2 of Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23
Maximum observed plasma (peak) drug concentration (Cmax) of savolitinib and its metabolites (M2 and M3) [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Savolitinib	2678 (27.92%)
Savolitinib Metabolite 2	730.1 (19.84%)
Savolitinib Metabolite 3	240.4 (34.65%)

No statistical analysis provided for Maximum observed plasma (peak) drug concentration (Cmax) of savolitinib and its metabolites (M2 and M3)

13. Secondary Outcome Measure: Time to reach maximum observed concentration (tmax) of savolitinib and its metabolites (M2 and M3) [ Time Frame: Day 1 and Day 2 in Period 2 ]

Measure Type	Secondary
Measure Name	Time to reach maximum observed concentration (tmax) of savolitinib and its metabolites (M2 and M3)
Measure Description	The Tmax of savolitinib and its metabolites M2 and M3 were evaluated.
Time Frame	Day 1 and Day 2 in Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23
Time to reach maximum observed concentration (tmax) of savolitinib and its metabolites (M2 and M3) [units: Hour (h)] Median (Full Range)
Savolitinib	2.02 (0.50 to 4.03)
Savolitinib Metabolite 2	2.03 (0.98 to 4.03)
Savolitinib Metabolite 3	2.02 (0.98 to 4.22)

No statistical analysis provided for Time to reach maximum observed concentration (tmax) of savolitinib and its metabolites (M2 and M3)

14. Secondary Outcome Measure: Terminal elimination half-life (t½λz) of savolitinib and its metabolites (M2 and M3) [ Time Frame: Day 1 and Day 2 in Period 2 ]

Measure Type	Secondary
Measure Name	Terminal elimination half-life (t½λz) of savolitinib and its metabolites (M2 and M3)
Measure Description	The t½λz of savolitinib and its metabolites M2 and M3 were evaluated.
Time Frame	Day 1 and Day 2 in Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23
Terminal elimination half-life (t½λz) of savolitinib and its metabolites (M2 and M3) [units: hour] Geometric Mean (Geometric Coefficient of Variation)
Savolitinib	3.589 (24.41%)
Savolitinib Metabolite 2	4.772 (29.88%)
Savolitinib Metabolite 3	6.095 (38.41%)

No statistical analysis provided for Terminal elimination half-life (t½λz) of savolitinib and its metabolites (M2 and M3)

15. Secondary Outcome Measure: Cumulative amount of unchanged drug excreted into the urine from time 0 to 48 hours [Ae(0-48)] of cocktail parent components [ Time Frame: Day 1 to Day 5 in Period 1 and Period 2 ]

Measure Type	Secondary
Measure Name	Cumulative amount of unchanged drug excreted into the urine from time 0 to 48 hours [Ae(0-48)] of cocktail parent components
Measure Description	The Ae (0-48h) for each component of drug cocktail alone in Period 1 and when administered in combination with savolitinib in Period 2 was evaluated.
Time Frame	Day 1 to Day 5 in Period 1 and Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Cumulative amount of unchanged drug excreted into the urine from time 0 to 48 hours [Ae(0-48)] of cocktail parent components [units: nanogram (ng)] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	0.05095 (23.28%)	0.04872 (27.34%)
Metformin	226.40 (8.728%)	197.2 (11.34%)
Rosuvastatin	0.4884 (47.86%)	0.5708 (50.24%)
Furosemide	0.4877 (23.97%)	0.4463 (25.85%)

No statistical analysis provided for Cumulative amount of unchanged drug excreted into the urine from time 0 to 48 hours [Ae(0-48)] of cocktail parent components

16. Secondary Outcome Measure: Percentage of dose excreted unchanged in urine from time 0 to 48h [Fe(0-48h)] of cocktail parent components [ Time Frame: Day 1 to Day 5 in Period 1 and Period 2 ]

Measure Type	Secondary
Measure Name	Percentage of dose excreted unchanged in urine from time 0 to 48h [Fe(0-48h)] of cocktail parent components
Measure Description	The Fe(0-48) for each component of drug cocktail alone in Period 1 and when administered in combination with savolitinib in Period 2 was evaluated.
Time Frame	Day 1 to Day 5 in Period 1 and Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Percentage of dose excreted unchanged in urine from time 0 to 48h [Fe(0-48h)] of cocktail parent components [units: Percentage] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	20.38 (23.28%)	19.49 (27.34%)
Metformin	45.28 (8.728%)	39.44 (11.34%)
Rosuvastatin	4.884 (47.86%)	5.708 (50.24%)
Furosemide	9.754 (23.97%)	8.926 (25.85%)

No statistical analysis provided for Percentage of dose excreted unchanged in urine from time 0 to 48h [Fe(0-48h)] of cocktail parent components

17. Secondary Outcome Measure: Renal clearance (CLR) of cocktail parent components [ Time Frame: Day 1 to Day in Period 1 and Period 2 ]

Measure Type	Secondary
Measure Name	Renal clearance (CLR) of cocktail parent components
Measure Description	The CLR for each component of drug cocktail alone in Period 1 and when administered in combination with savolitinib in Period 2 was evaluated.
Time Frame	Day 1 to Day in Period 1 and Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Renal clearance (CLR) of cocktail parent components [units: Liter/hour (L/h)] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	9.521 (27.78%)	8.170 (24.32%)
Metformin	33.94 (17.42%)	19.96 (18.56%)
Rosuvastatin	15.73 (19.77%)	15.03 (21.69%)
Furosemide	2.142 (38.34%)	2.051 (32.14%)

No statistical analysis provided for Renal clearance (CLR) of cocktail parent components

18. Secondary Outcome Measure: Time to reach maximum observed plasma concentration (Tmax) of the cocktail parent components [ Time Frame: Day 1 to Day 5 in Period 1 and Period 2 ]

Measure Type	Secondary
Measure Name	Time to reach maximum observed plasma concentration (Tmax) of the cocktail parent components
Measure Description	The Tmax of each drug component of drug cocktail administered alone in Period 1 and administered in combination with savolitinib in Period 2 were evaluated.
Time Frame	Day 1 to Day 5 in Period 1 and Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Time to reach maximum observed plasma concentration (Tmax) of the cocktail parent components [units: Hour (h)] Median (Full Range)
Digoxin	1.02 (0.50 to 4.00)	1.02 (0.50 to 4.02)
Metformin	4.00 (1.00 to 4.02)	4.00 (2.02 to 6.00)
Rosuvastatin	4.02 (3.02 to 6.03)	4.00 (1.00 to 6.00)
Furosemide	3.00 (1.02 to 4.02)	2.00 (1.00 to 4.05)

No statistical analysis provided for Time to reach maximum observed plasma concentration (Tmax) of the cocktail parent components

19. Secondary Outcome Measure: Plasma terminal elimination half-life (t½λz) of cocktail parent components [ Time Frame: Day 1 to Day 5 in Period 1 and Period 2 ]

Measure Type	Secondary
Measure Name	Plasma terminal elimination half-life (t½λz) of cocktail parent components
Measure Description	The t½λz for each drug component of the drug cocktail administered alone in Period 1 and when administered in combination with savolitinib in Period 2 were evaluated.
Time Frame	Day 1 to Day 5 in Period 1 and Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Plasma terminal elimination half-life (t½λz) of cocktail parent components [units: hour] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	52.56 (17.86%)	47.27 (19.22%)
Metformin	13.65 (50.11%)	13.48 (58.85%)
Rosuvastatin	14.50 (38.08%)	13.51 (39.81%)
Furosemide	2.701 (46.91%)	2.344 (32.34%)

No statistical analysis provided for Plasma terminal elimination half-life (t½λz) of cocktail parent components

20. Secondary Outcome Measure: Plasma Apparent total body clearance (CL/F) of cocktail parent components [ Time Frame: Day 1 to Day 5 in Period 1 and Period 2 ]

Measure Type	Secondary
Measure Name	Plasma Apparent total body clearance (CL/F) of cocktail parent components
Measure Description	The CL/F for each drug component of the drug cocktail administered alone in Period 1 and when administered in combination with savolitinib in Period 2 were evaluated.
Time Frame	Day 1 to Day 5 in Period 1 and Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Plasma Apparent total body clearance (CL/F) of cocktail parent components [units: L/h] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	14.53 (22.38%)	15.13 (19.88%)
Metformin	78.72 (17.85%)	55.06 (17.17%)
Rosuvastatin	288.4 (51.09%)	231.2 (50.16%)
Furosemide	23.21 (23.45%)	22.35 (26.70%)

No statistical analysis provided for Plasma Apparent total body clearance (CL/F) of cocktail parent components

21. Secondary Outcome Measure: Plasma Apparent volume of distribution based on the terminal phase (Vz/F) of cocktail parent components [ Time Frame: Day 1 to Day 5 in Period 1 and Period 2 ]

Measure Type	Secondary
Measure Name	Plasma Apparent volume of distribution based on the terminal phase (Vz/F) of cocktail parent components
Measure Description	The Vz/F for each drug component of the drug cocktail administered alone in Period 1 and when administered in combination with savolitinib in Period 2 were evaluated.
Time Frame	Day 1 to Day 5 in Period 1 and Period 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received at least 1 dose of IMP and for whom at least one of the primary PK parameters for savolitinib and its metabolites (M2 and M3), digoxin, metformin, rosuvastatin, and furosemide was calculated in both periods and who had no important protocol deviation thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail +Savolitinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Measured Values

	Period 1: Drug cocktail	Period 2: Drug cocktail +Savolitinib
Number of Participants Analyzed [units:participants]	23	23
Plasma Apparent volume of distribution based on the terminal phase (Vz/F) of cocktail parent components [units: Liter] Geometric Mean (Geometric Coefficient of Variation)
Digoxin	1102 (18.72%)	1032 (15.13%)
Metformin	1550 (49.64%)	1071 (64.79%)
Rosuvastatin	6034 (76.37%)	4508 (78.83%)
Furosemide	90.45 (46.97%)	75.56 (47.54%)

No statistical analysis provided for Plasma Apparent volume of distribution based on the terminal phase (Vz/F) of cocktail parent components

Serious Adverse Events

Time Frame	From screening (Day -28) to Follow-up (5 to 7 days after last PK sample) up to 9 weeks
Additional Description	No text entered.

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail+salvotinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Serious Adverse Events

	Period 1: Drug cocktail	Period 2: Drug cocktail+salvotinib
Total, serious adverse events
# participants affected / at risk	0/23 (0.00%)	0/23 (0.00%)

Other Adverse Events

Time Frame	From screening (Day -28) to Follow-up (5 to 7 days after last PK sample) up to 9 weeks
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Period 1: Drug cocktail	Participants received single dose of Drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 1 of the treatment
Period 2: Drug cocktail+salvotinib	Participants received Dose A of savolitinib in combination with the drug cocktail components (Dose B of digoxin, Dose C of furosemide, Dose D of metformin hydrochloride, and Dose E of rosuvastatin) in Period 2 of the treatment

Other Adverse Events

Period 1: Drug cocktail

Period 2: Drug cocktail+salvotinib

Total, other (not including serious) adverse events

# participants affected / at risk

4/23 (17.39%)

6/23 (26.09%)

Nervous system disorders

Headache¹

# participants affected / at risk

3/23 (13.04%)

6/23 (26.09%)

# events

Gastrointestinal disorders

Nausea¹

# participants affected / at risk

1/23 (4.35%)

3/23 (13.04%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 26.0

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: No unpublished information contained herein may be disclosed without prior written approval from AstraZeneca AB.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

Download
redacted CSR Synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

redacted CSR Synopsis

Trial Results Summaries