A Study to Assess the Effects of Fluvoxamine on Savolitinib Exposure in Healthy Male Subjects

Study identifier:D5084C00015

ClinicalTrials.gov identifier:NCT05888207

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase I, Open-label, Fixed-sequence Study to Assess the Effects of Strong CYP1A2 Inhibitor (Fluvoxamine) on Savolitinib Exposure in Healthy Male Subjects

Medical condition

Healthy male subjects

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Fluvoxamine, Savolitinib

Sex

Male

Actual Enrollment

Study type

Interventional

Age

18 Years - 55 Years

Date

Study Start Date: 02 Jun 2023

Primary Completion Date: 17 Aug 2023

Study Completion Date: 17 Aug 2023

Study design

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

Verification:

Verified 01 Jul 2024 by AstraZeneca

Collaborators

PAREXEL

Inclusion and exclusion criteria

Inclusion Criteria

• Healthy subjects with suitable veins for cannulation or repeated venipuncture.
• Male subjects must use barrier contraception.
• Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
• Regular bowel movements.

Exclusion Criteria

• History of any clinically significant disease or disorder, which in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject’s ability to participate in the study.
• 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 illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, vital signs, 12 lead ECG and physical examination.
• 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, 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, hepatitis C antibody, or HIV antibody.
• History of latent or chronic infections.
• Known or suspected drug or alcohol abuse or positive drugs of abuse test. History of excessive alcohol assumption or chronic alcohol induced disease. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol.
• Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 1 month (30 days) of Visit 2 (Day -1 of Period 1) or 5 half lives whichever longer in this study or participation in a method development study (no drug) 1 month prior to Visit 2. The period of exclusion begins 1 month after the final dose or 5 half-lives after the final dose or 1 month after the last visit, whichever is the longest.
• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity.
• Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the 6 months prior to screening.
• Use of any prescribed or non prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies (which include but are not limited to: kava, ephedra [ma hung], ginko biloba, dehydroepiandrosterone, yohimbe, saw palmetto and ginseng), megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer (> 5 half-lives) if the medication has a long half-life.
• Subject has clinical signs and symptoms consistent with COVID-19, or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission unless confirmed by a negative SARS CoV-2 PCR test.
• History of severe COVID-19 (hospitalization, extracorporeal membrane oxygenation, mechanically ventilated).
• Excessive intake of caffeine-containing drinks or food.
• Planned in-patient surgery, dental procedure, or hospitalization during the study.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug.
• Received a seasonal flu vaccine (including H1N1, H1N5) 28 days prior to first dose of study drug.

Location

Research Site

Brooklyn, MD, United States, 21225

Arms	Assigned Interventions
Experimental: Savolitinib/Savolitinib+Fluvoxamine In period 1, subjects will receive a single oral dose of savolitinib on Day 1 after overnight fasting. Following minimum 10 days of washout after the last dose of savolitinib, in period 2 subjects will take oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5 subject will receive a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, subjects will receive a twice daily oral dose of fluvoxamine alone.	Drug: Savolitinib Savolitinib will be administered as a single oral dose on Day 1 of Period 1 and on Day 5 of Period 2.

Arms

Assigned Interventions

Experimental: Savolitinib/Savolitinib+Fluvoxamine
In period 1, subjects will receive a single oral dose of savolitinib on Day 1 after overnight fasting. Following minimum 10 days of washout after the last dose of savolitinib, in period 2 subjects will take oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5 subject will receive a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, subjects will receive a twice daily oral dose of fluvoxamine alone.

Drug: Savolitinib
Savolitinib will be administered as a single oral dose on Day 1 of Period 1 and on Day 5 of Period 2.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was conducted from 02 Jun 2023 to 17 Aug 2023 at a single center, Parexel Early Phase Clinical Unit Baltimore, USA.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants who met the inclusion criteria and none of the exclusion criteria were enrolled to the study. All study assessments were performed as per the schedule of assessment.

Reporting Groups

	Description
Savolitinib/Savolitinib+Fluvoxamine	In period 1, participants received a single oral dose of savolitinib on Day 1 after overnight fasting. Following minimum 10 days of washout after the last dose of savolitinib, in period 2, participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Description

Savolitinib/Savolitinib+Fluvoxamine

In period 1, participants received a single oral dose of savolitinib on Day 1 after overnight fasting. Following minimum 10 days of washout after the last dose of savolitinib, in period 2, participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Participant Flow: Overall Study

	Savolitinib/Savolitinib+Fluvoxamine
STARTED	16
COMPLETED	16
NOT COMPLETED	0

Baseline Characteristics

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

The safety analysis set included all participants who received at least 1 dose of savolitinib and for whom any safety post-dose data was available.

Reporting Groups

	Description
Savolitinib/Savolitinib+Fluvoxamine	In period 1, participants received a single oral dose of savolitinib on Day 1 after overnight fasting. Following minimum 10 days of washout after the last dose of savolitinib, in period 2, participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Description

Savolitinib/Savolitinib+Fluvoxamine

Baseline Measures

	Savolitinib/Savolitinib+Fluvoxamine
Number of Participants [units: Participants]	16
Age Continuous [units: Years] Mean ± Standard Deviation	37.8 ± 9.1
Sex: Female, Male [units: Participants]
Female	0
Male	16
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0
Asian	2
Native Hawaiian or Other Pacific Islander	0
Black or African American	7
White	7
More than one race	0
Unknown or Not Reported	0

Outcome Measures

1. Primary Outcome Measure: Maximum observed plasma (peak) drug concentration (Cmax) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Primary
Measure Name	Maximum observed plasma (peak) drug concentration (Cmax)
Measure Description	The effects of fluvoxamine on pharmacokinetics (PK) parameter, Cmax of savolitinib in healthy male participants after administration of a single oral dose were evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib and its metabolites (M2 and M3) included all participants who received a savolitinib dose and who had at least one quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Maximum observed plasma (peak) drug concentration (Cmax) [units: nanogram per milliliter (ng/mL)] Geometric Mean (Geometric Coefficient of Variation)	1279 (40.11%)	2499 (24.24%)

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

Groups^[1]	All groups
Other^[5]	1.953
90% Confidence Interval	( 1.672 to 2.282 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical Comparison of Savolitinib Pharmacokinetic Parameters
[5]	Other relevant estimation information:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter with fixed effect for treatment and random effect for participants.

2. Primary Outcome Measure: Area under plasma concentration time curve from zero to infinity (AUCinf) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Primary
Measure Name	Area under plasma concentration time curve from zero to infinity (AUCinf)
Measure Description	The effects of fluvoxamine on PK parameter, AUCinf of savolitinib in healthy male participants after administration of a single oral dose were evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Area under plasma concentration time curve from zero to infinity (AUCinf) [units: hoursnanogram per milliliter (hng/mL)] Geometric Mean (Geometric Coefficient of Variation)	5553 (31.74%)	18020 (22.90%)

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

Groups^[1]	All groups
Other^[5]	3.246
90% Confidence Interval	( 2.867 to 3.675 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical Comparison of Savolitinib Pharmacokinetic Parameters
[5]	Other relevant estimation information:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter with fixed effect for treatment and random effect for participants.

3. Secondary Outcome Measure: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)
Measure Description	The AUClast of savolitinib and its metabolites (M2 and M3) when administered alone or in combination with fluvoxamine was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Savolitinib	5495 (31.98%)	17750 (22.56%)
M2	2224 (25.85%)	774.9 (28.65%)
M3	656.7 (30.45%)	2098 (24.71%)

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

Groups^[1]	All groups
Other^[5]	3.229
90% Confidence Interval	( 2.847 to 3.664 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical Comparison of Savolitinib Pharmacokinetic Parameters
[5]	Other relevant estimation information:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter with fixed effect for treatment and random effect for participants.

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

Groups^[1]	All groups
Other^[5]	0.3485
90% Confidence Interval	( 0.3143 to 0.3863 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical Comparison of Savolitinib M2 Pharmacokinetic Parameters
[5]	Other relevant estimation information:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter with fixed effect for treatment and random effect for participants.

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

Groups^[1]	All groups
Other^[5]	3.194
90% Confidence Interval	( 2.787 to 3.661 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical Comparison of Savolitinib M3 Pharmacokinetic Parameters
[5]	Other relevant estimation information:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter with fixed effect for treatment and random effect for participants.

4. Secondary Outcome Measure: Cmax for savolitinib metabolites M2 and M3 [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Cmax for savolitinib metabolites M2 and M3
Measure Description	The Cmax of savolitinib metabolites (M2 and M3) when savolitinib was administered alone or in combination with fluvoxamine was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Cmax for savolitinib metabolites M2 and M3 [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
M2	440.5 (23.93%)	52.92 (31.31%)
M3	137 (38.02%)	215.7 (32.29%)

Statistical Analysis 1 for Cmax for savolitinib metabolites M2 and M3

Groups^[1]	All groups
Other^[5]	0.1201
90% Confidence Interval	( 0.1042 to 0.1385 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical Comparison of Savolitinib M2 Pharmacokinetic Parameters
[5]	Other relevant estimation information:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter with fixed effect for treatment and random effect for participants.

Statistical Analysis 2 for Cmax for savolitinib metabolites M2 and M3

Groups^[1]	All groups
Other^[5]	1.575
90% Confidence Interval	( 1.366 to 1.816 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical Comparison of Savolitinib M3 Pharmacokinetic Parameters
[5]	Other relevant estimation information:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter with fixed effect for treatment and random effect for participants.

5. Secondary Outcome Measure: AUCinf for savolitinib metabolites M2 and M3 [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	AUCinf for savolitinib metabolites M2 and M3
Measure Description	The AUCinf of savolitinib metabolites (M2 and M3) when savolitinib was administered alone or in combination with fluvoxamine was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
AUCinf for savolitinib metabolites M2 and M3 [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
M2	2284 (26.52%)	837.9 (29.48%)
M3	684.3 (29.77%)	2234 (25.74%)

Statistical Analysis 1 for AUCinf for savolitinib metabolites M2 and M3

Groups^[1]	All groups
Other^[5]	0.3668
90% Confidence Interval	( 0.3323 to 0.4050 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical Comparison of Savolitinib M2 Pharmacokinetic Parameters
[5]	Other relevant estimation information:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter with fixed effect for treatment and random effect for participants.

Statistical Analysis 2 for AUCinf for savolitinib metabolites M2 and M3

Groups^[1]	All groups
Other^[5]	3.265
90% Confidence Interval	( 2.852 to 3.738 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical Comparison of Savolitinib M3 Pharmacokinetic Parameters
[5]	Other relevant estimation information:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter with fixed effect for treatment and random effect for participants.

6. Secondary Outcome Measure: Ratio of metabolite Cmax to parent Cmax (MRCmax) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Ratio of metabolite Cmax to parent Cmax (MRCmax)
Measure Description	The MRCmax of savolitinib and its metabolites (M2 and M3) when savolitinib was administered alone was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Ratio of metabolite Cmax to parent Cmax (MRCmax) [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)
M2	0.3444 (52.24%)	0.02118 (43.43%)
M3	0.1071 (40.84%)	0.08634 (43.37%)

No statistical analysis provided for Ratio of metabolite Cmax to parent Cmax (MRCmax)

7. Secondary Outcome Measure: Ratio of metabolite AUCinf to parent AUCinf (MRAUCinf) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Ratio of metabolite AUCinf to parent AUCinf (MRAUCinf)
Measure Description	The MRAUCinf of savolitinib and its metabolites (M2 and M3) when savolitinib was administered alone was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Ratio of metabolite AUCinf to parent AUCinf (MRAUCinf) [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)
M2	0.4114 (46.11%)	0.04649 (34.45%)
M3	0.1232 (27.28%)	0.1240 (25.99%)

No statistical analysis provided for Ratio of metabolite AUCinf to parent AUCinf (MRAUCinf)

8. Secondary Outcome Measure: Ratio of metabolite AUClast to parent AUClast (MRAUClast) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Ratio of metabolite AUClast to parent AUClast (MRAUClast)
Measure Description	The MRAUClast of savolitinib and its metabolites (M2 and M3) when savolitinib was administered alone was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Ratio of metabolite AUClast to parent AUClast (MRAUClast) [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)
M2	0.4047 (45.68%)	0.04367 (35.22%)
M3	0.1195 (26.83%)	0.1182 (26.56%)

No statistical analysis provided for Ratio of metabolite AUClast to parent AUClast (MRAUClast)

9. Secondary Outcome Measure: Time to reach peak or maximum observed concentration or response following drug administration (tmax) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Time to reach peak or maximum observed concentration or response following drug administration (tmax)
Measure Description	The tmax of savolitinib and its metabolites (M2 and M3) when savolitinib was administered alone was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Time to reach peak or maximum observed concentration or response following drug administration (tmax) [units: Hours] Median (Full Range)
Savolitinib	2.50 (1.00 to 4.02)	1.76 (0.98 to 4.02)
M2	2.00 (1.00 to 4.02)	3.00 (0.98 to 5.92)
M3	2.25 (1.00 to 4.02)	2.00 (0.98 to 4.02)

No statistical analysis provided for Time to reach peak or maximum observed concentration or response following drug administration (tmax)

10. Secondary Outcome Measure: Half-life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Half-life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz)
Measure Description	The t1/2λz of savolitinib and its metabolites (M2 and M3) when savolitinib was administered alone was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Half-life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz) [units: Hours] Geometric Mean (Geometric Coefficient of Variation)
Savolitinib	8.893 (54.01%)	7.978 (28.90%)
M2	11.92 (68.25%)	11.65 (31.74%)
M3	10.00 (62.61%)	12.21 (34.33%)

No statistical analysis provided for Half-life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz)

11. Secondary Outcome Measure: Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz)
Measure Description	The λz of savolitinib and its metabolites (M2 and M3) when savolitinib was administered alone was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz) [units: 1/hour] Geometric Mean (Geometric Coefficient of Variation)
Savolitinib	0.077942 (54.012%)	0.086886 (28.899%)
M2	0.058126 (68.250%)	0.059484 (31.741%)
M3	0.069315 (62.607%)	0.056761 (34.330%)

No statistical analysis provided for Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz)

12. Secondary Outcome Measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
Measure Description	The CL/F of savolitinib when savolitinib was administered alone was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Apparent total body clearance of drug from plasma after extravascular administration (CL/F) [units: Liter/hour] Geometric Mean (Geometric Coefficient of Variation)	54.02 (31.74%)	16.64 (22.90%)

No statistical analysis provided for Apparent total body clearance of drug from plasma after extravascular administration (CL/F)

13. Secondary Outcome Measure: Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F) [ Time Frame: Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7 ]

Measure Type	Secondary
Measure Name	Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F)
Measure Description	The Vz/F of savolitinib when savolitinib was administered alone was evaluated.
Time Frame	Period 1: Day 1 to Day 3 and Period 2: Day 5 to Day 7
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 for savolitinib, M2 and M3 included all participants who received a savolitinib dose and who had at least 1 quantifiable plasma concentration post-dose for savolitinib, M2 or M3 without any protocol deviation which might impact savolitinib plasma exposure.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Savolitinib+Fluvoxamine	In period 2 (after minimum 10 days of washout from the last dose of savolitinib), participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5, participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, participants received a twice daily oral dose of fluvoxamine alone.

Measured Values

	Savolitinib alone	Savolitinib+Fluvoxamine
Number of Participants Analyzed [units:participants]	16	16
Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F) [units: Liters] Geometric Mean (Geometric Coefficient of Variation)	693.1 (67.58%)	191.6 (34.78%)

No statistical analysis provided for Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F)

14. Secondary Outcome Measure: Number of participants with adverse events (AEs) [ Time Frame: From onset date on or after the date of first dose of investigational medicinal product (IMP) (Day 1) until the final Follow-up visit (approximately 9 weeks) ]

Measure Type	Secondary
Measure Name	Number of participants with adverse events (AEs)
Measure Description	Safety and tolerability of savolitnib were assessed.
Time Frame	From onset date on or after the date of first dose of investigational medicinal product (IMP) (Day 1) until the final Follow-up visit (approximately 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 savolitinib and for whom any safety post-dose data were available.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Fluvoxamine (Day 1 to 4)	Participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4 in Period 2 (after minimum 10 days of washout from the last dose of savolitinib).
Fluvoxamine + Savolitinib	Participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine on Day 5 in Period 2.
Fluvoxamine (Day 6)	Participants received a twice daily oral dose of fluvoxamine alone on Day 6 in Period 2.

Measured Values

	Savolitinib alone	Fluvoxamine (Day 1 to 4)	Fluvoxamine + Savolitinib	Fluvoxamine (Day 6)
Number of Participants Analyzed [units:participants]	16	16	16	16
Number of participants with adverse events (AEs) [units: Participants]
Any AE	1	1	1	0
Any serious adverse event (SAE)	0	0	0	0
Any SAE with outcome death	0	0	0	0
Any SAE with outcome death, possibly related to investigational medicinal product (IMP)	0	0	0	0
Any AE leading to discontinuation of IMP	0	0	0	0
Any AE possibly related to IMP	1	0	0	0
Any SAE possibly related to IMP	0	0	0	0

No statistical analysis provided for Number of participants with adverse events (AEs)

Serious Adverse Events

Time Frame	From onset date on or after the date of first dose of IMP (Day 1) until the final Follow-up visit (approximately 9 weeks)
Additional Description	The safety analysis set included all participants who received at least 1 dose of savolitinib and for whom any safety post-dose data were available.

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Fluvoxamine (Day 1 to 4)	Participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4 in Period 2 (after minimum 10 days of washout from the last dose of savolitinib).
Fluvoxamine + Savolitinib	Participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine on Day 5 in Period 2.
Fluvoxamine (Day 6)	Participants received a twice daily oral dose of fluvoxamine alone on Day 6 in Period 2.

Serious Adverse Events

	Savolitinib alone	Fluvoxamine (Day 1 to 4)	Fluvoxamine + Savolitinib	Fluvoxamine (Day 6)
Total, serious adverse events
# participants affected / at risk	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)

Other Adverse Events

Time Frame	From onset date on or after the date of first dose of IMP (Day 1) until the final Follow-up visit (approximately 9 weeks)
Additional Description	The safety analysis set included all participants who received at least 1 dose of savolitinib and for whom any safety post-dose data were available.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Savolitinib alone	Participants received a single oral dose of savolitinib on Day 1 in Period 1 after overnight fasting.
Fluvoxamine (Day 1 to 4)	Participants received oral doses of fluvoxamine alone, twice daily from Days 1 to 4 in Period 2 (after minimum 10 days of washout from the last dose of savolitinib).
Fluvoxamine + Savolitinib	Participants received a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine on Day 5 in Period 2.
Fluvoxamine (Day 6)	Participants received a twice daily oral dose of fluvoxamine alone on Day 6 in Period 2.

Other Adverse Events

Savolitinib alone

Fluvoxamine (Day 1 to 4)

Fluvoxamine + Savolitinib

Fluvoxamine (Day 6)

Total, other (not including serious) adverse events