This will be an open-label, randomised, 2 part (Part A and Part B), 2 treatment (savolitinib alone or in combination with famotidine), crossover study in healthy, non Japanese, male subjects, performed at a single study centre.
Parts A and B will each have 2 Periods (Period 1 and Period 2) with a crossover design. Part B will be conducted only if results of Part A suggest a clinically meaningful effect of famotidine on savolitinib pharmacokinetics (PK) parameters. In both parts subjects will be randomly assigned 1:1 to receive one of the 2 treatment sequences: savolitinib alone first followed by crossover to the combination treatment of savolitinib+famotidine, or the reverse sequence. Subjects will be admitted for 4 days from one day before the first dose of the study drug and discharged 2 days after. There will be a washout period (no study treatment) of 14 days between the 2 Periods. The essential difference between the 2 parts is that in the combination treatment, famotidine will be administered 2 hours before savolitinib in Part A and 6 hours before savolitinib in Part B. A given subject will receive a total of 1 dose of famotidine and 2 doses of savolitinib during the study. In this 2 part study, 16 subjects will be randomised in each part to ensure at least 14 evaluable subjects at the end of the last study period. If Part B is conducted, a total of 32 subjects overall are planned to be enrolled in the study. Additional subjects may be enrolled to ensure 14 evaluable subjects in each part if more than 2 subjects are deemed non evaluable.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
16
Subject will receive savolitinib tablet 600mg orally after a high-fat, high-calorie meal.
Subjects will receive famotidine tablet 40mg orally after an overnight (minimum 8hours) of fasting.
Research Site
Baltimore, Maryland, United States
Maximum observed plasma concentration (Cmax) ratio
Cmax ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess effect of the gastric acid modifier, famotidine, on the PK of savolitinib.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Area under plasma concentration-time curve from zero to infinity (AUC) ratio
AUC ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess effect of the gastric acid modifier, famotidine, on the PK of savolitinib.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Number of subjects with having adverse events and/or abnormal findings in vital signs and/or laboratory evaluation and/or physical examination
To investigate the safety and tolerability of savolitinib in combination with famotidine.
Time frame: From 28-day screening period to follow-up period i.e. 60 days
AUC geometric means ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone)
To assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Area under the plasma concentration curve from time zero to time of last quantifiable concentration AUC(0-t)
AUC(0-t) geometric means ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Cmax geometric means ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone)
To assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Cmax metabolite-to-parent ratios (MRCmax)
MRCmax ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
AUC metabolite-to-parent ratios (MRAUC)
MRAUC ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
AUC(0-t) metabolite-to-parent ratios [MRAUC(0-t)]
MRAUC(0-t) ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Time to reach maximum observed plasma concentration (tmax)
tmax ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½,λz)
t½,λz ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Terminal elimination rate constant (λz)
λz ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
Vz/F ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18
Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
CL/F ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess the effect of famotidine on the PK of savolitinib metabolites M2 and M3 and to describe the PK parameters and the PK concentration-time profiles for savolitinib, M2, and M3 when savolitinib is administered alone and in combination with famotidine.
Time frame: At pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours post-dose on Day 1-3 and Day 16-18