This is a Phase 1, randomized, 2 way crossover, open label study of the effect of PF-04965842 on metformin (a probe for MATE1/2K activity) PK in healthy adult participants. The effect of PF-04965842 on N1-methylnicotinamide (NMN; an endogenous biomarker for MATE1/2K) PK and its correlation to the effect on metformin PK will also be assessed. Participants will be randomized to 1 of 2 treatment sequences as described below. A total of 12 healthy male and/or female participants will be enrolled in the study so that 6 participants will be enrolled in each treatment sequence. Each treatment sequence will consist of 2 periods.
This is a Phase 1, randomized, 2 way crossover, open label study of the effect of PF-04965842 on metformin (a probe for MATE1/2K activity) PK in healthy adult participants. The effect of PF-04965842 on N1-methylnicotinamide (NMN; an endogenous biomarker for MATE1/2K) PK and its correlation to the effect on metformin PK will also be assessed. Participants will be randomized to 1 of 2 treatment sequences as described below. A total of 12 healthy male and/or female participants will be enrolled in the study so that 6 participants will be enrolled in each treatment sequence. Each treatment sequence will consist of 2 periods. Participants who discontinue from the study may be replaced at the sponsor's discretion. The replacement participant will receive the same treatment sequence as the participant who discontinued. Participants will be screened within 28 days of the first dose of investigational product. Participants will report to the clinical research unit (CRU) the day prior to Day 1 (ie Day -1) dosing in Period 1 for both treatment sequences. In both sequences, participants will remain in the CRU for a total of 8 days and 7 nights (including Period 1 and Period 2). There will be a minimum 4 day washout period between metformin dosing events. NMN and metformin PK will be assessed in plasma and urine over 24 and 48 hours, respectively.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Commercially available metformin (GLUCOPHAGE®) as 500 mg tablets.
PF 04965842 100 mg tablets
Pfizer Clinical Research Unit
Brussels, Belgium
Renal Clearance (CLr) of Metformin
CLr was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Ae) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCtau).
Time frame: For both Period 1 and Period 2 at intervals of 0-12, 12-24, 24-36, and 36-48 hours post metformin dose
Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Metformin
AUCinf is a measure of the serum concentration of the drug over time. It was used to characterize drug absorption.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Maximum Plasma Concentration (Cmax) of Metformin
Cmax is maximum observed plasma concentration.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Time for Cmax (Tmax) of Metformin
Tmax of metformin administrated with or without PF-04965842.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Area Under the Plasma Concentration Time Profile From Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Metformin
AUClast of metformin administrated with or without PF-04965842.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Apparent Clearance (CL/F) of Metformin
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Enrollment
12
CL/F is a quantitative measure of the rate at which drug was removed from the blood.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Apparent Volume of Distribution (Vz/F) of Metformin
Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Terminal Half-life (t1/2) of Metformin
t1/2 is the time measured for the plasma concentration to decrease by one half.
Time frame: Pre-dose and at 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48 hours post-dose of metformin on Day 1 for both Period 1 and Period 2
Cumulative Amount of Drug Recovered Unchanged in Urine From 0 to 48 Hours (Ae) of Metformin
Ae is the cumulative amount of drug recovered unchanged in urine during the dosing interval. Cumulative amount was calculated as sum of urine drug concentration in sample volume for each collection interval. Sample volume = (urine weight in gram \[g\]/1.020), where 1.020 g/mL is the approximate specific gravity of urine.
Time frame: For both Period 1 and Period 2 at intervals of 0-12, 12-24, 24-36, and 36-48 hours post metformin dose
Percent of Dose Recovered Unchanged in Urine From 0 to 24 Hours (Ae%) of Metformin
Ae% is percent of dose recovered unchanged in urine from 0 to 24 hours post-dose of metformin.
Time frame: For both Period 1 and Period 2 at intervals of 0-12 and 12-24 hours post metformin dose
Number of Participants With Laboratory Abnormalities
Laboratory parameters included: hematology (hemoglobin, hematocrit, erythrocytes, ery. mean corpuscular volume, ery. mean corpuscular hemoglobin, ery. mean corpuscular HGB concentration, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time, prothrombin time, prothrombin intl. normalized ratio, large unstained cells/leukocytes and large unstained cells), clinical chemistry (bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, blood urea nitrogen, urea, creatinine, urate, sodium, potassium, chloride, calcium, bicarbonate, urobilinogen and glucose -FASTING), urinalysis (specific gravity, pH, urine glucose, ketones, urine protein, urine hemoglobin, urine bilirubin, nitrite and leukocytes). Clinical significance of laboratory parameters is determined at the investigator's discretion.
Time frame: Screening (within 28 days prior to Day 1) to Day 7
Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria
Criteria for change in vital signs: pulse rate value less than (\<) 40 beats per minute (bpm) or value over than (\>) 120 bpm, systolic blood pressure (SBP) value \< 90 millimeter of mercury (mmHg) or change from baseline (Chg) equal to or over than (≥) 30 mmHg increase or ≥ Chg 30 mmHg decrease, diastolic blood pressure (DBP) value \< 50 mmHg or Chg ≥ 20 mmHg increase or Chg ≥ 20 mmHg decrease.
Time frame: Screening (within 28 days prior to Day 1) to Day 7
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related)
AEs with all causalities were any untoward medical occurrences in a study subject administered a product or medical device which did not necessarily had causal relationship with the treatment or usage. An SAE was an AE resulting in any of the following endpoints or deemed significant for any other reason: death; life threatening (immediate risk of death); inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Day 1 up to Day 40 (35 days after the last dose of metformin)
Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related)
AEs with all causalities were any untoward medical occurrences in a study subject administered a product or medical device which did not necessarily had causal relationship with the treatment or usage. An SAE was an AE resulting in any of the following endpoints or deemed significant for any other reason: death; life threatening (immediate risk of death); inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent are events between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Day 1 up to Day 40 (35 days after the last dose of metformin)