Study of PF 04965842 Effect on MATE1/2K Activity in Healthy Participants
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Sequence 1 Patients in sequence 1 will received treatment A (metformin) in Period 1 then complete at least 4 days of washout and continue to period 2 where treatment B (PF-04965842 + metformin) will be administered. |
Drug: Metformin
Commercially available metformin (GLUCOPHAGE®) as 500 mg tablets.
Other Names:
Drug: PF-04965842
PF 04965842 100 mg tablets
|
| Experimental: Sequence 2 Patients in Sequence 2 will start treatment B (PF-04965842 + metformin) then go through a washout period of at least 4 days and continue to Period 2 where treatment A (metformin) will be administered. |
Drug: Metformin
Commercially available metformin (GLUCOPHAGE®) as 500 mg tablets.
Other Names:
Drug: PF-04965842
PF 04965842 100 mg tablets
|
Outcome Measures
Primary Outcome Measures
- Renal Clearance (CLr) of Metformin [For both Period 1 and Period 2 at intervals of 0-12, 12-24, 24-36, and 36-48 hours post metformin dose]
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).
Secondary Outcome Measures
- Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Metformin [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]
AUCinf is a measure of the serum concentration of the drug over time. It was used to characterize drug absorption.
- Maximum Plasma Concentration (Cmax) of Metformin [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]
Cmax is maximum observed plasma concentration.
- Time for Cmax (Tmax) of Metformin [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]
Tmax of metformin administrated with or without PF-04965842.
- Area Under the Plasma Concentration Time Profile From Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Metformin [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]
AUClast of metformin administrated with or without PF-04965842.
- Apparent Clearance (CL/F) of Metformin [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]
CL/F is a quantitative measure of the rate at which drug was removed from the blood.
- Apparent Volume of Distribution (Vz/F) of Metformin [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]
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.
- Terminal Half-life (t1/2) of Metformin [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]
t1/2 is the time measured for the plasma concentration to decrease by one half.
- Cumulative Amount of Drug Recovered Unchanged in Urine From 0 to 48 Hours (Ae) of Metformin [For both Period 1 and Period 2 at intervals of 0-12, 12-24, 24-36, and 36-48 hours post metformin dose]
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.
- Percent of Dose Recovered Unchanged in Urine From 0 to 24 Hours (Ae%) of Metformin [For both Period 1 and Period 2 at intervals of 0-12 and 12-24 hours post metformin dose]
Ae% is percent of dose recovered unchanged in urine from 0 to 24 hours post-dose of metformin.
- Number of Participants With Laboratory Abnormalities [Screening (within 28 days prior to Day 1) to Day 7]
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.
- Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria [Screening (within 28 days prior to Day 1) to Day 7]
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.
- Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) [Day 1 up to Day 40 (35 days after the last dose of metformin)]
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.
- Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) [Day 1 up to Day 40 (35 days after the last dose of metformin)]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male and female participants who are overtly healthy as determined by medical evaluation including a detailed medical history, complete physical examination, laboratory tests, and cardiovascular tests.
-
Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
-
Female participants who are of child bearing potential must not be intending to become pregnant, currently pregnant, or lactating.
-
Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb).
-
Capable of giving signed informed consent.
Exclusion Criteria:
-
Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease.
-
Any condition possibly affecting drug absorption (eg, gastrectomy).
-
History of human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus infection; positive testing for HIV, hepatitis B surface antigen (HepBsAg), hepatitis B core antibody (HepBcAb), or hepatitis C virus antibody (HCVAb).
-
Other acute or chronic medical or psychiatric condition including recent (within the past year).
-
Evidence or history of clinically significant dermatological condition (eg, atopic dermatitis or psoriasis) or visible rash present during physical examination.
-
Clinically relevant history of lactic acidosis.
-
Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of investigational product.
-
A positive urine drug test.
-
Selected laboratory abnormalities.
-
History of regular alcohol consumption exceeding 14 drinks/week for female participants or 21 drinks/week for male participants (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months before screening.
-
Known relevant history of elevated liver function tests (LFTs).
-
History of tuberculosis (TB) (active or latent)
-
Any history of chronic infections, any history of recurrent infections, any history of latent infections, or any acute infection within 2 weeks of baseline.
-
History of disseminated herpes zoster, or disseminated herpes simplex, or recurrent localized dermatomal herpes zoster.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Pfizer Clinical Research Unit | Brussels | Belgium | B-1070 |
Sponsors and Collaborators
- Pfizer
Investigators
- Study Director: Pfizer CT.gov Call Center, Pfizer
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- B7451034
- DDI
- 2018-003683-31
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | A total of 12 healthy participants were enrolled in the study and 6 participants were assigned in each of the 2 treatment sequences, all receiving study treatment. |
| Arm/Group Title | Metformin Then Metformin + PF-04965842 | Metformin + PF-04965842 Then Metformin |
|---|---|---|
| Arm/Group Description | Participants were administered a single oral dose of metformin 500 mg on Day 1 in Period 1 followed by a washout period of at least 4 days. Then in Period 2 participants were administered a single oral dose of metformin 500 mg on Day 1 along with oral doses of PF-04965842 200 mg once daily (QD) for 2 days on Days 1-2. | Participants were administered a single oral dose of metformin 500 mg on Day 1 along with oral doses of PF-04965842 200 mg QD for 2 days on Days 1-2 in Period 1 followed by a washout period of at least 4 days. Then in Period 2 participants were administered a single oral dose of metformin 500 mg on Day 1. |
| Period Title: Period 1 | ||
| STARTED | 6 | 6 |
| COMPLETED | 6 | 6 |
| NOT COMPLETED | 0 | 0 |
| Period Title: Period 1 | ||
| STARTED | 6 | 6 |
| COMPLETED | 6 | 6 |
| NOT COMPLETED | 0 | 0 |
| Period Title: Period 1 | ||
| STARTED | 6 | 6 |
| COMPLETED | 6 | 6 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | All Participants |
|---|---|
| Arm/Group Description | This reporting group refers to the total 12 participants who were enrolled in the study. |
| Overall Participants | 12 |
| Age (Years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [Years] |
39.0
(8.42)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
0
0%
|
| Male |
12
100%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
1
8.3%
|
| Not Hispanic or Latino |
11
91.7%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
1
8.3%
|
| Black or African American |
1
8.3%
|
| White |
10
83.3%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
Outcome Measures
| Title | Renal Clearance (CLr) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 11 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [litre per hour (L/hr)] |
32.18
(39)
|
33.33
(28)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Metformin + PF-04965842, Metformin |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | The corresponding 90% confidence intervals equivalence criteria was (80%, 125%) acceptance range. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio |
| Estimated Value | 98.50 | |
| Confidence Interval |
(2-Sided) 90% 82.09 to 118.20 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Area Under the Plasma Concentration-time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 8 | 11 |
| Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter (ng*hr/mL)] |
5050
(16)
|
5202
(19)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Metformin + PF-04965842, Metformin |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | The corresponding 90% confidence intervals equivalence criteria was (80%, 125%) acceptance range. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio |
| Estimated Value | 93.49 | |
| Confidence Interval |
(2-Sided) 90% 85.15 to 102.65 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Maximum Plasma Concentration (Cmax) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 12 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)] |
634.7
(14)
|
720.7
(20)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Metformin + PF-04965842, Metformin |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | The corresponding 90% confidence intervals equivalence criteria was (80%, 125%) acceptance range. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio |
| Estimated Value | 88.07 | |
| Confidence Interval |
(2-Sided) 90% 80.99 to 95.76 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Time for Cmax (Tmax) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 12 | 12 |
| Median (Full Range) [Hours (hrs)] |
4.00
|
4.00
|
| Title | Area Under the Plasma Concentration Time Profile From Time 0 to the Time of Last Quantifiable Concentration (AUClast) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 12 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
4849
(18)
|
5145
(18)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Metformin + PF-04965842, Metformin |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Equivalence | |
| Comments | The corresponding 90% confidence intervals equivalence criteria was (80%, 125%) acceptance range. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio |
| Estimated Value | 94.25 | |
| Confidence Interval |
(2-Sided) 90% 88.19 to 100.73 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Apparent Clearance (CL/F) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 8 | 11 |
| Geometric Mean (Geometric Coefficient of Variation) [L/hr] |
98.97
(16)
|
96.13
(19)
|
| Title | Apparent Volume of Distribution (Vz/F) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 8 | 11 |
| Geometric Mean (Geometric Coefficient of Variation) [liter (L)] |
1087
(42)
|
1211
(37)
|
| Title | Terminal Half-life (t1/2) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 8 | 11 |
| Mean (Standard Deviation) [hrs] |
8.318
(4.2508)
|
9.261
(3.5165)
|
| Title | Cumulative Amount of Drug Recovered Unchanged in Urine From 0 to 48 Hours (Ae) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 11 | 12 |
| Median (Full Range) [milligram (mg)] |
168.0
|
170.5
|
| Title | Percent of Dose Recovered Unchanged in Urine From 0 to 24 Hours (Ae%) of Metformin |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Overall number of participants analyzed referred to participants evaluable for this outcome measure. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 11 | 12 |
| Median (Full Range) [percentage of dose] |
33.60
|
34.05
|
| Title | Number of Participants With Laboratory Abnormalities |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomly assigned to investigational product and who took at least 1 dose of investigational product. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 12 | 12 |
| Count of Participants [Participants] |
0
0%
|
0
NaN
|
| Title | Number of Participants With Categorical Vital Signs Meeting Pre-defined Criteria |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomly assigned to investigational product and who took at least 1 dose of investigational product. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 12 | 12 |
| Supine DBP Value < 50 mmHg |
0
0%
|
0
NaN
|
| Supine DBP Chg ≥ 20 mmHg increase |
0
0%
|
0
NaN
|
| Supine DBP Chg ≥ 20 mmHg decrease |
0
0%
|
0
NaN
|
| Supine pulse rate Value < 40 bpm |
0
0%
|
0
NaN
|
| Supine pulse rate Value > 120 bpm |
0
0%
|
0
NaN
|
| Supine SBP Value < 90 mmHg |
0
0%
|
0
NaN
|
| Supine SBP Chg ≥ 30 mmHg increase |
0
0%
|
0
NaN
|
| Supine SBP Chg ≥ 30 mmHg decrease |
0
0%
|
0
NaN
|
| Title | Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) (All Causalities and Treatment-related) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomly assigned to investigational product and who took at least 1 dose of investigational product. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 12 | 12 |
| AEs (all causalities) |
6
50%
|
4
NaN
|
| AEs (treatment-related) |
5
41.7%
|
4
NaN
|
| SAEs (all causalities) |
0
0%
|
0
NaN
|
| SAEs (treatment-related) |
0
0%
|
0
NaN
|
| Title | Percentage of Participants With Treatment-Emergent AEs and SAEs (All Causalities and Treatment-related) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| This analysis population was defined as all participants randomly assigned to investigational product and who took at least 1 dose of investigational product. |
| Arm/Group Title | Metformin + PF-04965842 | Metformin |
|---|---|---|
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. |
| Measure Participants | 12 | 12 |
| AEs (all causalities) |
50.0
416.7%
|
33.3
NaN
|
| AEs (treatment-related) |
41.7
347.5%
|
33.3
NaN
|
| SAEs (all causalities) |
0.0
0%
|
0.0
NaN
|
| SAEs (treatment-related) |
0.0
0%
|
0.0
NaN
|
Adverse Events
| Time Frame | Day 1 up to Day 40 (35 days after the last dose of metformin) | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Metformin + PF-04965842 | Metformin | ||
| Arm/Group Description | This reporting group refers to the participants who were randomized to the group of concomitantly single oral administration of metformin 500 mg QD on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 1-2 in either of the periods. | This reporting group refers to the participants who were randomized to the group of single oral administration of metformin 500 mg QD on Day 1 in either of the periods. | ||
All Cause Mortality |
||||
| Metformin + PF-04965842 | Metformin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 0/12 (0%) | ||
Serious Adverse Events |
||||
| Metformin + PF-04965842 | Metformin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | 0/12 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Metformin + PF-04965842 | Metformin | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/12 (50%) | 4/12 (33.3%) | ||
| Gastrointestinal disorders | ||||
| Abdominal discomfort | 1/12 (8.3%) | 1 | 0/12 (0%) | 0 |
| Anorectal discomfort | 1/12 (8.3%) | 1 | 0/12 (0%) | 0 |
| Diarrhoea | 4/12 (33.3%) | 4 | 3/12 (25%) | 3 |
| Nausea | 1/12 (8.3%) | 1 | 0/12 (0%) | 0 |
| General disorders | ||||
| Fatigue | 0/12 (0%) | 0 | 1/12 (8.3%) | 1 |
| Infections and infestations | ||||
| Nasopharyngitis | 0/12 (0%) | 0 | 1/12 (8.3%) | 1 |
| Musculoskeletal and connective tissue disorders | ||||
| Muscle spasms | 0/12 (0%) | 0 | 1/12 (8.3%) | 1 |
| Neck pain | 1/12 (8.3%) | 1 | 0/12 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
| Name/Title | Pfizer ClinicalTrials.gov Call Center |
|---|---|
| Organization | Pfizer, Inc |
| Phone | 1-800-718-1021 |
| ClinicalTrials.gov_Inquires@pfizer.com |
- B7451034
- DDI
- 2018-003683-31