Type 2 Diabetes Mellitus, Hepatic Impairment
Conditions
Brief summary
This is a study to assess the pharmacokinetics and safety of ertugliflozin (MK-8835, PF-04971729) in participants with hepatic impairment versus healthy participants. In Part 1 of the study, participants with moderate hepatic impairment (Child-Pugh score 7-9) and matched healthy participants will be enrolled; depending on results in Part 1, Part 2 may be conducted and will enroll participants with mild hepatic impairment (Child-Pugh score 5-6).
Interventions
Tablet
Sponsors
Pfizer
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
ALL PARTICIPANTS: * Body Mass Index (BMI) of 18 to 40 kg/m\^2; and a total body weight \>50 kg (110 lbs) * Male or female not of reproductive potential * If a female of reproductive potential, agrees to remain abstinent from heterosexual activity or agree to use or have their partner use 2 methods of acceptable contraception to prevent pregnancy while the participant is receiving study medication and for 14 days after the last dose of study medication PARTICIPANTS WITH NORMAL HEPATIC FUNCTION * Healthy with normal hepatic function PARTICIPANTS WITH HEPATIC IMPAIRMENT * Satisfy the criteria for Child-Pugh classification \[moderate (Part 1): Child-Pugh Scores 7-9 points, mild (Part 2): Child-Pugh Scores 5-6 points\] within 14 days before administration of study medication * A diagnosis of hepatic impairment due to primary liver disease and not secondary to other diseases * Stable hepatic impairment, defined as no clinically-significant change in disease status within the last 30 days * On a stable dose of medication and/or treatment regimen used to manage hepatic disease for at least 4 weeks prior to study start
Exclusion criteria
ALL PARTICIPANTS * A known hypersensitivity or intolerance to ertugliflozin or any other Sodium-Glucose co-Transporter 2 (SGLT2) inhibitor (i.e., canagliflozin \[Invokana\], dapagliflozin \[Farxiga\], empagliflozin, or ipragliflozin) * Febrile illness within 5 days prior to the first dose of study medication * Any clinically significant malabsorption condition * A positive urine drug screen for drugs of abuse or recreational drugs * Abuse of alcohol or binge drinking and/or any other illicit drug use or dependence within 6 months of study start * Treatment with an investigational drug within 30 days preceding the first dose of study medication * Pregnant or breastfeeding females * Use of herbal supplements within 28 days prior to the first dose of study medication * Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 56 days prior to dosing * History of sensitivity to heparin or heparin-induced thrombocytopenia PARTICIPANTS WITH NORMAL HEPATIC FUNCTION * Use of prescription drugs (hormonal methods of birth control are allowed), vitamins, and dietary supplements within 7 days prior to the first dose of study medication * Positive serology for Hepatitis B or C PARTICIPANTS WITH HEPATIC IMPAIRMENT * Hepatic carcinoma and hepatorenal syndrome or life expectancy less than 1 year * Undergone portal-caval shunt surgery * History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less than 1 month prior to study entry * Signs of significant hepatic encephalopathy * Severe ascites and/or pleural effusion * A transplanted kidney, heart or liver * Received any of the following medications within 7 days prior to the first dose of study medication or during the study: other SGLT2 inhibitors (eg, dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin); any potent drug-metabolizing enzyme-inducing drug, including rifampin, phenytoin, and carbamazepine; probenecid, valproic acid, gemfibrozil
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUClast) for Ertugliflozin | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | Area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (AUClast). |
| AUC From Hour 0 to Infinity (AUCinf) for Ertugliflozin | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | Area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Ertugliflozin | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. |
| AUClast for Fraction of Ertugliflozin Unbound in Plasma (AUClast,u) | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | Area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (Clast) for unbound drug (ertugliflozin only). |
| Number of Participants Who Experienced an Adverse Event | Up to 19 days | An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
| Cmax for Fraction of Ertugliflozin Unbound in Plasma (Cmax,u) | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | Maximum plasma concentration for unbound drug (ertugliflozin only). |
| AUCinf for Fraction of Ertugliflozin Unbound in Plasma (AUCinf,u) | Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours | Area under the plasma concentration-time profile from time zero extrapolated to infinite time for unbound drug (ertugliflozin only) (AUCinf, u). |
Participant flow
Recruitment details
Based on a statistical evaluation of the pharmacokinetic (PK) data obtained from participants with moderate hepatic impairment and matched healthy volunteers, and the pre-specified decision criteria, Part 2 of the study was not conducted and participants with mild hepatic impairment were not enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Ertugliflozin 15 mg (Moderate Hepatic Impairment) Participants received a single 15 mg oral dose (tablet) of ertugliflozin. | 8 |
| Ertugliflozin 15 mg (Normal Hepatic Function) Participants received a single 15 mg oral dose (tablet) of ertugliflozin. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Ertugliflozin 15 mg (Moderate Hepatic Impairment) | Ertugliflozin 15 mg (Normal Hepatic Function) | Total |
|---|---|---|---|
| Age, Continuous | 55.1 Years FULL_RANGE 3.4 | 55.5 Years FULL_RANGE 3 | 55.3 Years |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 8 | 3 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUClast) for Ertugliflozin
Area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (AUClast).
Time frame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
Population: The analysis population was all treated participants who had at least 1 measurement of the AUClast parameter. Based on a statistical evaluation of the PK data from participants with moderate hepatic impairment and matched healthy volunteers, Part 2 of the study was not conducted and participants with mild hepatic impairment were not enrolled.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 15 mg (Moderate Hepatic Impairment) | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUClast) for Ertugliflozin | 1413 ng•hr/mL | Geometric Coefficient of Variation 39 |
| Ertugliflozin 15 mg (Normal Hepatic Function) | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUClast) for Ertugliflozin | 1618 ng•hr/mL | Geometric Coefficient of Variation 14 |
90% CI: [68.01, 112.08]
Primary
AUC From Hour 0 to Infinity (AUCinf) for Ertugliflozin
Area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf).
Time frame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
Population: The analysis population was all treated participants who had at least 1 measurement of the AUCinf parameter. Based on a statistical evaluation of the PK data from participants with moderate hepatic impairment and matched healthy volunteers, Part 2 of the study was not conducted and participants with mild hepatic impairment were not enrolled.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 15 mg (Moderate Hepatic Impairment) | AUC From Hour 0 to Infinity (AUCinf) for Ertugliflozin | 1430 ng•hr/mL | Geometric Coefficient of Variation 39 |
| Ertugliflozin 15 mg (Normal Hepatic Function) | AUC From Hour 0 to Infinity (AUCinf) for Ertugliflozin | 1636 ng•hr/mL | Geometric Coefficient of Variation 14 |
90% CI: [68.11, 112.22]
Secondary
AUCinf for Fraction of Ertugliflozin Unbound in Plasma (AUCinf,u)
Area under the plasma concentration-time profile from time zero extrapolated to infinite time for unbound drug (ertugliflozin only) (AUCinf, u).
Time frame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
Population: The analysis population was all treated participants who had at least 1 measurement of the AUCinf,u parameter. Based on a statistical evaluation of the PK data from participants with moderate hepatic impairment and matched healthy volunteers, Part 2 of the study was not conducted and participants with mild hepatic impairment were not enrolled.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 15 mg (Moderate Hepatic Impairment) | AUCinf for Fraction of Ertugliflozin Unbound in Plasma (AUCinf,u) | 53.14 ng•hr/mL | Geometric Coefficient of Variation 44 |
| Ertugliflozin 15 mg (Normal Hepatic Function) | AUCinf for Fraction of Ertugliflozin Unbound in Plasma (AUCinf,u) | 55.40 ng•hr/mL | Geometric Coefficient of Variation 16 |
90% CI: [72.46, 126.97]
Secondary
AUClast for Fraction of Ertugliflozin Unbound in Plasma (AUClast,u)
Area under the plasma concentration-time profile from time zero to time of the last quantifiable concentration (Clast) for unbound drug (ertugliflozin only).
Time frame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
Population: The analysis population was all treated participants who had at least 1 measurement of the AUClast,u parameter. Based on a statistical evaluation of the PK data from participants with moderate hepatic impairment and matched healthy volunteers, Part 2 of the study was not conducted and participants with mild hepatic impairment were not enrolled.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 15 mg (Moderate Hepatic Impairment) | AUClast for Fraction of Ertugliflozin Unbound in Plasma (AUClast,u) | 52.47 ng•hr/mL | Geometric Coefficient of Variation 44 |
| Ertugliflozin 15 mg (Normal Hepatic Function) | AUClast for Fraction of Ertugliflozin Unbound in Plasma (AUClast,u) | 54.77 ng•hr/mL | Geometric Coefficient of Variation 15 |
90% CI: [72.4, 126.79]
Secondary
Cmax for Fraction of Ertugliflozin Unbound in Plasma (Cmax,u)
Maximum plasma concentration for unbound drug (ertugliflozin only).
Time frame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
Population: The analysis population was all treated participants who had at least 1 measurement of the Cmax,u parameter. Based on a statistical evaluation of the PK data from participants with moderate hepatic impairment and matched healthy volunteers, Part 2 of the study was not conducted and participants with mild hepatic impairment were not enrolled.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 15 mg (Moderate Hepatic Impairment) | Cmax for Fraction of Ertugliflozin Unbound in Plasma (Cmax,u) | 9.336 ng/mL | Geometric Coefficient of Variation 30 |
| Ertugliflozin 15 mg (Normal Hepatic Function) | Cmax for Fraction of Ertugliflozin Unbound in Plasma (Cmax,u) | 10.79 ng/mL | Geometric Coefficient of Variation 15 |
90% CI: [70.49, 106.2]
Secondary
Maximum Plasma Concentration (Cmax) of Ertugliflozin
Cmax is a measure of the maximum amount of drug in the plasma after the dose is given.
Time frame: Hour 0 (predose), and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, and 96 hours
Population: The analysis population was all treated participants who had at least 1 measurement of the Cmax parameter. Based on a statistical evaluation of the PK data from participants with moderate hepatic impairment and matched healthy volunteers, Part 2 of the study was not conducted and participants with mild hepatic impairment were not enrolled.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 15 mg (Moderate Hepatic Impairment) | Maximum Plasma Concentration (Cmax) of Ertugliflozin | 251.1 ng/mL | Geometric Coefficient of Variation 27 |
| Ertugliflozin 15 mg (Normal Hepatic Function) | Maximum Plasma Concentration (Cmax) of Ertugliflozin | 319.0 ng/mL | Geometric Coefficient of Variation 11 |
90% CI: [65.74, 94.23]
Secondary
Number of Participants Who Experienced an Adverse Event
An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to 19 days
Population: The analysis population was defined as all treated participants. Based on a statistical evaluation of the PK data from participants with moderate hepatic impairment and matched healthy volunteers, Part 2 of the study was not conducted and participants with mild hepatic impairment were not enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 15 mg (Moderate Hepatic Impairment) | Number of Participants Who Experienced an Adverse Event | 2 Participants |
| Ertugliflozin 15 mg (Normal Hepatic Function) | Number of Participants Who Experienced an Adverse Event | 3 Participants |