Renal Impairment
Conditions
Keywords
MK-3402
Brief summary
The purpose of this study is to compare the plasma and urine pharmacokinetics (PK) of MK-3402 in participants with impaired renal function and healthy control participants, to investigate the extent to which MK-3402 is removed from the plasma by hemodialysis (HD), and evaluate the safety and tolerability of MK-3402 in participants with impaired renal function.
Interventions
DRUGMK-3402
MK-3402 administered as a single dose of 100 mg IV infusion on the following dosage days: Panels A to D: Day 1 Panel E: Day 1 in Periods 1 and 2
Sponsors
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
* Is in good health based on medical history, physical examination, vital signs (VS) measurements, and electrocardiogram (ECG)s performed before randomization. * Is in good health based on laboratory safety tests obtained at the screening visit and before administration of the initial dose of study drug. * Has a body mass index (BMI) ≥18 kg/m2 and ≤40 kg/m2. BMI = weight (kg)/height (m)2. * Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of study intervention: * Refrain from donating sperm * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent or must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) * A female participant is eligible to participate if she is a woman of non-childbearing potential. * Panel A: Has a baseline estimated glomerular filtration rate (eGFR) ≥60 and \<90 mL/min/1.73 m2 based on the Modification of Diet in Renal Disease (MDRD) equation. * Panel B: Has a baseline eGFR ≥30 and \<60 mL/min/1.73 m2 based on the MDRD equation. * Panel C: Has a baseline eGFR ≥15 and \<30 mL/min/1.73 m2 based on the MDRD equation. * Panels A, B and C: Has had no clinically significant change in renal status at least 1 month prior to dosing and is not currently receiving or has not previously been on hemodialysis (HD). * Panel D: Has an eGFR ≥90 mL/min/1.73 m2 based on the MDRD equation. * Panel E: Has end stage renal disease (ESRD) and maintained on a stable regimen of at least 3 times per week HD for at least 3 months prior to first dosing.
Exclusion criteria
* Panels A, B, C and E: Has a history of any clinically significant concomitant disease or condition (including treatment for such conditions) or diseases whose current condition is considered clinically unstable that, in the opinion of the investigator, could either interfere with the study drug, compromise interpretation of study data, or pose an unacceptable risk to the patient. * Panel D: Has a history of clinically significant endocrine, gastrointestinal (GI), cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases. Participants with a remote history of uncomplicated medical events (eg, uncomplicated kidney stones, as defined as spontaneous passage and no recurrence in the last 5 years, or childhood asthma) may be enrolled in the study at the discretion of the investigator. * Is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder that would impact study conduct. Participants who have had situational depression may be enrolled in the study at the discretion of the investigator. * Has a history of cancer (malignancy). * Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or; (2) Other malignancies that have been successfully treated with appropriate follow up and therefore unlikely to recur for the duration of the study, in the opinion of the investigator and with agreement of the Sponsor (eg, malignancies that have been successfully treated ≥10 years prior to the prestudy screening visit). * Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic reaction) to prescription or nonprescription drugs or food. * Is positive for hepatitis B surface antigen (HBsAg), hepatitis C antibodies or human immunodeficiency virus (HIV). * Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit. * Panels A, B, C and E: Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies for the prohibited time period. * Panel D: Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), until the poststudy visit. There may be certain medications that are permitted. * Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to study drug administration. The window will be derived from the date of the last dose of study medication in the previous study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Dosing to Infinity (AUC0-inf) of MK-3402 | Pre-dose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1 | AUC0-inf is defined as area under the plasma concentration-time curve from dosing to infinity. |
| Plasma Concentration at the End of Infusion (Ceoi) of MK-3402 | Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1 | Ceoi is defined as the amount of study drug in plasma following IV infusion administration of study drug. Plasma samples were collected at pre-specified time points and Ceoi was assessed. |
| Time to Maximum Plasma Concentration (Tmax) of MK-3402 | Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1 | Tmax is defined as the time required for a study drug to reach maximum concentration in plasma. Plasma samples were collected at pre-specified time points and Tmax was assessed. |
| Apparent Plasma Half-life (t½) of MK-3402 | Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1 | t½ is defined as the time required for plasma drug concentration of study drug to decrease by 50% from peak. |
| Apparent Plasma Clearance (CL) of MK-3402 | Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1 | CL is defined as the time it takes for the study drug to be completely removed from the body's plasma. |
| Volume of Distribution (Vd) of MK-3402 | Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1 | Vd is defined as the distributed volume of study drug in plasma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hemodialysis Clearance Based on Plasma (CLD Dialysate) of MK-3402 | Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion | Plasma dialysis samples were to be collected at pre-specified time points to measure CLD dialysate. |
| Amount Recovered in Urine From 0 to 24 Hours (Ae0-24) of MK-3402 | Pre-dose and 0-4, 4-8, 8-12, and 12-24 hours postdose | Ae0-24 is defined as the amount of study drug unchanged in urine after 0-24 hours. Urine samples were collected at pre-specified intervals and Ae0-24 was assessed. |
| Number of Participants With Adverse Events (AE) | Up to 15 days | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug |
| Renal Clearance (CLr) of MK-3402 | Pre-dose and 0-4, 4-8, 8-12, and 12-24 hours postdose | CLr is defined as the time it takes for the study drug to be completely removed by the kidneys. |
| Fraction of Dose Recovered in Urine (Fe) of MK-3402 | Pre-dose and 0-4, 4-8, 8-12, and 12-24 hours postdose | Fe is defined as the fraction of the dose of study drug in urine. |
| Number of Participants Who Discontinued From Study Due to an AE | Up to 15 days | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug |
| Dialysis Clearance Based on Plasma (CLDplasma) of MK-3402 | Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion | Plasma dialysis samples were to be collected at pre-specified time points to calculate CLDplasma. |
| Concentration of Dialysate (CD) of MK-3402 | Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion | Plasma dialysis samples were to be collected at pre-specified time points to calculate CD. |
| Amount of Drug Recovered From the Dialysate From Plasma (AED) of MK-3402 | Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion | Plasma dialysis samples were to be collected at pre-specified time points to calculate AED. |
| Percentage of AED (% Dose) of MK-3402 | Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion. | Plasma dialysis samples were to be collected at pre-specified time points to calculate AED (% dose). |
Countries
United States
Participant flow
Recruitment details
Male/female participants with mild, moderate, or severe renal impairment (RI), end stage renal disease (ESRD), or healthy matched adults between the ages of 18 and 75 years (inclusive) were recruited at 2 study sites in the United States. However, the study was terminated early due to business reasons prior to enrollment of healthy control participants and participants with severe RI or ESRD, and thus no comparisons could be made.
Participants by arm
| Arm | Count |
|---|---|
| Panel A: Mild Renal Impairment Participants with mild renal impairment will receive a single dose of 100 mg MK-3402 via intravenous (IV) infusion on Day 1. | 4 |
| Panel B: Moderate Renal Impairment Participants with moderate renal impairment will receive a single dose of 100 mg MK-3402 via IV infusion on Day 1. | 5 |
| Total | 9 |
Baseline characteristics
| Characteristic | Panel B: Moderate Renal Impairment | Total | Panel A: Mild Renal Impairment |
|---|---|---|---|
| Age, Continuous | 67.6 years STANDARD_DEVIATION 2.6 | 64.4 years STANDARD_DEVIATION 6 | 60.5 years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 9 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 8 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 5 |
| other Total, other adverse events | 0 / 4 | 2 / 5 |
| serious Total, serious adverse events | 0 / 4 | 0 / 5 |
Outcome results
Primary
Apparent Plasma Clearance (CL) of MK-3402
CL is defined as the time it takes for the study drug to be completely removed from the body's plasma.
Time frame: Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1
Population: Participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Panel A: Mild Renal Impairment | Apparent Plasma Clearance (CL) of MK-3402 | 3.13 L/hr | Geometric Coefficient of Variation 18.5 |
| Panel B: Moderate Renal Impairment | Apparent Plasma Clearance (CL) of MK-3402 | 2.28 L/hr | Geometric Coefficient of Variation 16.1 |
Primary
Apparent Plasma Half-life (t½) of MK-3402
t½ is defined as the time required for plasma drug concentration of study drug to decrease by 50% from peak.
Time frame: Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1
Population: Participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Panel A: Mild Renal Impairment | Apparent Plasma Half-life (t½) of MK-3402 | 5.06 hours | Geometric Coefficient of Variation 15.2 |
| Panel B: Moderate Renal Impairment | Apparent Plasma Half-life (t½) of MK-3402 | 8.12 hours | Geometric Coefficient of Variation 9.1 |
Primary
Area Under the Curve From Dosing to Infinity (AUC0-inf) of MK-3402
AUC0-inf is defined as area under the plasma concentration-time curve from dosing to infinity.
Time frame: Pre-dose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1
Population: Participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Panel A: Mild Renal Impairment | Area Under the Curve From Dosing to Infinity (AUC0-inf) of MK-3402 | 71.9 hr*µmol/L | Geometric Coefficient of Variation 18.2 |
| Panel B: Moderate Renal Impairment | Area Under the Curve From Dosing to Infinity (AUC0-inf) of MK-3402 | 96.4 hr*µmol/L | Geometric Coefficient of Variation 17.5 |
Primary
Plasma Concentration at the End of Infusion (Ceoi) of MK-3402
Ceoi is defined as the amount of study drug in plasma following IV infusion administration of study drug. Plasma samples were collected at pre-specified time points and Ceoi was assessed.
Time frame: Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1
Population: Participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Panel A: Mild Renal Impairment | Plasma Concentration at the End of Infusion (Ceoi) of MK-3402 | 16.8 µmol/L | Geometric Coefficient of Variation 26 |
| Panel B: Moderate Renal Impairment | Plasma Concentration at the End of Infusion (Ceoi) of MK-3402 | 14.3 µmol/L | Geometric Coefficient of Variation 31.1 |
Primary
Time to Maximum Plasma Concentration (Tmax) of MK-3402
Tmax is defined as the time required for a study drug to reach maximum concentration in plasma. Plasma samples were collected at pre-specified time points and Tmax was assessed.
Time frame: Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1
Population: Participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panel A: Mild Renal Impairment | Time to Maximum Plasma Concentration (Tmax) of MK-3402 | 0.59 hours |
| Panel B: Moderate Renal Impairment | Time to Maximum Plasma Concentration (Tmax) of MK-3402 | 0.57 hours |
Primary
Volume of Distribution (Vd) of MK-3402
Vd is defined as the distributed volume of study drug in plasma.
Time frame: Predose and 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, and 48 hours postdose on Day 1
Population: Participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Panel A: Mild Renal Impairment | Volume of Distribution (Vd) of MK-3402 | 22.9 liters | Geometric Coefficient of Variation 5.3 |
| Panel B: Moderate Renal Impairment | Volume of Distribution (Vd) of MK-3402 | 26.6 liters | Geometric Coefficient of Variation 20.4 |
Secondary
Amount of Drug Recovered From the Dialysate From Plasma (AED) of MK-3402
Plasma dialysis samples were to be collected at pre-specified time points to calculate AED.
Time frame: Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion
Population: The study was terminated early prior to enrollment of participants on dialysis, and thus no data were collected for this endpoint.
Secondary
Amount Recovered in Urine From 0 to 24 Hours (Ae0-24) of MK-3402
Ae0-24 is defined as the amount of study drug unchanged in urine after 0-24 hours. Urine samples were collected at pre-specified intervals and Ae0-24 was assessed.
Time frame: Pre-dose and 0-4, 4-8, 8-12, and 12-24 hours postdose
Population: Participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Panel A: Mild Renal Impairment | Amount Recovered in Urine From 0 to 24 Hours (Ae0-24) of MK-3402 | 91.8 mg | Geometric Coefficient of Variation 32.7 |
| Panel B: Moderate Renal Impairment | Amount Recovered in Urine From 0 to 24 Hours (Ae0-24) of MK-3402 | 61.5 mg | Geometric Coefficient of Variation 42.4 |
Secondary
Concentration of Dialysate (CD) of MK-3402
Plasma dialysis samples were to be collected at pre-specified time points to calculate CD.
Time frame: Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion
Population: The study was terminated early prior to enrollment of participants on dialysis, and thus no data were collected for this endpoint.
Secondary
Dialysis Clearance Based on Plasma (CLDplasma) of MK-3402
Plasma dialysis samples were to be collected at pre-specified time points to calculate CLDplasma.
Time frame: Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion
Population: The study was terminated early prior to enrollment of participants on dialysis, and thus no data were collected for this endpoint.
Secondary
Fraction of Dose Recovered in Urine (Fe) of MK-3402
Fe is defined as the fraction of the dose of study drug in urine.
Time frame: Pre-dose and 0-4, 4-8, 8-12, and 12-24 hours postdose
Population: Participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Panel A: Mild Renal Impairment | Fraction of Dose Recovered in Urine (Fe) of MK-3402 | 86.8 percentage | Geometric Coefficient of Variation 35.1 |
| Panel B: Moderate Renal Impairment | Fraction of Dose Recovered in Urine (Fe) of MK-3402 | 59.7 percentage | Geometric Coefficient of Variation 41.2 |
Secondary
Hemodialysis Clearance Based on Plasma (CLD Dialysate) of MK-3402
Plasma dialysis samples were to be collected at pre-specified time points to measure CLD dialysate.
Time frame: Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion
Population: The study was terminated early prior to enrollment of participants on dialysis, and thus no data were collected for this endpoint.
Secondary
Number of Participants Who Discontinued From Study Due to an AE
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug
Time frame: Up to 15 days
Population: All participants who received ≥1 dose of study drug are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Panel A: Mild Renal Impairment | Number of Participants Who Discontinued From Study Due to an AE | 0 Participants |
| Panel B: Moderate Renal Impairment | Number of Participants Who Discontinued From Study Due to an AE | 0 Participants |
Secondary
Number of Participants With Adverse Events (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug
Time frame: Up to 15 days
Population: All participants who received ≥1 dose of study drug are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Panel A: Mild Renal Impairment | Number of Participants With Adverse Events (AE) | 0 Participants |
| Panel B: Moderate Renal Impairment | Number of Participants With Adverse Events (AE) | 2 Participants |
Secondary
Percentage of AED (% Dose) of MK-3402
Plasma dialysis samples were to be collected at pre-specified time points to calculate AED (% dose).
Time frame: Panel E, Period 2: Pre-dose and 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after the start of infusion.
Population: The study was terminated early prior to enrollment of participants on dialysis, and thus no data were collected for this endpoint.
Secondary
Renal Clearance (CLr) of MK-3402
CLr is defined as the time it takes for the study drug to be completely removed by the kidneys.
Time frame: Pre-dose and 0-4, 4-8, 8-12, and 12-24 hours postdose
Population: Participants who complied with the protocol sufficiently to ensure that generated data will be likely to exhibit the effects of treatment, according to the underlying scientific model, are included. As the study was terminated early, no participants were enrolled in Panels C, D, or E.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Panel A: Mild Renal Impairment | Renal Clearance (CLr) of MK-3402 | 2.81 L/h | Geometric Coefficient of Variation 48.6 |
| Panel B: Moderate Renal Impairment | Renal Clearance (CLr) of MK-3402 | 1.52 L/h | Geometric Coefficient of Variation 36.7 |