Healthy Volunteers, Renal Impairment
Conditions
Brief summary
The purpose of this study is to characterize the effect of renal function on the plasma, urine, and dialysate pharmacokinetic profile of MK-6183 (CB-238,618) in humans. The study will also assess the safety profile and tolerability of MK-6183 in healthy participants, participants with varying degrees of renal impairment (RI), or participants with end-stage renal disease (ESRD) requiring hemodialysis (HD), based on estimated glomerular filtration rate (eGFR).
Interventions
DRUGMK-6183
MK-6183 (CB-238,614) is supplied as lyophilized powder 500 mg vial and mixed into solution for 100 mL intravenous (IV) administration over 1 hour.
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Participants who are healthy; or who have mild, moderate, or severe RI; or who have ESRD requiring HD. Participants with ESRD requiring HD should have been receiving HD 3 times per week for at least 3 months preceding the initial dose in this study
Exclusion criteria
* For healthy participants (Group A): history or presence of any clinically significant illness (e.g., cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, musculoskeletal, or psychiatric) or any other condition, including clinically significant anemia, which in the opinion of the investigator would jeopardize the safety of the participant or the validity of the study results * For participants with RI (Groups B to E): as above, except that RI and other medical conditions commonly associated with renal impairment (eg, hypertension, diabetes, which should be stable for at least three months preceding the initial dose of study medication in this study) are allowed * Clinically significant abnormalities on physical examination, medical history, 12-lead electrocardiogram (ECG), vital signs, or laboratory values, as judged by the investigator or designee. Subjects with renal impairment should have clinical laboratory values consistent with their disease and approved by the investigator * Evidence of clinically significant hepatic impairment including alanine aminotransferase or aspartate aminotransferase \>1.5 × upper limit of normal (ULN) or bilirubin \>1 × ULN * Hemoglobin \<8 g/dL, unless considered stable and not clinically significant in the opinion of the investigator in subjects with ESRD and on HD * Participants with renal impairment who are not on a chronic stable drug regimen, defined as starting a new drug or changing dosage within 14 days prior to administration of study medication, except for drugs administered in relationship to HD * Participants with fluctuating or rapidly deteriorating renal function (assessment of the stability of the subject's renal function will be determined by the investigator) * Participant has a currently functioning renal transplant and/or has been on significant immunosuppressant therapy, as determined by the investigator, within the last 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fraction of the Administered Dose of MK-6183 Excreted Unchanged in Urine or Dialysate (Fe) | Groups A to D (urine): 0 to 24, 24 to 48, and 48 to 72 hours post-dose; Group E (dialysate): 0 to 1, 1 to 2, 2 to 3, and 3 to 4 hours after starting HD | Fe is the fraction (percentage) of the administered dose that was excreted unchanged in urine (Groups A to D) or dialysate (Group E: Period 1; HD commenced 3 hours after dosing). |
| Renal Clearance of MK-6183 (CLr) | 0 to 24, 24 to 48, and 48 to 72 hours post-dose | CLr is the clearance of drug from plasma via the kidneys. Only data from Groups A, B, C, and D is presented; participants in Group E (Period 1) had no detectable urine data. Data for Group E: Period 1 are presented below in the dialysate clearance measure. |
| Dialysate Clearance of MK-6183 (CLd) | 0 to 1, 1 to 2, 2 to 3, and 3 to 4 hours after starting HD | CLd is the amount of drug cleared from plasma via dialysis. Only data collected during HD (Group E: Period 1) is presented (HD commenced 3 hours after dosing). |
| Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Last Measurable Concentration (AUC0-last) of MK-6183 | Groups A to D & Group E: Period 2: Pre-dose and 0.5, 1 (end of infusion; EOI), 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose | AUC0-last is the area under the plasma concentration-time curve from the time of dosing to the last post-dose measurable concentration. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of plasma sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. |
| AUC From Dosing to ∞ (AUC0-∞) of MK-6183 | Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose | AUC0-∞ is the extrapolated area under the plasma concentration-time curve from the time of dosing to infinity. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of plasma sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. For statistical analyses, Group A is the reference and least squares (LS) mean ratios for tests (Groups B to E) are calculated as test/reference; Group E: Period 1 and Group E: Period 2 were also compared. |
| Maximum Plasma Drug Concentration (Cmax) of MK-6183 | Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose | Cmax is the maximum observed post-dose drug concentration in plasma. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. For statistical analyses, Group A is the reference and LS mean ratios for tests (Groups B to E) are calculated as test/reference; Group E: Period 1 and Group E: Period 2 were also compared. |
| Apparent Total Body Clearance of MK-6183 From Plasma (CL) | Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose | CL is a measure of the clearance of drug from plasma via metabolism and excretion. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of plasma sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. |
| Volume of Distribution at Steady State (Vss) of MK-6183 | Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose | Vss is the apparent volume of distribution at steady state for MK-6183. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. |
| Apparent Plasma Half-life (t½) of MK-6183 | Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose | t½ is the amount of time required for the plasma concentration of MK-6183 to reduce by 50%. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. |
| Cumulative Amount of MK-6183 Excreted in Urine or Dialysate (Ae) | Groups A to D (urine): 0 to 24, 24 to 48, and 48 to 72 hours post-dose; Group E (dialysate): 0 to 1, 1 to 2, 2 to 3, and 3 to 4 hours after starting HD | Ae is the cumulative amount of drug excreted unchanged in urine or dialysate. For Groups A, B, C, and D, Ae was assessed in urine. For Group E: Period 1, Ae was assessed in dialysate (participants in Group E had no detectable urine data) at hourly collection intervals during HD (HD commenced 3 hours after dosing). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Discontinuing From the Study Due to an AE | Up to 12 days | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. |
| Number of Participants Experiencing an Adverse Event (AE) | Up to 12 days | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. |
Participant flow
Recruitment details
Healthy participants, participants with varying degrees of renal impairment (RI), and participants with end-stage renal disease (ESRD) requiring hemodialysis (HD) (renal status was based on estimated glomerular filtration rate \[eGFR\]) were recruited at 2 study sites in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Group A: Healthy Healthy participants with normal renal function (Stage 1: eGFR ≥90 mL/min/1.73m\^2) received MK-6183 1 g as a 1-hour IV infusion. | 8 |
| Group B: Mild RI Participants with mild RI (Stage 2: eGFR ≥60 to \<90 mL/min/1.73m\^2) received MK-6183 1 g as a 1-hour IV infusion. | 8 |
| Group C: Moderate RI Participants with moderate RI (Stage 3: eGFR ≥30 to \<60 mL/min/1.73m\^2) received MK-6183 500 mg as a 1-hour IV infusion. | 8 |
| Group D: Severe RI Participants with severe RI (Stage 4: eGFR \<30 mL/min/1.73m\^2 \[not receiving HD\]) received MK-6183 500 mg as a 1-hour IV infusion. | 8 |
| Group E: ESRD-HD Participants with ESRD who underwent HD for at least 3 months preceding the initial dose in this study (Stage 5) received MK-6183 250 mg as a 1-hour infusion twice (once prior to HD and once after HD \[doses given 48 hours apart\]). | 8 |
| Total | 40 |
Baseline characteristics
| Characteristic | Group A: Healthy | Group B: Mild RI | Group C: Moderate RI | Group D: Severe RI | Group E: ESRD-HD | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 55.3 Years STANDARD_DEVIATION 2.43 | 63.8 Years STANDARD_DEVIATION 11.16 | 69.1 Years STANDARD_DEVIATION 4.88 | 65.3 Years STANDARD_DEVIATION 10.47 | 55.1 Years STANDARD_DEVIATION 7.55 | 61.7 Years STANDARD_DEVIATION 44.81 |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 1 Participants | 4 Participants | 1 Participants | 11 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 7 Participants | 4 Participants | 7 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 4 / 8 | 2 / 8 | 2 / 8 | 3 / 8 | 4 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Apparent Plasma Half-life (t½) of MK-6183
t½ is the amount of time required for the plasma concentration of MK-6183 to reduce by 50%. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose.
Time frame: Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Population: All participants who received MK-6183 and had viable results are included. One participant from Group E: Period 1 and 1 participant from Group E: Period 2 were excluded due to implausible concentration values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | Apparent Plasma Half-life (t½) of MK-6183 | 2.1 Hours | Standard Deviation 0.45 |
| Group B: Mild RI | Apparent Plasma Half-life (t½) of MK-6183 | 2.8 Hours | Standard Deviation 0.33 |
| Group C: Moderate RI | Apparent Plasma Half-life (t½) of MK-6183 | 4.0 Hours | Standard Deviation 1.28 |
| Group D: Severe RI | Apparent Plasma Half-life (t½) of MK-6183 | 6.8 Hours | Standard Deviation 1.9 |
| Group E: ESRD-HD Period 1 | Apparent Plasma Half-life (t½) of MK-6183 | 18.1 Hours | Standard Deviation 3.79 |
| Group E: ESRD-HD Period 2 | Apparent Plasma Half-life (t½) of MK-6183 | 19.2 Hours | Standard Deviation 5.04 |
Primary
Apparent Total Body Clearance of MK-6183 From Plasma (CL)
CL is a measure of the clearance of drug from plasma via metabolism and excretion. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of plasma sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose.
Time frame: Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Population: All participants who received MK-6183 and had viable results are included. One participant from Group E: Period 1 and 1 participant from Group E: Period 2 were excluded due to implausible concentration values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | Apparent Total Body Clearance of MK-6183 From Plasma (CL) | 11.5 L/hour | Standard Deviation 1.23 |
| Group B: Mild RI | Apparent Total Body Clearance of MK-6183 From Plasma (CL) | 9.0 L/hour | Standard Deviation 1.65 |
| Group C: Moderate RI | Apparent Total Body Clearance of MK-6183 From Plasma (CL) | 5.5 L/hour | Standard Deviation 1.64 |
| Group D: Severe RI | Apparent Total Body Clearance of MK-6183 From Plasma (CL) | 2.4 L/hour | Standard Deviation 0.96 |
| Group E: ESRD-HD Period 1 | Apparent Total Body Clearance of MK-6183 From Plasma (CL) | 2.9 L/hour | Standard Deviation 0.26 |
| Group E: ESRD-HD Period 2 | Apparent Total Body Clearance of MK-6183 From Plasma (CL) | 0.9 L/hour | Standard Deviation 0.3 |
Primary
Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Last Measurable Concentration (AUC0-last) of MK-6183
AUC0-last is the area under the plasma concentration-time curve from the time of dosing to the last post-dose measurable concentration. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of plasma sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose.
Time frame: Groups A to D & Group E: Period 2: Pre-dose and 0.5, 1 (end of infusion; EOI), 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Population: All participants who received MK-6183 and had viable results are included. One participant from Group E: Period 1 and 1 participant from Group E: Period 2 were excluded due to implausible concentration values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Last Measurable Concentration (AUC0-last) of MK-6183 | 87.6 ug*hr/mL | Standard Deviation 8.49 |
| Group B: Mild RI | Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Last Measurable Concentration (AUC0-last) of MK-6183 | 114.8 ug*hr/mL | Standard Deviation 23.2 |
| Group C: Moderate RI | Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Last Measurable Concentration (AUC0-last) of MK-6183 | 97.5 ug*hr/mL | Standard Deviation 25.71 |
| Group D: Severe RI | Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Last Measurable Concentration (AUC0-last) of MK-6183 | 228.0 ug*hr/mL | Standard Deviation 63.24 |
| Group E: ESRD-HD Period 1 | Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Last Measurable Concentration (AUC0-last) of MK-6183 | 77.4 ug*hr/mL | Standard Deviation 8.79 |
| Group E: ESRD-HD Period 2 | Area Under the Plasma Concentration-time Curve (AUC) From Dosing to Last Measurable Concentration (AUC0-last) of MK-6183 | 270.6 ug*hr/mL | Standard Deviation 76.7 |
Primary
AUC From Dosing to ∞ (AUC0-∞) of MK-6183
AUC0-∞ is the extrapolated area under the plasma concentration-time curve from the time of dosing to infinity. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of plasma sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. For statistical analyses, Group A is the reference and least squares (LS) mean ratios for tests (Groups B to E) are calculated as test/reference; Group E: Period 1 and Group E: Period 2 were also compared.
Time frame: Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Population: All participants who received MK-6183 and had viable results are included. One participant from Group E: Period 1 and 1 participant from Group E: Period 2 were excluded due to implausible concentration values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | AUC From Dosing to ∞ (AUC0-∞) of MK-6183 | 87.8 ug*hr/mL | Standard Deviation 8.43 |
| Group B: Mild RI | AUC From Dosing to ∞ (AUC0-∞) of MK-6183 | 115.1 ug*hr/mL | Standard Deviation 23.44 |
| Group C: Moderate RI | AUC From Dosing to ∞ (AUC0-∞) of MK-6183 | 97.8 ug*hr/mL | Standard Deviation 25.7 |
| Group D: Severe RI | AUC From Dosing to ∞ (AUC0-∞) of MK-6183 | 228.6 ug*hr/mL | Standard Deviation 63.44 |
| Group E: ESRD-HD Period 1 | AUC From Dosing to ∞ (AUC0-∞) of MK-6183 | 86.8 ug*hr/mL | Standard Deviation 7.63 |
| Group E: ESRD-HD Period 2 | AUC From Dosing to ∞ (AUC0-∞) of MK-6183 | 296.3 ug*hr/mL | Standard Deviation 78.66 |
90% CI: [1.06, 1.58]
90% CI: [0.889, 1.32]
90% CI: [2.06, 3.06]
90% CI: [0.806, 1.21]
90% CI: [2.67, 4.02]
90% CI: [0.236, 0.378]
Primary
Cumulative Amount of MK-6183 Excreted in Urine or Dialysate (Ae)
Ae is the cumulative amount of drug excreted unchanged in urine or dialysate. For Groups A, B, C, and D, Ae was assessed in urine. For Group E: Period 1, Ae was assessed in dialysate (participants in Group E had no detectable urine data) at hourly collection intervals during HD (HD commenced 3 hours after dosing).
Time frame: Groups A to D (urine): 0 to 24, 24 to 48, and 48 to 72 hours post-dose; Group E (dialysate): 0 to 1, 1 to 2, 2 to 3, and 3 to 4 hours after starting HD
Population: All participants who received MK-6183 and had viable results are included. For Group E, only results from Period 1 are presented as Period 2 sampling occurred post-HD.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | Cumulative Amount of MK-6183 Excreted in Urine or Dialysate (Ae) | 840.5 mg | Standard Deviation 65.33 |
| Group B: Mild RI | Cumulative Amount of MK-6183 Excreted in Urine or Dialysate (Ae) | 699.1 mg | Standard Deviation 234.69 |
| Group C: Moderate RI | Cumulative Amount of MK-6183 Excreted in Urine or Dialysate (Ae) | 360.0 mg | Standard Deviation 33.82 |
| Group D: Severe RI | Cumulative Amount of MK-6183 Excreted in Urine or Dialysate (Ae) | 309.1 mg | Standard Deviation 51.3 |
| Group E: ESRD-HD Period 1 | Cumulative Amount of MK-6183 Excreted in Urine or Dialysate (Ae) | 122.9 mg | Standard Deviation 29.21 |
Primary
Dialysate Clearance of MK-6183 (CLd)
CLd is the amount of drug cleared from plasma via dialysis. Only data collected during HD (Group E: Period 1) is presented (HD commenced 3 hours after dosing).
Time frame: 0 to 1, 1 to 2, 2 to 3, and 3 to 4 hours after starting HD
Population: All participants who received MK-6183 and had viable results are included. Only data for Group E: Period 1 is presented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | Dialysate Clearance of MK-6183 (CLd) | 1.4 Liters/hour | Standard Deviation 0.42 |
Primary
Fraction of the Administered Dose of MK-6183 Excreted Unchanged in Urine or Dialysate (Fe)
Fe is the fraction (percentage) of the administered dose that was excreted unchanged in urine (Groups A to D) or dialysate (Group E: Period 1; HD commenced 3 hours after dosing).
Time frame: Groups A to D (urine): 0 to 24, 24 to 48, and 48 to 72 hours post-dose; Group E (dialysate): 0 to 1, 1 to 2, 2 to 3, and 3 to 4 hours after starting HD
Population: All participants who received MK-6183 and had viable results are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | Fraction of the Administered Dose of MK-6183 Excreted Unchanged in Urine or Dialysate (Fe) | 84.0 mg | Standard Deviation 6.53 |
| Group B: Mild RI | Fraction of the Administered Dose of MK-6183 Excreted Unchanged in Urine or Dialysate (Fe) | 69.9 mg | Standard Deviation 23.47 |
| Group C: Moderate RI | Fraction of the Administered Dose of MK-6183 Excreted Unchanged in Urine or Dialysate (Fe) | 72.0 mg | Standard Deviation 6.76 |
| Group D: Severe RI | Fraction of the Administered Dose of MK-6183 Excreted Unchanged in Urine or Dialysate (Fe) | 61.8 mg | Standard Deviation 10.26 |
| Group E: ESRD-HD Period 1 | Fraction of the Administered Dose of MK-6183 Excreted Unchanged in Urine or Dialysate (Fe) | 49.2 mg | Standard Deviation 11.68 |
Primary
Maximum Plasma Drug Concentration (Cmax) of MK-6183
Cmax is the maximum observed post-dose drug concentration in plasma. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose. For statistical analyses, Group A is the reference and LS mean ratios for tests (Groups B to E) are calculated as test/reference; Group E: Period 1 and Group E: Period 2 were also compared.
Time frame: Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Population: All participants who received MK-6183 and had viable results are included. One participant from Group E: Period 1 and 1 participant from Group E: Period 2 were excluded due to implausible concentration values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | Maximum Plasma Drug Concentration (Cmax) of MK-6183 | 45.3 ug/mL | Standard Deviation 5.23 |
| Group B: Mild RI | Maximum Plasma Drug Concentration (Cmax) of MK-6183 | 47.2 ug/mL | Standard Deviation 8.19 |
| Group C: Moderate RI | Maximum Plasma Drug Concentration (Cmax) of MK-6183 | 24.2 ug/mL | Standard Deviation 5.95 |
| Group D: Severe RI | Maximum Plasma Drug Concentration (Cmax) of MK-6183 | 30.8 ug/mL | Standard Deviation 3.9 |
| Group E: ESRD-HD Period 1 | Maximum Plasma Drug Concentration (Cmax) of MK-6183 | 12.9 ug/mL | Standard Deviation 4.6 |
| Group E: ESRD-HD Period 2 | Maximum Plasma Drug Concentration (Cmax) of MK-6183 | 15.6 ug/mL | Standard Deviation 6.59 |
90% CI: [0.554, 0.831]
90% CI: [0.846, 1.27]
90% CI: [0.428, 0.641]
90% CI: [0.221, 0.336]
90% CI: [0.265, 0.402]
90% CI: [0.65, 1]
Primary
Renal Clearance of MK-6183 (CLr)
CLr is the clearance of drug from plasma via the kidneys. Only data from Groups A, B, C, and D is presented; participants in Group E (Period 1) had no detectable urine data. Data for Group E: Period 1 are presented below in the dialysate clearance measure.
Time frame: 0 to 24, 24 to 48, and 48 to 72 hours post-dose
Population: All participants who received MK-6183 and had viable results are included. CLr data are not presented for Group E.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | Renal Clearance of MK-6183 (CLr) | 9.6 Liters/hour | Standard Deviation 1.14 |
| Group B: Mild RI | Renal Clearance of MK-6183 (CLr) | 6.1 Liters/hour | Standard Deviation 2.13 |
| Group C: Moderate RI | Renal Clearance of MK-6183 (CLr) | 4.0 Liters/hour | Standard Deviation 1.61 |
| Group D: Severe RI | Renal Clearance of MK-6183 (CLr) | 1.7 Liters/hour | Standard Deviation 1.07 |
Primary
Volume of Distribution at Steady State (Vss) of MK-6183
Vss is the apparent volume of distribution at steady state for MK-6183. Blood samples for Group E were collected both prior to and during HD (Period 1) and after HD (Period 2) \[data from Periods 1 and 2 were analyzed separately\]. In Period 1, HD commenced 3.5 hours post-dose (HD duration was 3.5 to 4 hours) and sample collection continued until 48 hours post-dose. The specific time frame of sample collection for Group E: Period 1 was pre-dose, 0.5 hours post-dose, EOI, 1.5 hours post-dose, 2 hours post-dose, 3 hours post-dose (pre-HD), 3.5 hours post-dose with HD, 5 hours post-dose with HD, pre-end of HD, 30 min post-HD, 1 hour post-HD, 2 hours post-HD, 12 hours post-dose, 24 hours post-dose, and 48 hours post-dose.
Time frame: Groups A to D & Group E: Period 2: Pre-dose and 0.5, EOI, 1.5, 2, 3, 6, 12, 24, 48, and 72 hours post-dose
Population: All participants who received MK-6183 and had viable results are included. One participant from Group E: Period 1 and 1 participant from Group E: Period 2 were excluded due to implausible concentration values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: Healthy | Volume of Distribution at Steady State (Vss) of MK-6183 | 21.4 Liters | Standard Deviation 2.64 |
| Group B: Mild RI | Volume of Distribution at Steady State (Vss) of MK-6183 | 22.8 Liters | Standard Deviation 4.43 |
| Group C: Moderate RI | Volume of Distribution at Steady State (Vss) of MK-6183 | 23.9 Liters | Standard Deviation 6.03 |
| Group D: Severe RI | Volume of Distribution at Steady State (Vss) of MK-6183 | 19.4 Liters | Standard Deviation 2.55 |
| Group E: ESRD-HD Period 1 | Volume of Distribution at Steady State (Vss) of MK-6183 | 52.1 Liters | Standard Deviation 16.57 |
| Group E: ESRD-HD Period 2 | Volume of Distribution at Steady State (Vss) of MK-6183 | 25.3 Liters | Standard Deviation 8.33 |
Secondary
Number of Participants Discontinuing From the Study Due to an AE
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 12 days
Population: All treated participants are included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: Healthy | Number of Participants Discontinuing From the Study Due to an AE | 0 Participants |
| Group B: Mild RI | Number of Participants Discontinuing From the Study Due to an AE | 0 Participants |
| Group C: Moderate RI | Number of Participants Discontinuing From the Study Due to an AE | 0 Participants |
| Group D: Severe RI | Number of Participants Discontinuing From the Study Due to an AE | 0 Participants |
| Group E: ESRD-HD Period 1 | Number of Participants Discontinuing From the Study Due to an AE | 0 Participants |
Secondary
Number of Participants Experiencing an Adverse Event (AE)
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 12 days
Population: All treated participants are included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A: Healthy | Number of Participants Experiencing an Adverse Event (AE) | 4 Participants |
| Group B: Mild RI | Number of Participants Experiencing an Adverse Event (AE) | 2 Participants |
| Group C: Moderate RI | Number of Participants Experiencing an Adverse Event (AE) | 2 Participants |
| Group D: Severe RI | Number of Participants Experiencing an Adverse Event (AE) | 3 Participants |
| Group E: ESRD-HD Period 1 | Number of Participants Experiencing an Adverse Event (AE) | 4 Participants |