A Study of MK-8527 in Participants With Moderate and Severe Renal Impairment (MK-8527-008)

• MK-8527 (Drug): Oral Capsule

Primary outcomes

• Area Under the Concentration Versus Time Curve From Time 0 to Last Quantifiable Sample (AUC0-last) of MK-8527 in Plasma [Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours post dose]: Blood samples were collected at pre-specified time points to determine the AUC0-last of MK-8527 in participant's plasma. AUC0 to last of MK-8527 was defined as the area under the concentration-time curve from time 0 to the time of the last quantifiable (above lower limit of quantitation) concentration. AUC0-last was calculated using noncompartmental analysis.
• Area Under the Concentration Versus Time Curve From Time 0 to Infinity (AUC0-inf) of MK-8527 in Plasma [Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours post dose]: Blood samples were collected at pre-specified time points to determine the AUC0-inf of MK-8527 in participant's plasma. AUC0-inf was defined as AUC0-last + (Cest,last/λz) where Cest,last was the estimated last measurable concentration, and λz was the apparent first-order terminal elimination rate constant.
• Maximum Concentration (Cmax) of MK-8527 in Plasma [Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours post dose]: Blood samples were collected at pre-specified time points to determine the Cmax of MK-8527 in participant's plasma. Cmax was defined as the maximum observed concentration of MK-8527 in plasma after the administration of a given dose.
• Time to Maximum Concentration (Tmax) of MK-8527 in Plasma [Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours post dose]: Blood samples were collected at pre-specified time points to determine the tmax of MK-8527 in participant's plasma. Tmax of MK-8527 in plasma was determined by deriving the difference between the time of the blood draw associated with the Cmax and the time of study drug administration
• Apparent Terminal Half-life (t1/2) of MK-8527 in Plasma [Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours post dose]: Blood samples were collected at pre-specified time points to determine the t1/2 of MK-8527 in participant's plasma. t1/2 was defined as 0.693/Apparent terminal elimination rate constant (λz).
• Apparent Clearance (CL/F) of MK-8527 in Plasma [Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours post dose]: Blood samples were collected at pre-specified time points to determine the CL/F of MK-8527 in participant's plasma. CL/F was defined as dose/(AUC0-inf).
• Apparent Volume of Distribution During Terminal Phase (Vz/F) of MK-8527 in Plasma [Predose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours post dose]: Blood samples were collected at pre-specified time points to determine the Vz/F of MK-8527 in participant's plasma. Vz/F of MK-8527 in plasma was determined using the formula Dose/(AUC0-inf × λz).

Secondary outcomes

• Number of Participants Who Experience One or More Adverse Events (AEs) [Up to approximately 29 days]: An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
• Number of Participants Who Discontinue Study Due to an AE [Up to approximately 29 days]: An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
• AUC0-last of MK-8527-triphosphate (TP) in Peripheral Blood Mononuclear Cells (PBMCs) [Predose, 4, 12, 24, 48, 96, 120, 144, 168, 336, 504, 672 hours post dose]: Blood samples were collected at pre-specified time points to determine the AUC0-last of MK-8527-TP, the active triphosphate anabolite of MK-8527, in participant's PBMCs. AUC0 to last of MK-8527 was defined as the area under the concentration-time curve from time 0 to the time of the last quantifiable (above lower limit of quantitation) concentration.
• AUC0-inf of MK-8527-TP in PBMCs [Predose, 4, 12, 24, 48, 96, 120, 144, 168, 336, 504, 672 hours post dose]: Blood samples were collected at pre-specified time points to determine the AUC0-inf of MK-8527-TP, the active triphosphate anabolite of MK-8527, in participant's PBMCs. AUC0-inf was defined as AUC0-last + (Cest,last/λz) where Cest,last was the estimated last measurable concentration, and λz was the apparent first-order terminal elimination rate constant.
• Cmax of MK-8527-TP in PBMCs [Predose, 4, 12, 24, 48, 96, 120, 144, 168, 336, 504, 672 hours post dose]: Blood samples were collected at pre-specified time points to determine the Cmax of MK-8527-TP, the active triphosphate anabolite of MK-8527, in participant's PBMCs. Cmax was defined as the maximum observed concentration of MK-8527-TP after the administration of a given dose.
• Concentration at 168 Hours (C168) of MK-8527-TP in PBMCs [168 hours post dose]: Blood samples were collected at pre-specified time points to determine the C168 of MK-8527-TP, the active triphosphate anabolite of MK-8527, in participant's PBMCs. Geometric mean of C168 of MK-8527-TP in PBMCs was determined.
• Concentration at 672 Hours (C672) of MK-8527-TP in PBMCs in Participants With Moderate and Severe Renal Impairment [672 hours post dose]: Blood samples were collected at pre-specified time points to determine the C672 of MK-8527-TP, the active triphosphate anabolite of MK-8527, in participant's PBMCs. Geometric mean of C672 of MK-8527-TP in PBMCs was determined.
• C672 of MK-8527-TP in PBMCs in Healthy Participants [672 hours post dose]: Blood samples were collected at pre-specified time points to determine the C672 of MK-8527-TP, the active triphosphate anabolite of MK-8527, in participant's PBMCs. Since ≤ 50% of healthy participants had BLQ values, the BLQ value was set to zero and the median, minimum, and maximum was reported for C672.
• Tmax of MK-8527-TP in PBMCs [Predose, 4, 12, 24, 48, 96, 120, 144, 168, 336, 504, 672 hours post dose]: Blood samples were collected at pre-specified time points to determine the Tmax of MK-8527-TP, the active triphosphate anabolite of MK-8527, in participant's PBMCs. Tmax of MK-8527-TP was determined by deriving the difference between the time of the blood draw associated with the Cmax and the time of study drug administration
• T1/2 of MK-8527-TP in PBMCs [Predose, 4, 12, 24, 48, 96, 120, 144, 168, 336, 504, 672 hours post dose]: Blood samples were collected at pre-specified time points to determine the t1/2 of MK-8527-TP, the active triphosphate anabolite of MK-8527, in participant's PBMCs. t1/2 was defined as 0.693/Apparent terminal elimination rate constant (λz).

Sex: All, ages: 18 Years to 75 Years, accepts healthy volunteers

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

Moderate and Severe RI

* With the exception of RI, is in sufficient health for study participation.
* Has stable renal function.

Healthy

* Matches mean age to participants with moderate and severe RI.
* Has normal renal function.

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

All participants

* History of cancer (malignancy).
* Positive test results for Human-immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg), or Hepatitis C virus (HCV).
* Had a major surgery or lost significant volume of blood within 56 days prior to dosing.
* Donated plasma within 7 days prior to dosing.

Moderate and Severe RI

* Failed renal transplant or had a nephrectomy.
* End stage renal disease requiring dialysis.
* Any significant arrhythmia or conduction abnormality.
* Has non-sustained or sustained ventricular tachycardia.

Participant flow

Outcome results

• Number of Participants Who Experience One or More Adverse Events (AEs) (Secondary), Count of participants, Participants: Healthy 0; Moderate Renal Impairment 0; Severe Renal Impairment 0
• Number of Participants Who Discontinue Study Due to an AE (Secondary), Count of participants, Participants: Healthy 0; Moderate Renal Impairment 0; Severe Renal Impairment 0
• AUC0-last of MK-8527-triphosphate (TP) in Peripheral Blood Mononuclear Cells (PBMCs) (Secondary), Geometric mean, pmol*hr/10^6 cells: Healthy 217 +/- 37.2; Moderate Renal Impairment 493 +/- 51.6; Severe Renal Impairment 588 +/- 37.6
• AUC0-inf of MK-8527-TP in PBMCs (Secondary), Geometric mean, pmol*hr/10^6 cells: Healthy 235 +/- 35.9; Moderate Renal Impairment 468 +/- 27.5; Severe Renal Impairment 552 +/- 5.9
• Cmax of MK-8527-TP in PBMCs (Secondary), Geometric mean, pmol/10^6 cells: Healthy 1.77 +/- 28.4; Moderate Renal Impairment 3.82 +/- 78.4; Severe Renal Impairment 3.18 +/- 14.7
• Concentration at 168 Hours (C168) of MK-8527-TP in PBMCs (Secondary), Geometric mean, pmol/10^6 cells: Healthy 0.470 +/- 39.3; Moderate Renal Impairment 0.948 +/- 118.9; Severe Renal Impairment 1.03 +/- 46.0
• Concentration at 672 Hours (C672) of MK-8527-TP in PBMCs in Participants With Moderate and Severe Renal Impairment (Secondary), Geometric mean, pmol/10^6 cells: Healthy ; Moderate Renal Impairment 0.183 +/- 54.1; Severe Renal Impairment 0.248 +/- 50.7
• C672 of MK-8527-TP in PBMCs in Healthy Participants (Secondary), Median, pmol/10^6 cells: Healthy 0.0673 (0.00 to 0.0874); Moderate Renal Impairment ; Severe Renal Impairment
• Tmax of MK-8527-TP in PBMCs (Secondary), Median, hr: Healthy 23.08 (11.92 to 23.92); Moderate Renal Impairment 23.92 (23.53 to 167.07); Severe Renal Impairment 23.01 (23.00 to 23.53)
• T1/2 of MK-8527-TP in PBMCs (Secondary), Geometric mean, hr: Healthy 170 +/- 44.1; Moderate Renal Impairment 212 +/- 24.6; Severe Renal Impairment 251 +/- 36.2
• Area Under the Concentration Versus Time Curve From Time 0 to Last Quantifiable Sample (AUC0-last) of MK-8527 in Plasma (Primary), Geometric mean, nM·hr: Healthy 769 +/- 21.4; Moderate Renal Impairment 1160 +/- 24.6; Severe Renal Impairment 1430 +/- 20.1
• Area Under the Concentration Versus Time Curve From Time 0 to Infinity (AUC0-inf) of MK-8527 in Plasma (Primary), Geometric mean, nM·hr: Healthy 918 +/- 22.2; Moderate Renal Impairment 1640 +/- 30.0; Severe Renal Impairment 2060 +/- 24.0
• Maximum Concentration (Cmax) of MK-8527 in Plasma (Primary), Geometric mean, nM: Healthy 112 +/- 25.7; Moderate Renal Impairment 161 +/- 48.9; Severe Renal Impairment 91.7 +/- 22.1
• Time to Maximum Concentration (Tmax) of MK-8527 in Plasma (Primary), Median, hr: Healthy 0.75 (0.52 to 1.53); Moderate Renal Impairment 0.75 (0.50 to 1.00); Severe Renal Impairment 0.99 (0.25 to 6.00)
• Apparent Terminal Half-life (t1/2) of MK-8527 in Plasma (Primary), Geometric mean, hr: Healthy 84.2 +/- 14.1; Moderate Renal Impairment 118 +/- 32.5; Severe Renal Impairment 113 +/- 38.0
• Apparent Clearance (CL/F) of MK-8527 in Plasma (Primary), Geometric mean, Liter/hr: Healthy 21.2 +/- 22.2; Moderate Renal Impairment 11.8 +/- 30.0; Severe Renal Impairment 9.45 +/- 24.0
• Apparent Volume of Distribution During Terminal Phase (Vz/F) of MK-8527 in Plasma (Primary), Geometric mean, Liter: Healthy 2570 +/- 29.7; Moderate Renal Impairment 2020 +/- 27.0; Severe Renal Impairment 1540 +/- 36.5

Adverse events

Time frame: up to approximately 30 days

• Study Protocol and Statistical Analysis Plan (PDF, 2023-12-11)

• Medical Director, Study director, Merck Sharp & Dohme LLC