Cancer, Pharmacokinetics
Conditions
Brief summary
The purpose of this study is to assess the safety, tolerability and pharmacokinetics (PK) of MK-7252 in healthy adults. Participants receive ascending doses of MK-7252 over five treatment periods. Each treatment period is separated by a 7-day washout period. Upon review of the interim safety and preliminary PK data of human exposure to date, Protocol Amendment 3 includes a third panel of participants, Panel C, to assess the PK of higher doses of MK-7252 and to assess the food effect of MK-7252.
Detailed description
Three panels (Panels A, B, and C) of 8 healthy participants (n=6 MK-7252, n=2 placebo) are enrolled. In Panels A and B, participants will alternately receive single rising doses of MK-7252 or placebo for 5 treatment periods. In Panel C, participants will receive single rising doses of MK-7252 or placebo for up to 5 treatment periods. All doses in Panels A and B will be administered in the fasted state during the 5 treatment periods. Doses in Panel C will be administered in a fasted state in treatment periods 1 through 4 and the treatment period 1 dose will be repeated in a fed state during treatment period 5. Panel A will begin first. At least 3 days will elapse before participants in Panel B will receive the next higher dose. For all panels, there will be at least 7 days washout between treatment periods for any given participant. Participants may only be enrolled in one panel of the study. The planned dose levels may be adjusted downward or replaced based on evaluation of safety, tolerability, pharmacokinetic and/or pharmacodynamic data observed after previous treatment periods. All participants in the treatment periods of all panels (with exception of 120 mg fasted/fed periods in Panel C) will be randomly assigned to either study drug or placebo; that is a participant could be assigned to receive study drug in one period and placebo in another. As per the protocol allocation plan, the same participants in Panel C will receive 120 mg MK-7252 in a fasted and fed state. In addition, during any of the treatment periods if a participant demonstrates change in any one of the protocol-defined parameters lasting ≥2 hours, dose escalation in that participant will be halted and the participant may be withdrawn from the study or re-challenged at same dose or at a lower or divided dose. Participants that meet criteria listed will be followed up until parameters no longer meet stopping rule criteria. During the study, participants in Panel A were planned to receive placebo, 1 mg, 6 mg, 24 mg, 72 mg and 108 mg, all in a fasted state in 5 periods. Participants in Panel B were planned to receive placebo, 3 mg, 12 mg, 48 mg, 72 mg and 162 mg, all in a fasted state in 5 periods. All periods in Panels A and B were conducted. Participants in Panel C were planned to receive placebo fasted, placebo fed, 120 mg fasted, 240 mg fasted, 360 mg fasted, 540 mg fasted, and 120 mg fed in 5 periods. Periods 4 and 5 were not conducted and, as a result, the 240 mg fasted, 360 mg fasted, 540 mg fasted, 120 mg fed, and placebo fed doses were not administered. A 180 mg fasted dose was added during Period 3.
Interventions
DRUGMK-7252
1 mg/mL or 20 mg/mL of powder for oral suspension administered with a water volume that brings the total ingested volume to approximately 240 mL
DRUGPlacebo
Placebo powder for oral suspension administered with a water volume that brings the total ingested volume to approximately 240 mL
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female participants of non-childbearing potential (Note: If postmenopausal female: participant is without menses for at least 1 year and has a documented follicle stimulating hormone \[FSH\] level in the postmenopausal range at pre-trial \[screening\] - OR - If surgically sterile female: participant is status post hysterectomy, oophorectomy or tubal ligation.) * Body Mass Index (BMI) between 18.5 and 32 kg/m\^2, inclusive. BMI = weight (kg)/height (m)\^2. * While in semi-recumbent position, has a systolic blood pressure ≤140 mmHg and diastolic blood pressure ≤90 mm Hg and a respiratory rate ≤20 breaths/min at the pre-study (screening) visit and prior to randomization. * Judged to be in good health based on medical history, physical examination, vital sign measurements and electrocardiogram (ECG) performed prior to randomization. * Non-smoker and/or has not used nicotine or nicotine-containing products (e.g., nicotine patch) for at least approximately 3 months.
Exclusion criteria
* Mentally or legally incapacitated, has significant emotional problems at the time of pretrial (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years. * History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases. * History of liver disease (chronic hepatitis, cirrhosis, etc.). * History of cancer (malignancy). Exceptions include adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix and other malignancies which have been successfully treated ≥10 years prior to the pre-study (screening) visit. * History of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food. * Tests positive for hepatitis B surface antigen, 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 pre-study (screening) visit. * Participated in another investigational study within 4 weeks (or 5 half-lives), whichever is greater, prior to the pre-study (screening) visit. * QTc interval ≥470 msec (for males) and ≥480 msec (for females). * Taken a Proton Pump Inhibitor (PPI) during the 5 days prior to start of study treatment. * Unable to refrain from or anticipates the use of any medication, including prescription and non-prescription 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 post-study visit. * Consumes \>3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer \[354 mL/12 ounces\], wine \[118 mL/4 ounces\], or distilled spirits \[29.5 mL/1 ounce\]) per day. * Consumes excessive amounts, defined as \>6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day. * Regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 1 year. Participants must have a negative result for urine drug screen test prior to randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced at Least One Adverse Event (AE) | Up to approximately 21 weeks | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have had a causal relationship with this treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. Adverse events are reported by dose taken at time of event and not by panel or period. The adverse events for placebo are pooled over periods across panels. The number of participants who experienced at least one AE is presented. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 19 weeks | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have had a causal relationship with this treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. Discontinuations are reported by dose taken at time of event. The discontinuations for placebo are pooled over periods across panels. The number of participants who discontinued study treatment due to an AE is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, and 12 hours postdose | Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUC0-12hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUC0-12hr following a high-fat breakfast (fed state) was planned to be compared to the plasma AUC0-12hr in the fasted stated in Panel C, the fed state dose was not administered. |
| MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose | Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUClast reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUClast following a high-fat breakfast (fed state) was planned to be compared to the plasma AUClast in the fasted stated in Panel C, the fed state dose was not administered. |
| MK-7252 Maximal Plasma Concentration (Cmax) | Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose | Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 Cmax reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma Cmax following a high-fat breakfast (fed state) was planned to be compared to the plasma Cmax in the fasted stated in Panel C, the fed state dose was not administered. |
| MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 12 hours postdose | Blood samples were obtained 12 hours postdose to calculate the plasma MK-7252 C12hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. For participants in a given dose that had C12hr values less than the lower limit of quantification (LLOQ), the C12hr value was imputed as half x LLOQ. The LLOQ was 2.74 nmol/L. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma C12hr following a high-fat breakfast (fed state) was planned to be compared to the plasma C12hr in the fasted stated in Panel C, the fed state dose was not administered. |
| MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | 24 hours postdose | Blood samples were obtained 24 hours postdose to calculate the plasma MK-7252 C24hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. For participants in a given dose that had C24hr values less than the lower limit of quantification (LLOQ), the C24hr value was imputed as half x LLOQ. The LLOQ was 2.74 nmol/L. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma C24hr following a high-fat breakfast (fed state) was planned to be compared to the plasma C24hr in the fasted stated in Panel C, the fed state dose was not administered. |
| MK-7252 Time to Reach Maximal Concentration (Tmax) | Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose | Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 Tmax. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma Tmax following a high-fat breakfast (fed state) was planned to be compared to the plasma Tmax in the fasted stated in Panel C, the fed state dose was not administered. |
| MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | Predose (Day 1) and 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose | Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUC0-∞ reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. Pharmacokinetic (PK) results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUC0-∞ following a high-fat breakfast (fed state) was planned to be compared to the plasma AUC0-∞ in the fasted stated in Panel C, the fed state dose was not administered. |
| Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | Baseline (Predose Day 1) and 4 hours postdose | Assessment of the change from baseline in SBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 SBP measurements: baseline and 4 hours postdose. SBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in SBP and a negative number indicates a decrease in SBP. |
| Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | Baseline (Predose Day 1) and 24 hours postdose | Assessment of the change from baseline in SBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 SBP measurements: baseline and 24 hours postdose. SBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in SBP and a negative number indicates a decrease in SBP. |
| Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | Baseline (Predose Day 1) and 4 hours postdose | Assessment of the change from baseline in DBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 DBP measurements: baseline and 4 hours postdose. DBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in DBP and a negative number indicates a decrease in DBP. |
| Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | Baseline (Predose Day 1) and 24 hours postdose | Assessment of the change from baseline in DBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 DBP measurements: baseline and 24 hours postdose. DBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in DBP and a negative number indicates a decrease in DBP. |
| Change From Baseline in Heart Rate (HR) at 4 Hours | Baseline (Predose Day 1) and 4 hours postdose | Assessment of the change from baseline in HR was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 HR measurements: baseline and 4 hours postdose. HR results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in HR and a negative number indicates a decrease in HR. |
| Change From Baseline in Heart Rate (HR) at 24 Hours | Baseline (Predose Day 1) and 24 hours postdose | Assessment of the change from baseline in HR was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 HR measurements: baseline and 24 hours postdose. HR results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in HR and a negative number indicates a decrease in HR. |
| MK-7252 Apparent Terminal Half-life (t½) | Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose | Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 t½ reported as Geometric Mean with Percent Geometric Coefficient of Variation. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma t½ following a high-fat breakfast (fed state) was planned to be compared to the plasma t½ in the fasted stated in Panel C, the fed state dose was not administered. |
| MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, and 24 hours postdose | Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUC0-24hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUC0-24hr following a high-fat breakfast (fed state) was planned to be compared to the plasma AUC0-24hr in the fasted stated in Panel C, the fed state dose was not administered. |
Countries
Belgium
Participant flow
Pre-assignment details
Participants in Panels A and B received a single-rising dose of MK-7252 or placebo in 5 alternating dosing periods. Participants in Panel C received a single-rising dose of MK-7252 or placebo in 3/5 planned periods (P). A 180 mg dose was added (P3). P4-5 were not run so the 240, 360, 540, and 120 mg fed and placebo fed doses were not given.
Participants by arm
| Arm | Count |
|---|---|
| Panel A Within each of the 5 rising dose treatment periods, 6 participants received a single dose of MK-7252 (1 mg, 6 mg, 24 mg, 72 mg, or 108 mg) and 2 participants received placebo in a fasted state. Dosing periods alternated with Panel B. | 8 |
| Panel B Within each of the 5 rising dose treatment periods, 6 participants received a single dose of MK-7252 (3 mg, 12 mg, 48 mg, 72 mg, or 162 mg) and 2 participants received placebo in a fasted state. Dosing periods alternated with Panel A. | 8 |
| Panel C Within each of 3 single dose treatment periods, 6 participants received a single dose of MK-7252 (120 mg or 180 mg) and 2 participants received placebo in a fasted state. The 120 mg dose of MK-7252 was administered in the first 2 periods and the 180 mg dose was administered in the third period. | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | Panel A | Panel B | Panel C | Total |
|---|---|---|---|---|
| Age, Continuous | 33.0 Years STANDARD_DEVIATION 10.2 | 35.0 Years STANDARD_DEVIATION 9.5 | 34.4 Years STANDARD_DEVIATION 9.3 | 34.1 Years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 8 Participants | 8 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 8 Participants | 24 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 8 Participants | 21 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 12 | 0 / 6 | 0 / 8 | 0 / 6 | 0 / 5 | 0 / 22 | 0 / 24 |
| other Total, other adverse events | 2 / 6 | 5 / 6 | 4 / 6 | 5 / 6 | 5 / 6 | 4 / 6 | 7 / 12 | 5 / 6 | 6 / 8 | 4 / 6 | 2 / 5 | 15 / 22 | 3 / 24 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 12 | 0 / 6 | 0 / 8 | 0 / 6 | 0 / 5 | 0 / 22 | 0 / 24 |
Outcome results
Primary
Number of Participants Who Discontinued Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have had a causal relationship with this treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. Discontinuations are reported by dose taken at time of event. The discontinuations for placebo are pooled over periods across panels. The number of participants who discontinued study treatment due to an AE is presented.
Time frame: Up to approximately 19 weeks
Population: All participants who received at least 1 dose of study treatment and discontinued during the study period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-7252 1 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-7252 3 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-7252 6 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-7252 12 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-7252 24 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-7252 48 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-7252 72 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 1 Participants |
| MK-7252 108 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-7252 120 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 1 Participants |
| MK-7252 162 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-7252 180 mg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| Placebo | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
Primary
Number of Participants Who Experienced at Least One Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have had a causal relationship with this treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. Adverse events are reported by dose taken at time of event and not by panel or period. The adverse events for placebo are pooled over periods across panels. The number of participants who experienced at least one AE is presented.
Time frame: Up to approximately 21 weeks
Population: All participants who received at least 1 dose of study treatment and experienced an AE during the study period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-7252 1 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 2 Participants |
| MK-7252 3 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 5 Participants |
| MK-7252 6 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 4 Participants |
| MK-7252 12 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 5 Participants |
| MK-7252 24 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 5 Participants |
| MK-7252 48 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 4 Participants |
| MK-7252 72 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 7 Participants |
| MK-7252 108 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 5 Participants |
| MK-7252 120 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 6 Participants |
| MK-7252 162 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 4 Participants |
| MK-7252 180 mg | Number of Participants Who Experienced at Least One Adverse Event (AE) | 2 Participants |
| Placebo | Number of Participants Who Experienced at Least One Adverse Event (AE) | 15 Participants |
Secondary
Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours
Assessment of the change from baseline in DBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 DBP measurements: baseline and 24 hours postdose. DBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in DBP and a negative number indicates a decrease in DBP.
Time frame: Baseline (Predose Day 1) and 24 hours postdose
Population: All participants who received at least 1 dose of study treatment and had DBP assessments at baseline and 24 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-7252 1 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 0.61 mmHg | Standard Error 1.31 |
| MK-7252 3 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 2.78 mmHg | Standard Error 3.13 |
| MK-7252 6 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | -2.67 mmHg | Standard Error 2.86 |
| MK-7252 12 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | -3.33 mmHg | Standard Error 2.23 |
| MK-7252 24 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 2.33 mmHg | Standard Error 1.69 |
| MK-7252 48 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | -1.11 mmHg | Standard Error 2.03 |
| MK-7252 72 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 2.11 mmHg | Standard Error 1.91 |
| MK-7252 108 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 1.72 mmHg | Standard Error 1.62 |
| MK-7252 120 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | -0.78 mmHg | Standard Error 2.49 |
| MK-7252 162 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 4.11 mmHg | Standard Error 1.89 |
| MK-7252 180 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 1.28 mmHg | Standard Error 1.59 |
| Placebo | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 4.00 mmHg | Standard Error 1.15 |
| Panel C MK-7252 180 mg Period 3 | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 4.73 mmHg | Standard Error 1.16 |
| Placebo | Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours | 1.99 mmHg | Standard Error 0.83 |
Secondary
Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours
Assessment of the change from baseline in DBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 DBP measurements: baseline and 4 hours postdose. DBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in DBP and a negative number indicates a decrease in DBP.
Time frame: Baseline (Predose Day 1) and 4 hours postdose
Population: All participants who received at least 1 dose of study treatment and had DBP assessments at baseline and 4 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-7252 1 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 1.11 mmHg | Standard Error 1.77 |
| MK-7252 3 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 1.61 mmHg | Standard Error 1.06 |
| MK-7252 6 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 0.33 mmHg | Standard Error 1.88 |
| MK-7252 12 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 2.28 mmHg | Standard Error 3.24 |
| MK-7252 24 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 6.33 mmHg | Standard Error 1.55 |
| MK-7252 48 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 6.22 mmHg | Standard Error 1.56 |
| MK-7252 72 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 5.50 mmHg | Standard Error 2.03 |
| MK-7252 108 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 7.28 mmHg | Standard Error 2.24 |
| MK-7252 120 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 4.61 mmHg | Standard Error 1.24 |
| MK-7252 162 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 5.33 mmHg | Standard Error 1.43 |
| MK-7252 180 mg | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 5.28 mmHg | Standard Error 1.24 |
| Placebo | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 11.27 mmHg | Standard Error 3.12 |
| Panel C MK-7252 180 mg Period 3 | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 5.67 mmHg | Standard Error 1.96 |
| Placebo | Change From Baseline in Diastolic Blood Pressure (DBP) at 4 Hours | 0.61 mmHg | Standard Error 0.83 |
Secondary
Change From Baseline in Heart Rate (HR) at 24 Hours
Assessment of the change from baseline in HR was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 HR measurements: baseline and 24 hours postdose. HR results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in HR and a negative number indicates a decrease in HR.
Time frame: Baseline (Predose Day 1) and 24 hours postdose
Population: All participants who received at least 1 dose of study treatment and had HR assessments at baseline and 24 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-7252 1 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | -2.78 beats per minute | Standard Error 2.01 |
| MK-7252 3 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | 2.72 beats per minute | Standard Error 2.03 |
| MK-7252 6 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | 1.83 beats per minute | Standard Error 1.38 |
| MK-7252 12 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | 3.89 beats per minute | Standard Error 1.55 |
| MK-7252 24 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | 2.89 beats per minute | Standard Error 1.19 |
| MK-7252 48 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | 1.67 beats per minute | Standard Error 1.41 |
| MK-7252 72 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | 2.94 beats per minute | Standard Error 1.73 |
| MK-7252 108 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | 2.17 beats per minute | Standard Error 2.15 |
| MK-7252 120 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | -0.61 beats per minute | Standard Error 1.46 |
| MK-7252 162 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | 2.67 beats per minute | Standard Error 2.18 |
| MK-7252 180 mg | Change From Baseline in Heart Rate (HR) at 24 Hours | -0.72 beats per minute | Standard Error 2.53 |
| Placebo | Change From Baseline in Heart Rate (HR) at 24 Hours | 1.40 beats per minute | Standard Error 1.26 |
| Panel C MK-7252 180 mg Period 3 | Change From Baseline in Heart Rate (HR) at 24 Hours | 2.33 beats per minute | Standard Error 1.13 |
| Placebo | Change From Baseline in Heart Rate (HR) at 24 Hours | 2.23 beats per minute | Standard Error 1.27 |
Secondary
Change From Baseline in Heart Rate (HR) at 4 Hours
Assessment of the change from baseline in HR was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 HR measurements: baseline and 4 hours postdose. HR results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in HR and a negative number indicates a decrease in HR.
Time frame: Baseline (Predose Day 1) and 4 hours postdose
Population: All participants who received at least 1 dose of study treatment and had HR assessments at baseline and 4 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-7252 1 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | -4.22 beats per minute | Standard Error 1.82 |
| MK-7252 3 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | -0.28 beats per minute | Standard Error 2.66 |
| MK-7252 6 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | -1.22 beats per minute | Standard Error 1.68 |
| MK-7252 12 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | -0.89 beats per minute | Standard Error 1.76 |
| MK-7252 24 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | 0.22 beats per minute | Standard Error 0.88 |
| MK-7252 48 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | 0.17 beats per minute | Standard Error 1.72 |
| MK-7252 72 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | 6.83 beats per minute | Standard Error 7.05 |
| MK-7252 108 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | 2.28 beats per minute | Standard Error 2.99 |
| MK-7252 120 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | 0.83 beats per minute | Standard Error 2.21 |
| MK-7252 162 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | 1.33 beats per minute | Standard Error 2.1 |
| MK-7252 180 mg | Change From Baseline in Heart Rate (HR) at 4 Hours | 2.17 beats per minute | Standard Error 6.07 |
| Placebo | Change From Baseline in Heart Rate (HR) at 4 Hours | -1.53 beats per minute | Standard Error 1.36 |
| Panel C MK-7252 180 mg Period 3 | Change From Baseline in Heart Rate (HR) at 4 Hours | 1.27 beats per minute | Standard Error 2.15 |
| Placebo | Change From Baseline in Heart Rate (HR) at 4 Hours | -1.27 beats per minute | Standard Error 0.91 |
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours
Assessment of the change from baseline in SBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 SBP measurements: baseline and 24 hours postdose. SBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in SBP and a negative number indicates a decrease in SBP.
Time frame: Baseline (Predose Day 1) and 24 hours postdose
Population: All participants who received at least 1 dose of study treatment and had SBP assessments at baseline and 24 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-7252 1 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | 2.83 mmHg | Standard Error 3.4 |
| MK-7252 3 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | 0.89 mmHg | Standard Error 3 |
| MK-7252 6 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | -1.11 mmHg | Standard Error 1.56 |
| MK-7252 12 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | -3.56 mmHg | Standard Error 2.47 |
| MK-7252 24 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | -0.17 mmHg | Standard Error 2.75 |
| MK-7252 48 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | -0.56 mmHg | Standard Error 2.48 |
| MK-7252 72 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | 7.56 mmHg | Standard Error 1.32 |
| MK-7252 108 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | 3.56 mmHg | Standard Error 1.81 |
| MK-7252 120 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | 0.22 mmHg | Standard Error 3.36 |
| MK-7252 162 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | 3.17 mmHg | Standard Error 1.61 |
| MK-7252 180 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | 4.67 mmHg | Standard Error 3.51 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | -0.13 mmHg | Standard Error 4.98 |
| Panel C MK-7252 180 mg Period 3 | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | 7.27 mmHg | Standard Error 3.86 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours | 5.84 mmHg | Standard Error 1.48 |
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours
Assessment of the change from baseline in SBP was obtained using a validated, semi-automated oscillometric device. Baseline was defined as the average of predose measurements. A measurement set was considered 2 SBP measurements: baseline and 4 hours postdose. SBP results are reported by dose taken. Placebo measurements are pooled over periods across panels. A positive number indicates an increase in SBP and a negative number indicates a decrease in SBP.
Time frame: Baseline (Predose Day 1) and 4 hours postdose
Population: All participants who received at least 1 dose of study treatment and had SBP assessments at baseline and 4 hours postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-7252 1 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 5.61 mmHg | Standard Error 1.94 |
| MK-7252 3 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 1.56 mmHg | Standard Error 2.57 |
| MK-7252 6 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 0.50 mmHg | Standard Error 2.66 |
| MK-7252 12 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 4.39 mmHg | Standard Error 2.08 |
| MK-7252 24 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 6.78 mmHg | Standard Error 3.71 |
| MK-7252 48 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 12.17 mmHg | Standard Error 1.57 |
| MK-7252 72 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 14.00 mmHg | Standard Error 4.28 |
| MK-7252 108 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 9.83 mmHg | Standard Error 0.84 |
| MK-7252 120 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 11.28 mmHg | Standard Error 1.9 |
| MK-7252 162 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 5.33 mmHg | Standard Error 2.15 |
| MK-7252 180 mg | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 18.17 mmHg | Standard Error 7.65 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 3.80 mmHg | Standard Error 4.15 |
| Panel C MK-7252 180 mg Period 3 | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 6.13 mmHg | Standard Error 4.52 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) at 4 Hours | 3.22 mmHg | Standard Error 1.84 |
Secondary
MK-7252 Apparent Terminal Half-life (t½)
Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 t½ reported as Geometric Mean with Percent Geometric Coefficient of Variation. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma t½ following a high-fat breakfast (fed state) was planned to be compared to the plasma t½ in the fasted stated in Panel C, the fed state dose was not administered.
Time frame: Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Population: All participants who received study treatment and complied with the protocol sufficiently to ensure that data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Periods (P) 4 and 5 of Panel C were not conducted; the planned 120 mg fed dose (P5) was not administered.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-7252 1 mg | MK-7252 Apparent Terminal Half-life (t½) | NA hr | — |
| MK-7252 3 mg | MK-7252 Apparent Terminal Half-life (t½) | NA hr | — |
| MK-7252 6 mg | MK-7252 Apparent Terminal Half-life (t½) | 1.29 hr | Geometric Coefficient of Variation 12.18 |
| MK-7252 12 mg | MK-7252 Apparent Terminal Half-life (t½) | 1.34 hr | Geometric Coefficient of Variation 14.99 |
| MK-7252 24 mg | MK-7252 Apparent Terminal Half-life (t½) | 1.60 hr | Geometric Coefficient of Variation 19.86 |
| MK-7252 48 mg | MK-7252 Apparent Terminal Half-life (t½) | 1.35 hr | Geometric Coefficient of Variation 9.93 |
| MK-7252 72 mg | MK-7252 Apparent Terminal Half-life (t½) | 1.76 hr | Geometric Coefficient of Variation 60.34 |
| MK-7252 108 mg | MK-7252 Apparent Terminal Half-life (t½) | 1.59 hr | Geometric Coefficient of Variation 19.54 |
| MK-7252 120 mg | MK-7252 Apparent Terminal Half-life (t½) | 3.09 hr | Geometric Coefficient of Variation 81.14 |
| MK-7252 162 mg | MK-7252 Apparent Terminal Half-life (t½) | 5.97 hr | Geometric Coefficient of Variation 92.18 |
| MK-7252 180 mg | MK-7252 Apparent Terminal Half-life (t½) | 1.96 hr | Geometric Coefficient of Variation 52.8 |
| Placebo | MK-7252 Apparent Terminal Half-life (t½) | 2.40 hr | Geometric Coefficient of Variation 71.03 |
| Panel C MK-7252 180 mg Period 3 | MK-7252 Apparent Terminal Half-life (t½) | 2.90 hr | Geometric Coefficient of Variation 152.97 |
Secondary
MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr)
Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUC0-12hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUC0-12hr following a high-fat breakfast (fed state) was planned to be compared to the plasma AUC0-12hr in the fasted stated in Panel C, the fed state dose was not administered.
Time frame: Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, and 12 hours postdose
Population: All participants who received study treatment and complied with the protocol sufficiently to ensure that data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Periods (P) 4 and 5 of Panel C were not conducted; the planned 120 mg fed dose (P5) was not administered.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7252 1 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 47.8 hr•nmol/L |
| MK-7252 3 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 121 hr•nmol/L |
| MK-7252 6 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 278 hr•nmol/L |
| MK-7252 12 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 558 hr•nmol/L |
| MK-7252 24 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 1140 hr•nmol/L |
| MK-7252 48 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 2020 hr•nmol/L |
| MK-7252 72 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 5130 hr•nmol/L |
| MK-7252 108 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 3450 hr•nmol/L |
| MK-7252 120 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 6220 hr•nmol/L |
| MK-7252 162 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 9240 hr•nmol/L |
| MK-7252 180 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 7170 hr•nmol/L |
| Placebo | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 5480 hr•nmol/L |
| Panel C MK-7252 180 mg Period 3 | MK-7252 Area Under the Concentration-Time Curve From Zero to 12 Hours Postdose (AUC0-12hr) | 10200 hr•nmol/L |
Secondary
MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr)
Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUC0-24hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUC0-24hr following a high-fat breakfast (fed state) was planned to be compared to the plasma AUC0-24hr in the fasted stated in Panel C, the fed state dose was not administered.
Time frame: Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, and 24 hours postdose
Population: All participants who received study treatment and complied with the protocol sufficiently to ensure that data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Periods (P) 4 and 5 of Panel C were not conducted; the planned 120 mg fed dose (P5) was not administered.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7252 1 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 47.8 hr•nmol/L |
| MK-7252 3 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 122 hr•nmol/L |
| MK-7252 6 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 279 hr•nmol/L |
| MK-7252 12 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 559 hr•nmol/L |
| MK-7252 24 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 1150 hr•nmol/L |
| MK-7252 48 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 2030 hr•nmol/L |
| MK-7252 72 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 5210 hr•nmol/L |
| MK-7252 108 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 3490 hr•nmol/L |
| MK-7252 120 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 6420 hr•nmol/L |
| MK-7252 162 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 9530 hr•nmol/L |
| MK-7252 180 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 7240 hr•nmol/L |
| Placebo | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 5510 hr•nmol/L |
| Panel C MK-7252 180 mg Period 3 | MK-7252 Area Under the Concentration-Time Curve From Zero to 24 Hours Postdose (AUC0-24hr) | 10300 hr•nmol/L |
Secondary
MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞)
Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUC0-∞ reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. Pharmacokinetic (PK) results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUC0-∞ following a high-fat breakfast (fed state) was planned to be compared to the plasma AUC0-∞ in the fasted stated in Panel C, the fed state dose was not administered.
Time frame: Predose (Day 1) and 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Population: All participants who received study treatment and complied with the protocol sufficiently to ensure that data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Periods (P) 4-5 of Panel C were not conducted; the planned 120 mg fed dose (P 5) was not administered.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7252 1 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | NA hr•nmol/L |
| MK-7252 3 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | NA hr•nmol/L |
| MK-7252 6 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 288 hr•nmol/L |
| MK-7252 12 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 583 hr•nmol/L |
| MK-7252 24 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 1190 hr•nmol/L |
| MK-7252 48 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 2040 hr•nmol/L |
| MK-7252 72 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 5090 hr•nmol/L |
| MK-7252 108 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 3500 hr•nmol/L |
| MK-7252 120 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 6680 hr•nmol/L |
| MK-7252 162 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 9840 hr•nmol/L |
| MK-7252 180 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 7260 hr•nmol/L |
| Placebo | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 5520 hr•nmol/L |
| Panel C MK-7252 180 mg Period 3 | MK-7252 Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) | 10300 hr•nmol/L |
Secondary
MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast)
Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 AUClast reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma AUClast following a high-fat breakfast (fed state) was planned to be compared to the plasma AUClast in the fasted stated in Panel C, the fed state dose was not administered.
Time frame: Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Population: All participants who received study treatment and complied with the protocol sufficiently to ensure that data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Periods (P) 4 and 5 of Panel C were not conducted; the planned 120 mg fed dose (P5) was not administered.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7252 1 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 38.7 hr•nmol/L |
| MK-7252 3 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 101 hr•nmol/L |
| MK-7252 6 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 250 hr•nmol/L |
| MK-7252 12 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 543 hr•nmol/L |
| MK-7252 24 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 1130 hr•nmol/L |
| MK-7252 48 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 2030 hr•nmol/L |
| MK-7252 72 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 5170 hr•nmol/L |
| MK-7252 108 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 3420 hr•nmol/L |
| MK-7252 120 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 6330 hr•nmol/L |
| MK-7252 162 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 9750 hr•nmol/L |
| MK-7252 180 mg | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 7250 hr•nmol/L |
| Placebo | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 5500 hr•nmol/L |
| Panel C MK-7252 180 mg Period 3 | MK-7252 Area Under the Concentration-Time Curve From Zero to Last Measurable Concentration (AUClast) | 10300 hr•nmol/L |
Secondary
MK-7252 Maximal Plasma Concentration (Cmax)
Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 Cmax reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma Cmax following a high-fat breakfast (fed state) was planned to be compared to the plasma Cmax in the fasted stated in Panel C, the fed state dose was not administered.
Time frame: Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Population: All participants who received study treatment and complied with the protocol sufficiently to ensure that data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Periods (P) 4 and 5 of Panel C were not conducted; the planned 120 mg fed dose (P5) was not administered.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7252 1 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 21.2 nmol/L |
| MK-7252 3 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 51.7 nmol/L |
| MK-7252 6 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 117 nmol/L |
| MK-7252 12 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 220 nmol/L |
| MK-7252 24 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 447 nmol/L |
| MK-7252 48 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 830 nmol/L |
| MK-7252 72 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 1860 nmol/L |
| MK-7252 108 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 1380 nmol/L |
| MK-7252 120 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 2290 nmol/L |
| MK-7252 162 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 3380 nmol/L |
| MK-7252 180 mg | MK-7252 Maximal Plasma Concentration (Cmax) | 3160 nmol/L |
| Placebo | MK-7252 Maximal Plasma Concentration (Cmax) | 2550 nmol/L |
| Panel C MK-7252 180 mg Period 3 | MK-7252 Maximal Plasma Concentration (Cmax) | 3880 nmol/L |
Secondary
MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr)
Blood samples were obtained 12 hours postdose to calculate the plasma MK-7252 C12hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. For participants in a given dose that had C12hr values less than the lower limit of quantification (LLOQ), the C12hr value was imputed as half x LLOQ. The LLOQ was 2.74 nmol/L. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma C12hr following a high-fat breakfast (fed state) was planned to be compared to the plasma C12hr in the fasted stated in Panel C, the fed state dose was not administered.
Time frame: 12 hours postdose
Population: All participants who received study treatment and complied with the protocol sufficiently to ensure that data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Periods (P) 4 and 5 of Panel C were not conducted; the planned 120 mg fed dose (P5) was not administered.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7252 1 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | NA nmol/L |
| MK-7252 3 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | NA nmol/L |
| MK-7252 6 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | NA nmol/L |
| MK-7252 12 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | NA nmol/L |
| MK-7252 24 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 2.19 nmol/L |
| MK-7252 48 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 2.95 nmol/L |
| MK-7252 72 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 11.7 nmol/L |
| MK-7252 108 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 7.06 nmol/L |
| MK-7252 120 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 21.0 nmol/L |
| MK-7252 162 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 31.8 nmol/L |
| MK-7252 180 mg | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 10.4 nmol/L |
| Placebo | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 7.16 nmol/L |
| Panel C MK-7252 180 mg Period 3 | MK-7252 Plasma Concentration at 12 Hours Postdose (C12hr) | 16.7 nmol/L |
Secondary
MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr)
Blood samples were obtained 24 hours postdose to calculate the plasma MK-7252 C24hr reported as back-transformed least squares mean and confidence interval calculated using a linear mixed effects model performed on natural log-transformed values. For participants in a given dose that had C24hr values less than the lower limit of quantification (LLOQ), the C24hr value was imputed as half x LLOQ. The LLOQ was 2.74 nmol/L. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma C24hr following a high-fat breakfast (fed state) was planned to be compared to the plasma C24hr in the fasted stated in Panel C, the fed state dose was not administered.
Time frame: 24 hours postdose
Population: All participants who received study treatment, complied with the protocol to ensure data were likely to exhibit effects of treatment according to the scientific model, and had data available for endpoint. Periods 4-5 of Panel C was not conducted and planned 120 mg fed dose not administered. Analysis was not performed due to values being \<LLOQ.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7252 1 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 3 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 6 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 12 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 24 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 48 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 72 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 108 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 120 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 162 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| MK-7252 180 mg | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| Placebo | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
| Panel C MK-7252 180 mg Period 3 | MK-7252 Plasma Concentration at 24 Hours Postdose (C24hr) | NA nmol/L |
Secondary
MK-7252 Time to Reach Maximal Concentration (Tmax)
Blood samples were obtained predose (Day 1) and at designated times postdose to calculate the plasma MK-7252 Tmax. PK results were reported by dose taken in Panels A and B. For Panel C, PK results were reported by dose taken and by individual period. Periods in a panel were not conducted if it became evident that exposures at the escalated dosing would not adequately reach the projected PK target. Although the plasma Tmax following a high-fat breakfast (fed state) was planned to be compared to the plasma Tmax in the fasted stated in Panel C, the fed state dose was not administered.
Time frame: Predose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 10, 12, 24, 48, and 72 hours postdose
Population: All participants who received study treatment and complied with the protocol sufficiently to ensure that data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Periods (P) 4 and 5 of Panel C were not conducted; the planned 120 mg fed dose (P5) was not administered.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MK-7252 1 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 1.00 hr |
| MK-7252 3 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 0.75 hr |
| MK-7252 6 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 0.75 hr |
| MK-7252 12 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 1.00 hr |
| MK-7252 24 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 1.00 hr |
| MK-7252 48 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 0.75 hr |
| MK-7252 72 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 1.00 hr |
| MK-7252 108 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 1.00 hr |
| MK-7252 120 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 0.75 hr |
| MK-7252 162 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 0.75 hr |
| MK-7252 180 mg | MK-7252 Time to Reach Maximal Concentration (Tmax) | 0.75 hr |
| Placebo | MK-7252 Time to Reach Maximal Concentration (Tmax) | 1.00 hr |
| Panel C MK-7252 180 mg Period 3 | MK-7252 Time to Reach Maximal Concentration (Tmax) | 1.00 hr |