A Single and Multiple-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-8521 in Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 61
- 主要终点
- Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)
研究概览
简要总结
This study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of MK-8521.
Part 1 primary hypothesis: Administration of single subcutaneous (SC) doses of MK-8521 is sufficiently safe and well- tolerated in healthy participants, based on assessment of clinical and laboratory adverse experiences, to permit continued clinical investigation.
Part 2: Administration of multiple once daily SC doses of MK-8521 is sufficiently safe and well-tolerated in healthy lean and obese participants, based on assessment of clinical and laboratory adverse experiences, to permit continued clinical investigation.
详细描述
This was a 3 part, randomized, single and multiple ascending-dose trial that evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of MK-8521 in healthy non-obese male (Part 1-Panels A and B, Panels C, D, and E of Part 2, and Part 3 Panel H) participants between the ages of 18 and 45 years and obese male participants (Part 2, Panel F) 45 to 65 years of age. An optional Panel G in Part 2 per protocol did not occur.
Part 1 was a single rising dose study to assess the safety and pharmacokinetics of single subcutaneous (SC) doses of MK-8521. Two panels of 8 healthy young non-obese male participants were dosed in up to 3 alternating dosing periods of MK-8521 or placebo (in a 6:2 ratio). Participants had a minimum 7 day washout between dosing periods.
Part 2 was a multiple-rising dose study to assess the safety and pharmacokinetics of multiple SC doses of MK-8521. Three panels (C-E) of 8 healthy young non-obese male participants received daily SC doses of MK-8521 or placebo (in a 6:2 ratio) as a titration regimen for 10 consecutive days. One panel (Panel F) of 8 older obese male participants received daily SC doses of MK-8521 or placebo (in a 6:2 ratio) as a titration regimen for 14 consecutive days.
Part 3 was a single dose, 3-period crossover study in 12 healthy lean male participants. Participants were randomized into 6 treatment groups and received a sequence of 3 treatments (MK-8521 at 35μg, 125μg and placebo). All participants in Part 3 received MK-8521 (high dose of 125μg and low dose of 35 μg) and placebo. There was a minimum 7 day washout between each dosing period for each individual participant.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Males of either 18 to 45 or 45 to 70 years of age depending on the component of the study
- •Body Mass Index between either 18-25 or 30-40 kg/m^2 depending on the component of the study
- •Is in good health
- •Is a non-smoker and/or has not used nicotine for at least 3 months
排除标准
- •Is mentally or legally incapacitated, has significant emotional problems or has a history of psychiatric disorders in the past 5 years
- •Has a history of the following abnormalities or diseases: endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological.
- •History of cancer
- •History of significant multiple or severe allergies or has had an anaphylactic reaction or significant intolerability to drugs or food
- •Positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV)
- •Had major surgery, donated or lost 1 unit (500 mL) of blood or participated in another study within prior 4 weeks
- •Has irritable bowel disease or recurrent nausea, vomiting, diarrhea or abdominal pain
- •History of acute or chronic pancreatitis
- •Uses 2 weeks prior to trial, or anticipates using during trial, medications, drugs or herbal remedies such as St. John's Wort
- •Consumes greater than 3 glasses of alcohol per day
- •Consumes greater than 6 servings of caffeinated beverages per day
- •Regularly uses illicit drugs or has a history of drug (including alcohol) abuse within prior 3 months
- •Has known hypersensitivity to glucagon or any glucagon like peptide 1 (GLP-1) receptor agonist
- •Is unwilling/unable to consume standardized meals and/or is on a carbohydrate restricted diet
- •Has history of hypersensitivity to pharmacologic insulins
研究组 & 干预措施
Part 1 - Panel A - MK-8521 100μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 100μg in the first treatment period, and matching placebo (PBO) in the second treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 100μg (Drug)
Part 1 - Panel A - MK-8521 100μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 100μg in the first treatment period, and matching placebo (PBO) in the second treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 1 - Panel A - PBO > MK-8521 300μg
Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, and MK-8521 300μg in the second treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 300μg (Drug)
Part 1 - Panel A - PBO > MK-8521 300μg
Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, and MK-8521 300μg in the second treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 1 - Panel A - MK-8521 100μg > MK-8521 300μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 100μg in the first treatment period, and MK-8521 300μg in the second treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 100μg (Drug)
Part 1 - Panel A - MK-8521 100μg > MK-8521 300μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 100μg in the first treatment period, and MK-8521 300μg in the second treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 300μg (Drug)
Part 1 - Panel B - MK-8521 150μg > PBO > MK-8521 175μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, PBO in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 150μg (Drug)
Part 2 - Panel F - MK-8521 72μg > MK-8521 125μg
Obese male participants of 45 to 65 years of age received a single dose of MK-8521 72μg Days 1 to 7 and MK-8521 125μg Days 8 to 14 in a single treatment period.
干预措施: MK-8521 125μg (Drug)
Part 1 - Panel B - MK-8521 150μg > PBO > MK-8521 175μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, PBO in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 175μg (Drug)
Part 1 - Panel B - MK-8521 150μg > PBO > MK-8521 175μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, PBO in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 1- Panel B- MK-8521 150μg > MK-8521 200μg > MK-8521 175μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, MK-8521 200μg in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 150μg (Drug)
Part 1- Panel B- MK-8521 150μg > MK-8521 200μg > MK-8521 175μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, MK-8521 200μg in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 175μg (Drug)
Part 1- Panel B- MK-8521 150μg > MK-8521 200μg > MK-8521 175μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, MK-8521 200μg in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 200μg (Drug)
Part 1 - Panel B - MK-8521 150μg > MK-8521 200μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, MK-8521 200μg in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 150μg (Drug)
Part 1 - Panel B - MK-8521 150μg > MK-8521 200μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, MK-8521 200μg in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 200μg (Drug)
Part 1 - Panel B - MK-8521 150μg > MK-8521 200μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 150μg in the first treatment period, MK-8521 200μg in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 1 - Panel B - PBO > MK-8521 200μg > MK-8521 175μg
Healthy male participants of 18 to 45 years of age received PBO in the first treatment period, MK-8521 200μg in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 175μg (Drug)
Part 1 - Panel B - PBO > MK-8521 200μg > MK-8521 175μg
Healthy male participants of 18 to 45 years of age received PBO in the first treatment period, MK-8521 200μg in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 200μg (Drug)
Part 1 - Panel B - PBO > MK-8521 200μg > MK-8521 175μg
Healthy male participants of 18 to 45 years of age received PBO in the first treatment period, MK-8521 200μg in the second treatment period, and MK-8521 175μg in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 2 - Panel C - MK-8521 50μg > MK-8521 72μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 50μg Days 1 to 5 and MK-8521 72μg Days 6 to 10 in a single treatment period.
干预措施: MK-8521 50/72μg (Drug)
Part 2 - Panel D - MK-8521 100μg > MK-8521 150μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 100μg Days 1 to 5 and MK-8521 150μg Days 6 to 10 in a single treatment period.
干预措施: MK-8521 100μg (Drug)
Part 2 - Panel D - MK-8521 100μg > MK-8521 150μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 100μg Days 1 to 5 and MK-8521 150μg Days 6 to 10 in a single treatment period.
干预措施: MK-8521 100/150μg (Drug)
Part 2 - Panel E - MK-8521 125μg > MK-8521 150μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg Days 1 to 5 and MK-8521 150μg Days 6 to 10 in a single treatment period.
干预措施: MK-8521 125μg (Drug)
Part 2 - Panel E - MK-8521 125μg > MK-8521 150μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg Days 1 to 5 and MK-8521 150μg Days 6 to 10 in a single treatment period.
干预措施: MK-8521 125/150μg (Drug)
Part 2 - Panel F - MK-8521 72μg > MK-8521 125μg
Obese male participants of 45 to 65 years of age received a single dose of MK-8521 72μg Days 1 to 7 and MK-8521 125μg Days 8 to 14 in a single treatment period.
干预措施: MK-8521 72/125μg (Drug)
Part 2 - Panels C+D+E - Pooled Placebo
Healthy male participants of 18 to 45 years of age received PBO once daily for 10 days.
干预措施: Placebo (Drug)
Part 2 - Panel F - Placebo
Obese male participants of 45 to 65 years of age received a single dose of PBO Days 1 to 14.
干预措施: Placebo (Drug)
Part 3 - Panel H - MK-8521 125μg > MK-8521 35μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg (high dose) in the first treatment period, MK-8521 35μg (low dose) in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 35μg (Drug)
Part 3 - Panel H - MK-8521 125μg > MK-8521 35μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg (high dose) in the first treatment period, MK-8521 35μg (low dose) in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 125μg (Drug)
Part 3 - Panel H - MK-8521 125μg > MK-8521 35μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg (high dose) in the first treatment period, MK-8521 35μg (low dose) in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 3 - Panel H - MK-8521 35μg > PBO > MK-8521 125μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 35μg (low dose) in the first treatment period, PBO MK-8521 in the second treatment period, and 125μg (high dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 35μg (Drug)
Part 3 - Panel H - MK-8521 35μg > PBO > MK-8521 125μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 35μg (low dose) in the first treatment period, PBO MK-8521 in the second treatment period, and 125μg (high dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 125μg (Drug)
Part 3 - Panel H - MK-8521 35μg > PBO > MK-8521 125μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 35μg (low dose) in the first treatment period, PBO MK-8521 in the second treatment period, and 125μg (high dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 3 - Panel H - PBO > MK- 8521 125μg > MK-8521 35μg
Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, MK- 8521 125μg (high dose) in the second treatment period, and MK-8521 35μg (low dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 35μg (Drug)
Part 3 - Panel H - PBO > MK- 8521 125μg > MK-8521 35μg
Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, MK- 8521 125μg (high dose) in the second treatment period, and MK-8521 35μg (low dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 125μg (Drug)
Part 3 - Panel H - PBO > MK- 8521 125μg > MK-8521 35μg
Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, MK- 8521 125μg (high dose) in the second treatment period, and MK-8521 35μg (low dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 3 - Panel H - PBO > MK- 8521 35μg > MK-8521 125μg
Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, MK- 8521 35μg (low dose) in the second treatment period, and MK-8521 125μg (high dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 35μg (Drug)
Part 3 - Panel H - PBO > MK- 8521 35μg > MK-8521 125μg
Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, MK- 8521 35μg (low dose) in the second treatment period, and MK-8521 125μg (high dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 125μg (Drug)
Part 3 - Panel H - PBO > MK- 8521 35μg > MK-8521 125μg
Healthy male participants of 18 to 45 years of age received a single dose of PBO in the first treatment period, MK- 8521 35μg (low dose) in the second treatment period, and MK-8521 125μg (high dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 3 - Panel H - MK-8521 125μg > PBO > MK-8521 35μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg (high dose) in the first treatment period, PBO in the second treatment period, and MK-8521 35μg (low dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 35μg (Drug)
Part 3 - Panel H - MK-8521 125μg > PBO > MK-8521 35μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg (high dose) in the first treatment period, PBO in the second treatment period, and MK-8521 35μg (low dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 125μg (Drug)
Part 3 - Panel H - MK-8521 125μg > PBO > MK-8521 35μg
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 125μg (high dose) in the first treatment period, PBO in the second treatment period, and MK-8521 35μg (low dose) in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
Part 3 - Panel H - MK-8521 35μg > MK-8521 125μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 35μg (low dose) in the first treatment period, MK-8521 125μg (high dose) in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 35μg (Drug)
Part 3 - Panel H - MK-8521 35μg > MK-8521 125μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 35μg (low dose) in the first treatment period, MK-8521 125μg (high dose) in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: MK-8521 125μg (Drug)
Part 3 - Panel H - MK-8521 35μg > MK-8521 125μg > PBO
Healthy male participants of 18 to 45 years of age received a single dose of MK-8521 35μg (low dose) in the first treatment period, MK-8521 125μg (high dose) in the second treatment period, and PBO in the third treatment period. There was a minimum of a 7-day washout period between treatment periods.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants Who Experienced at Least One Adverse Event (AE) (Part 1)
时间窗: From Day 1 through post-trial visit (Up to 8 weeks)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)
时间窗: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)
Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.
Number of Participants With an Adverse Event (AE) (Part 2)
时间窗: From Day 1 through post-trial visit (Up to 7 weeks)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Number of Participants Who Discontinued Treatment Due to an AE (Part 1)
时间窗: Up to 8 weeks (Part 1)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)
时间窗: Days 1, 7 and 14 (Part 2) (Panel F)
Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections occurred at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)
时间窗: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, E and F) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel C-E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
Cmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)
时间窗: Days 1, 7 and 14 (Part 2) (Panel F)
AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)
时间窗: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
Trough plasma concentration (measured concentration at the end of a dosing interval at steady state \[taken directly before next administration\]). Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, and E) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
Trough Plasma Concentration (Ctrough) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)
时间窗: Days 1, 7 and 14 (Part 2) (Panel F)
Trough plasma concentration (measured concentration at the end of a dosing interval at steady state \[taken directly before next administration\]). Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Tmax for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)
时间窗: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, and E) are presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
Area Under the Concentration Time Curve of MK-8521 From 0 to Infinity (AUC0-∞) After a Single Dose (Part 1)
时间窗: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)
AUC0-∞ is a measure of the mean concentration levels of drug in the plasma after the dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.
Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 1)
时间窗: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)
Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. Method of dispersion is coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo.
Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 1)
时间窗: Pre-dose, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24, 30, 34, 48, 72, 96, 120 hrs. post-dose (Part 1)
Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. A summary of pharmacokinetic parameters following administration of single SC (subcutaneous) injection of MK-8521 in healthy non-obese male participants (Part I, Panels A-B, Period 1-3 \[100-300μg\]) is presented. No pharmacokinetic analysis was performed on participants receiving Placebo.
Number of Participants Who Discontinued Treatment Due to an AE (Part 2)
时间窗: Up to 7 weeks (Part 2)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)
时间窗: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part II, Panel C, D, and E) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
AUC 0-24hr for Plasma Concentration of Participants Treated After Multiple Doses of MK-8521 (Part 2, Panel F)
时间窗: Days 1, 7 and 14 (Part 2) (Panel F)
AUC0-24hr is a measure of the mean concentration levels of drug in the plasma 0 to 24 hrs. after the dose. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion coefficient of variation (%CV). No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections for the determination of plasma MK-8521 concentrations were collected at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)
时间窗: Days 1, 5 and 10 (Part 2) (Panels C, D, E)
Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 10 Days (with dose escalation on Day 5) to healthy non-obese male participants (Part 2, Panel C, D, and E) are presented. Method of dispersion is coefficient of variation (%CV). Apparent terminal t1/2 was not reported for certain days since the terminal phase was not adequately captured with sampling up to 24hr post dose. No pharmacokinetic analysis was performed on participants receiving Placebo. Blood was collected for Part 2, Panel C, D, and E: Days 1, 4, 5, 9, 10 pre-dose; Days 1, 5, 10: 2, 4, 8, 10, 12, 16, 24 hrs. post dose; Day 10: 72, 96, 120 hrs. post-dose.
Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part F)
时间窗: Days 1, 7 and 14 (Part 2) (Panel F)
Apparent Terminal Half-life (t1/2) is the time required for a given drug concentration in the plasma to decrease by 50%. Mean pharmacokinetic parameter values for MK-8521 following administration of multiple subcutaneous once daily doses for 14 Days (with dose escalation on Day 7) to obese male participants (Part 2, Panel F) are presented. Method of dispersion is coefficient of variation (%CV). Apparent terminal t1/2 was not reported for certain days since the terminal phase was not adequately captured with sampling up to 24hr post dose. No pharmacokinetic analysis was performed on participants receiving Placebo. Blood collections occurred at the following time points for Part 2, Panel F: Days 1, 3, 4, 5, 7, 9, 11, 13, 14 pre-dose; Days 1, 7, 14: 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 24 hrs. post-dose; Day 14: 72, 96, 120 hrs. post-dose.
Number of Participants With an Adverse Event (AE) (Part 3)
时间窗: Up to 6 weeks (Part 3)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Number of Participants Who Discontinued Treatment Due to an AE (Part 3)
时间窗: Up to 6 weeks (Part 3)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Average Concentration (Cave) of MK-8521 Corresponding to Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)
时间窗: From -10 to 160 minutes after GGI on Day 1 (Part 3)
Pancreatic beta cell sensitivity to ambient glucose concentration after a single dose of MK-8521 125μg/35μg or placebo at Tmax was quantified as the slope of insulin secretion rate relative to glucose concentration (ISR/G) during GGI (160 minutes duration) and assessed against MK-8521 average plasma concentration (Cave) during the GGI to preliminarily characterize the PK/ pharmacodynamic (PD) relationship. Study drug was administered on Day -1. Plasma concentrations of MK-8521 were determined at -10 min pre-GGI and 40, 80, 120 \& 160 min and blood concentrations of glucose, insulin \& C-peptide were determined at -10, -5 (pre-GGI), 20, 40, 60, 80, 100, 120, 140 \& 160 minutes after start of GGI on Day 1 of each period. ISR calculated by deconvolution of C-peptide concentrations using a two-compartmental model was regressed on glucose concentration via simple linear regression; beta cell glucose sensitivity was defined as slope from the regression line.
次要结局
- Change From Baseline in Time-weighted Average From 0 to 24 Hrs (TWA0-24hr) of Heart Rate (HR) After a Single Dose of MK-8521 (Part 1)(Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1))
- Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)(Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1))
- Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With A Single Dose of MK-8521 (Part 1)(Baseline (predose), up to 24 hours post-dose on Day 1, up to 24 hours post-dose on Day 2 (Part 1))
- Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel C, D, and E)(Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10)
- Change From Baseline in TWA 0-24 Hrs. Heart Rate (HR) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)(Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 8, and 14)
- Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panels C, D, and E)(Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10)
- Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Systolic Blood Pressure (SBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)(Baseline (predose; up to 16 hrs on Day -1), up to 16 hrs on Day -1, predose & up to 24 hours postdose on Days 1, 8, and 14)
- Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Part C, D, and E)(Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 6, and 10)
- Change From Baseline in TWA 0-24 Hrs. Semi-recumbent Diastolic Blood Pressure (DBP) of Participants Treated With Multiple Doses of MK-8521 (Part 2, Panel F)(Baseline (predose; up to 16 hrs on Day -1), predose & up to 24 hours postdose on Days 1, 8, and 14)
- Slope of Insulin Secretion Rate/Glucose (ISR/G) During Graded Glucose Infusion (GGI) at Tmax After a Single Dose of MK-8521 (Part 3)(From -10 to 160 minutes after GGI on Day 1)
- Ratio of ISR/G at the Highest Glucose Infusion Rate During GGI Due to Treatment With A Single Dose of MK-8521 (Part 3)(From -10 to 160 minutes after GGI on Day 1)
- Glucose (TWA0-160min) During GGI at Tmax After a Single Dose of MK-8521 (Part 3)(From -10 to 160 minutes after GGI on Day 1)
- Maximum Glycemic Excursion (Gmax) During GGI and Tmax After a Single Dose of MK-8521 (Part 3)(From -10 to 160 minutes after GGI on Day 1)
- Area Under the Curve (AUC) 0-∞ for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)(Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3))
- Area Under the Curve (AUC) 0-24hr. for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)(Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3))
- Peak Plasma Concentration (Cmax) of Participants Treated With a Single Dose of MK-8521 (Part 3)(Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3))
- Time Taken to Reach Cmax (Tmax) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)(Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI (Part 3))
- Apparent Terminal Half-life (t1/2) for Plasma Concentration of Participants Treated With a Single Dose of MK-8521 (Part 3)(Day 1: predose, -60, -10 min pre-GGI, 40 min, 80 min, 120 min, 160 min, 360 min, and 600 min after start of GGI(Part 3))