An Investigator-and-subject Blind, Phase 1 Study To Characterize The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Repeat Doses Of Pf-06648671 In Healthy Adult Subjects And Healthy Elderly Subjects
概览
- 阶段
- 1 期
- 干预措施
- PF-06648671
- 疾病 / 适应症
- Healthy Adult Subjects and Healthy Elderly Subjects
- 发起方
- Pfizer
- 入组人数
- 92
- 试验地点
- 1
- 主要终点
- Plasma Decay half life
- 状态
- 已完成
- 最后更新
- 9年前
概览
简要总结
This is an investigator-and-subject blind, phase 1 study to characterize the safety, tolerability, pharmacokinetics and central and peripheral pharmacodynamics of 14-day repeated ascending doses of PF-06648671 once a day in healthy adults (part 1) and repeated doses at the maximum tolerated dose (MTD) defined in part 1 in healthy elderly subjects (part 2). The study also include an optional cohort (part 3) to evaluate the drug interaction between PF-06648671 at MTD and CYP3A probe, midazolam
研究者
入排标准
入选标准
- •Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the study:
- •For Part 1 and Part 3 specific: Healthy female subjects of non childbearing potential and male subjects who, at the time of screening, are between the ages of 18 and 55 years, inclusive (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12 lead ECG and clinical laboratory tests).
- •For Part 2 specific: Female subjects of non childbearing potential and male subjects who, at the time of screening, are between the age of 65 and 85 years, inclusive. Subjects must be in good health as determined by the Investigator based on a detailed medical history, full physical examination (including blood pressure and pulse rate measurement), 12 lead ECG and clinical laboratory tests. Subjects with mild, chronic, stable disease eg, controlled hypertension, non insulin dependent diabetes, osteoarthritis may be enrolled if deemed medically prudent by the investigator. Subjects taking daily prescription or non prescription medications for management of acceptable chronic medical conditions must be on a stable dose of these, as defined by non change in dose for the 3 months prior to the first dose of study medication and no planned changes during the conduct of the study.
- •Female subjects of non childbearing potential must meet at least one of the following criteria:
- •Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level confirming the post menopausal state;
- •Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- •Have medically confirmed ovarian failure. All other female subjects (including females with tubal ligations will be considered to be of childbearing potential.
- •Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lbs).
- •For Part 2 specific: the creatinine clearance greater than 60 mL/min using the Cockcroft Gault method.
- •Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
排除标准
- •For Part 1 and Part 3 specific: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) at the discretion of the investigator.
- •For Part 2 specific: Recent (eg, last 6 months) evidence or history of unstable disease or moderate to severe conditions which would, in the Investigator's opinion, interfere with the study evaluations or impact on the safety of participating subjects including but not limited to anemia, liver disease, stroke.
- •Any condition possibly affecting drug absorption (eg, gastrectomy).
- •A positive urine drug screen.
- •History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) within 6 months of Screening.
- •Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of study medication, whichever is longer.
- •Screening supine blood pressure ≥140 mm Hg (systolic) or ≥ 90 mm Hg (diastolic), following at least 5 minutes of supine rest. If blood pressure (BP) is ≥ 140 mm Hg (systolic) or 90 mm Hg (diastolic), the BP should be repeated two more times, following 2 minutes rest and the average of the three BP values should be used to determine the subject's eligibility.
- •Screening supine12 lead ECG demonstrating QTcf \>450 or a QRS interval \>120 msec. If QTcf exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTc or QRS values should be used to determine the subject's eligibility.
- •Subjects with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study specific laboratory and confirmed by a single repeat, if deemed necessary:
- •Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transminase (SGPT) 1.5x upper limit of normal (ULN);
研究组 & 干预措施
Multiple Doses PF-06648671 (Cohort1)
Healthy subjects receive 14-day repeated dose once a day at 4 mg of PF-06648671 or matching placebo
干预措施: PF-06648671
Multiple Doses PF-06648671 (Cohort1)
Healthy subjects receive 14-day repeated dose once a day at 4 mg of PF-06648671 or matching placebo
干预措施: Placebo
Multiple Doses PF-06648671 (cohort 2)
Healthy subject receive 14-day repeated dose once a day at 12 mg of PF-06648671 or matching placebo
干预措施: PF-06648671
Multiple Doses PF-06648671 (cohort 2)
Healthy subject receive 14-day repeated dose once a day at 12 mg of PF-06648671 or matching placebo
干预措施: Placebo
Multiple doses PF-06648671 (cohort 3)
Healthy subject receive 14-day repeated dose once a day at 40 mg of PF-06648671 or matching placebo and CSF LP is collected at baseline and steady state predose on day 1 and 14
干预措施: PF-06648671
Multiple doses PF-06648671 (cohort 3)
Healthy subject receive 14-day repeated dose once a day at 40 mg of PF-06648671 or matching placebo and CSF LP is collected at baseline and steady state predose on day 1 and 14
干预措施: Placebo
Multiple Doses PF-06648671 (cohort 4)
Healthy subject receive 14-day repeated dose once a day at 40 mg of PF-06648671 or matching placebo
干预措施: PF-06648671
Multiple Doses PF-06648671 (cohort 4)
Healthy subject receive 14-day repeated dose once a day at 40 mg of PF-06648671 or matching placebo
干预措施: Placebo
Multiple Doses PF-06648671 (cohort 5)
Healthy subject receive 14-day repeated dose once a day at 100 mg of PF-06648671 or matching placebo, CSF LP is collected at baseline 72 hours prior to day 1 dosing and at steady-state on Day 15, 24 hours after last dosing on day 14
干预措施: PF-06648671
Multiple Doses PF-06648671 (cohort 5)
Healthy subject receive 14-day repeated dose once a day at 100 mg of PF-06648671 or matching placebo, CSF LP is collected at baseline 72 hours prior to day 1 dosing and at steady-state on Day 15, 24 hours after last dosing on day 14
干预措施: Placebo
Multiple Doses in Healthy Elderly (cohort 7)
Healthy Elderly subjects receive 14-day repeated dose once a day at MTD PF-06648671 defined in healthy adult subjects (part 1)
干预措施: PF-06648671
Multiple Doses in Healthy Elderly (cohort 7)
Healthy Elderly subjects receive 14-day repeated dose once a day at MTD PF-06648671 defined in healthy adult subjects (part 1)
干预措施: Placebo
Multiple Doses PF-06648671 (cohort 8)
Healthy subjects receive 14-day repeated dose once a day at 360 mg of PF-06648671 or matching placebo, CSF LP is collected at baseline 72 hours prior to day 1 dosing and at steady-state on Day 15, 24 hours post last dose
干预措施: PF-06648671
Multiple Doses PF-06648671 (cohort 8)
Healthy subjects receive 14-day repeated dose once a day at 360 mg of PF-06648671 or matching placebo, CSF LP is collected at baseline 72 hours prior to day 1 dosing and at steady-state on Day 15, 24 hours post last dose
干预措施: Placebo
Midazolam DDI (optional cohort 9)
Healthy Subjects receive single dose of 2 mg midazolam in period 1 followed by 14 days PF-06648671 once a day and coadministration of PF-06648671 and midazolam 2 mg in period 2 (Optional cohort)
干预措施: PF-06648671
Midazolam DDI (optional cohort 9)
Healthy Subjects receive single dose of 2 mg midazolam in period 1 followed by 14 days PF-06648671 once a day and coadministration of PF-06648671 and midazolam 2 mg in period 2 (Optional cohort)
干预措施: Midazolam
Multiple Doses PF-06648671 (cohort 6)
Healthy subject receive 14-day repeated dose once a day at 200 mg of PF-06648671 or matching placebo, CSF LP is collected at baseline 72 hours prior to day 1 dosing and at steady-state on Day 25, 24 hours after last dosing on day 14
干预措施: PF-06648671
Multiple Doses PF-06648671 (cohort 6)
Healthy subject receive 14-day repeated dose once a day at 200 mg of PF-06648671 or matching placebo, CSF LP is collected at baseline 72 hours prior to day 1 dosing and at steady-state on Day 25, 24 hours after last dosing on day 14
干预措施: Placebo
结局指标
主要结局
Plasma Decay half life
时间窗: 0-24 hours on day 1 and 7 and 0-72 hours on day 14
t1/2 post last dose on Day 14
Oral clearance (CL/F)
时间窗: 0-24 hours on day 1 and 7 and 0-72 hours on day 14
CL/F on day 14
Accumulation factor of Cmax
时间窗: 0-24 hours on day 1 and 7 and 0-72 hours on day 14
PF-06648671 plasma Cmax on day 7 and 14 relative to day 1 in part 1, day 14 to day 1 in part 2
Renal clearance (CLr)
时间窗: 0-24 hours on day 14
Renal clearance of PF-06648671 on day 14
Time to Reach Maximum Observed Plasma concentration (Tmax)
时间窗: 0-24 hours on day 1 and 7 and 0-72 hours on day 14
Tmax on day 1, 7 and 14 in part 1, day 1 and 14 in part 2
Maximum Observed PF-06648671 Plasma Concentration (Cmax)
时间窗: 0-24 hours on day 1 and 7 and 0-72 hours on day 14
Cmax on day 1, 7 and day 14 in part 1, Cmax on day 1 and 14 in part 2
PF-06648671 Plasma Area Under the Curve from Time Zero to 24 hour after dosing (AUC24)
时间窗: 0-24 hours on day 1 and 7 and 0-72 hours on day 14
AUC24 on day 1, 7 and 14 in part 1, day 1 and 14 in part 2
CSF Abeta 40 and 42 concentration change from baseline
时间窗: 0 hr on day 1 and 0 hr on day 14 or 15
CSF Abeta 40 and 42 concentration on day 14 (cohort 3) or on day 15 (cohorts 5, 6 and 8) prior to dosing compared to day 1 baseline
Plasma AUC of midazolam alone vs co-administration with PF-06648671 in optional part 3
时间窗: 0-24hr on day 1 and 0-48hr on day 14
the AUC ratio of midazolam between day 14 in period 2 vs day 1 in period 1 in optional part 3
Plasma Cmax of midazolam alone vs co-administration with PF-06648671 in optional part 3
时间窗: 0-24hr on day 1 and 0-48hr on day 14
the Cmax ratio of midazolam between day 14 in period 2 vs day 1 in period 1 in optional part 3
Volume of distribution (Vz/F)
时间窗: 0-24 hours on day 1 and 7 and 0-72 hours on day 14
Vz/F on day 14
Observed PF-06648671 CSF concentration
时间窗: 0 hr on day 1 and 0 hr on day 14 or 15
PF-06648671 CSF concentration on day 1 and day 14 (cohort 3) or day 15 (cohorts 5, 6 and 8) prior to dosing in part 1
Accumulation factor of AUC24
时间窗: 0-24 hours on day 1 and 7 and 0-72 hours on day 14
accumulation of PF-06648671 plasma AUC24 on day 7 and day 14 relative to day 1 in part 1, AUC on day 14 relative to day 1 in part 2
% parent drug in urine (Ae%)
时间窗: 0-24 hr on day 14
percentage of parent drug recovered in urine over 24 hours on day 14 in part 1 and part 2
次要结局
- CSF Abeta 37, 38 and total concentration change from baseline(0 hr on day 1 and 0 hr on day 14)
- Plasma Abeta change from baseline(0-24hr on day 1 and 0-72hr on day 14)