A PHASE 1, OPEN-LABEL, TWO-PART STUDY TO EVALUATE THE EFFECT OF TWO STEADY-STATE DOSE LEVELS OF PF-06882961 ON THE PHARMACOKINETICS OF SINGLE ORAL DOSES OF ATORVASTATIN AND MIDAZOLAM IN HEALTHY ADULTS AND AN ORAL CONTRACEPTIVE IN HEALTHY POST-MENOPAUSAL FEMALES
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- (Part A) Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) of Atorvastatin in Periods 1, 4, and 7
研究概览
简要总结
The purpose of this study is to characterize the effect of PF-06882961, administered at 2 steady-state dose levels, on the PK of single doses of atorvastatin (20 mg) or midazolam (5 mg), administered separately, in healthy adult male and female participants (Part A), or an OC in healthy PM female participants (Part B).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Part A Only - Healthy male and female participants must be 18 to 65 years of age, inclusive, at the time of signing the ICD (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, physical examination, including blood pressure and pulse rate measurement, standard 12 lead ECG and clinical laboratory tests).
- •Part B Only - Healthy PM female participants between 40 and 65 years of age, inclusive, at the time of signing the ICD (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, physical examination, including BP and PR measurement, standard 12 lead ECG and clinical laboratory tests). Subjects must be amenorrheic for at least 12 months. Women who are 60 years of age or younger must also have an FSH that is within the laboratory's reference range for PM women.
- •Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
- •BMI- 20.0 kg/m2 to <30.0 kg/m2 at Screening.
- •Stable body weight, defined as <5 % change (per participant report) for 90 days before Screening.
- •Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.
排除标准
- •Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
- •Any condition possibly affecting drug absorption (eg, prior bariatric surgery, gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or pancreatic insufficiency).
- •Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
- •Known intolerance or hypersensitivity to GLP-1R agonists.
- •Known hypersensitivity to atorvastatin or midazolam (for participants in Part A), or LE and EE (for participants in Part B).
- •Personal or family history of MTC or MEN2 or study participants with suspected MTC per the investigator's judgment.
- •Symptomatic gallbladder disease.
- •History of major depressive disorder or history of other severe psychiatric disorders (eg, schizophrenia or bipolar disorder) within the last 2 years from screening.
- •Any lifetime history of a suicide attempt.
- •Use of prescription or nonprescription drugs and dietary and herbal supplements within 7 days or 5 half lives (whichever is longer) prior to the first dose of study intervention.
- •Systemic therapy with any of the medications that are moderate or strong CYP3A4/5, CYP2C9 and/or CYP2C19 inhibitors within 28 days or 5 half-lives (whichever is longer) or moderate or strong CYP3A, CYP2C9 and/or CYP2C19 inducers within 28 days or 5 half-lives (whichever is longer) prior to the first dose of study intervention.
- •Systemic therapy with inhibitors of the BCRP transporter within 28 days or 5 half lives (whichever is longer) prior to the first dose of study intervention.
- •Current use of any prohibited concomitant medication(s) or those unwilling/unable to use a permitted concomitant medication(s).
- •Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of study intervention used in this study (whichever is longer).
- •Known prior participation in a trial involving PF-
- •A PHQ-9 score ≥15 obtained at Screening or Day -1 in Study.
- •Response of "yes" to question 4 or 5, or on any suicidal behavioral question on the C SSRS at Screening or Day -1 in Study.
- •A positive urine drug test.
- •Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest. BP should be measured in triplicate and the average of the 3 BP values should be used to determine the participant's eligibility. Note: At screening, the participant's arm circumference should be measured (eg, using a flexible anthropometric tape) at the midpoint of the length of the upper arm and the appropriate cuff selected and used throughout the study.
- •Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF interval >450 msec, complete LBBB, signs of an acute or indeterminate age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second or third degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values should be used to determine the participant's eligibility. Computer interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants.
- •Participants 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 test, if deemed necessary:
- •HbA1c ≥6.5%.
- •Aspartate AST or ALT level ≥2 times the ULN.
- •Total bilirubin level ≥1.5 times the ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is ≤ ULN.
- •TSH >1.5x the ULN or <LLN.
- •Serum calcitonin > the ULN.
- •Amylase or lipase > the ULN.
- •Fasting blood glucose ≥126 mg/dL.
- •Fasting C-peptide <0.8 ng/mL.
- •eGFR <70 mL/min/1.73 m2 as calculated by the CKD-EPI equation.
- •Positive testing for HIV, HepBsAg, or HCVAb. Study participants positive for HCVAb are to be excluded unless known to have been treated with a known curative therapy and negative for HCV RNA. Hepatitis B vaccination is allowed.
- •A positive SARS-CoV-2 test.
- •Participation in a formal weight reduction program (eg, Weight Watchers) within 90 days prior to Screening.
- •History of alcohol abuse or binge drinking and/or any other illicit drug use or dependence within 6 months of Screening. Binge drinking is defined as a pattern of 5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
- •Current use of tobacco or nicotine containing products in excess of the equivalent of 5 cigarettes per day.
- •Known or suspected illicit drug use.
- •Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more within 60 days prior to dosing randomization (Day-1).
- •History of sensitivity to heparin or heparin induced thrombocytopenia if Hep-lock is used for IV blood draw.
- •Unwilling or unable to comply with the criteria in the Lifestyle Considerations section of this protocol.
- •Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.
研究组 & 干预措施
Part A
To evaluate the effect of 2 steady-state dose levels of PF-06882961 on the Single Dose pharmacokinetics of atorvastatin (20 mg tablet) and midazolam (5 mg syrup).
干预措施: PF-06882961 (Drug)
Part A
To evaluate the effect of 2 steady-state dose levels of PF-06882961 on the Single Dose pharmacokinetics of atorvastatin (20 mg tablet) and midazolam (5 mg syrup).
干预措施: Atorvastatin (Drug)
Part A
To evaluate the effect of 2 steady-state dose levels of PF-06882961 on the Single Dose pharmacokinetics of atorvastatin (20 mg tablet) and midazolam (5 mg syrup).
干预措施: Midazolam (Drug)
Part B
To evaluate the effect of 2 steady-state dose levels of PF-06882961 on the Single Dose pharmacokinetics of an Oral Contraceptive (Levonorgestrel 0.15 mg and Ethinyl Estradiol 0.03 mg tablet).
干预措施: PF-06882961 (Drug)
Part B
To evaluate the effect of 2 steady-state dose levels of PF-06882961 on the Single Dose pharmacokinetics of an Oral Contraceptive (Levonorgestrel 0.15 mg and Ethinyl Estradiol 0.03 mg tablet).
干预措施: Levonorgestrel & Ethinyl Estradiol (Drug)
结局指标
主要结局
(Part A) Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) of Atorvastatin in Periods 1, 4, and 7
时间窗: For Part A Periods 1, 4, and 7: At 0 (prior to atorvastatin dose), 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, 36, 48, 72 hours (only Periods 1 & 4) post atorvastatin dose on Day 1 of each period.
Atorvastatin was given on Day 1 in Periods 1, 4 and 7 of Part A and blood samples were collected for atorvastatin pharmacokinetic (PK) at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
(Part A) AUCinf of Midazolam in Periods 2, 5, and 8
时间窗: For Part A Periods 2, 5, and 8: At 0 (prior to midazolam dose), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24 hours (only for Periods 2 & 5) post midazolam dose on Day 1 of each period.
Midazolam was given on Day 1 in Periods 2, 5 and 8 of Part A and blood samples were collected for midazolam PK at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
(Part B) AUCinf of Ethinyl Estradiol in Periods 1, 3 and 5
时间窗: For Part B Periods 1, 3, 5: At 0 (prior to EE dose), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72, 96, 120 hours post EE dose on Day 1 in Periods 1, 3, 5 of each period.
Ethinyl estradiol (EE) was given on Day 1 in Periods 1, 3 and 5 of Part B and blood samples were collected for ethinyl estradiol PK at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
(Part B) AUCinf of Levonorgestrel in Periods 1, 3 and 5
时间窗: For Part B Periods 1, 3, 5: At 0 (prior to levonorgestrel dose), 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72, 96, 120 hours post levonorgestrel dose on Day 1 of each period.
Levonorgestrel was given on Day 1 in Periods 1, 3 and 5 of Part B and blood samples were collected for levonorgestrel PK at the preset time points described in the Time Frame. AUCinf calculated area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
次要结局
- (Part A) Number of Participants With Clinical Laboratory Abnormalities During Part A of the Study (Without Regard to Baseline Abnormality)(From Baseline up to follow-up visit (Days 69-72) in Part A of the study.)
- (Part A) Number of Participants With Treatment Emergent Adverse Events (TEAE) During Part A of the Study(From Baseline up to follow-up telephone contact (Days 90-97) in Part A of the study.)
- (Part B) Number of Participants With Categorical Scores on the PHQ-9(Study Day -1 (D-1) (ie, Period 1 Day-1 [P1D-1]), D6 (P2D1), D13 (P2D8), D20 (P2D15), D27 (P2D22), D37 (P3D1), D42 (P4D1), D50 (P4D9), D60 (P4D19), D66 (P5D6), and at follow-up visit (Days 72-75) of Part B.)
- (Part B) Number of Participants With TEAE During Part B of the Study(From Baseline up to follow-up telephone contact (Days 94-101) in Part B of the study.)
- (Part B) Number of Participants With Clinical Laboratory Abnormalities During Part B of the Study (Without Regard to Baseline Abnormality)(From Baseline up to follow-up visit (Days 72-75) in Part B of the study.)
- (Part A) Percentage of Change From Baseline in Body Weight(Percentage of change from Baseline 1: from the last pre-dose measurement in Part A Period 1 (ie, Baseline 1) to Day 2 of Part A Period 8; percentage of Change from the last predose measurement in Part A Period 3 (ie, Baseline 2) to Day 2 of Period 8.)
- (Part A) Number of Participants With Vital Signs Abnormalities During Part A of the Study(From Baseline up to follow-up visit (Days 69-72) in Part A of the study.)
- (Part B) Number of Participants With Vital Signs Abnormalities During Part B of the Study(From Baseline up to follow-up visit (Days 72-75) in Part B of the study.)
- (Part B) Percentage of Change From Baseline in Body Weight(Percentage of Change from Baseline 1:from the last pre-dose measurement in Part B Period 1 (ie, Baseline 1) to Day 2 of Part B Period 8;percentage of Change from the last predose measurement in Part B Period 2 (ie, Baseline 2) to Day 6 of Part B Period 5.)
- (Part A) Number of Participants With Treatment Emergent Electrocardiograms (ECG) Abnormalities During Part A of the Study(From Baseline up to follow-up visit (Days 69-72) in Part A of the study.)
- (Part B) Number of Participants With Treatment Emergent ECG Abnormalities During Part B of the Study(From Baseline up to follow-up visit (Days 72-75) in Part B of the study.)
- (Part A) Number of Participants With Categorical Scores on the Columbia Suicide Severity Rating Scale (C-SSRS)(Study Day -1 (D-1) (ie, Period 1 Day-1 [P1D-1]), D5 (P3D1), D12 (P3D8), D19 (P3D15), D27 (P3D23), D36 (P4D1), D40 (P6D1), D48 (P6D9), D58 (P6D19), D62 (P8D1), and at follow-up visit (Days 69-72) of Part A.)
- (Part B) Number of Participants With Categorical Scores on the C-SSRS(Study Day -1 (D-1) (ie, Period 1 Day-1 [P1D-1]), D6 (P2D1), D13 (P2D8), D20 (P2D15), D27 (P2D22), D37 (P3D1), D42 (P4D1), D50 (P4D9), D60 (P4D19), D66 (P5D6), and at follow-up visit (Days 72-75) of Part B.)
- (Part A) Number of Participants With Categorical Scores on the Patient Health Questionnaire (PHQ-9)(Study Day -1 (D-1) (ie, Period 1 Day-1 [P1D-1]), D5 (P3D1), D12 (P3D8), D19 (P3D15), D27 (P3D23), D36 (P4D1), D40 (P6D1), D48 (P6D9), D58 (P6D19), D62 (P8D1), and at follow-up visit (Days 69-72) of Part A.)