A Phase I, Single Dose, Open-Label Study Comparing the Pharmacokinetics and Safety of Pretomanid in Subjects With Mild, Moderate, and Severe Hepatic Impairment to Matched, Non-Hepatically Impaired Subjects
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 14
- 试验地点
- 2
- 主要终点
- AUC(0-infinity): Area Under the Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points
研究概览
简要总结
This is a Phase 1, single dose (200 mg), open-label study comparing the pharmacokinetics and safety of Pretomanid in subjects with mild, moderate, and severe hepatic impairment to matched, non-hepatically impaired subjects. There will be approximately 36 total subjects, adult males and females, 18 to 70 years of age, inclusive. The study will be conducted at 2 sites, study duration is approximately 24 months, and subject participation duration is approximately 5 weeks (including screening). Primary objective: To evaluate the pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.
详细描述
This is a Phase 1, single dose (200 mg), open-label study comparing the pharmacokinetics and safety of Pretomanid in subjects with mild, moderate, and severe hepatic impairment to matched, non-hepatically impaired subjects. This study will enroll approximately 6 subjects with mild hepatic impairment (Child-Pugh A), approximately 6 subjects with moderate hepatic impairment (Child-Pugh B), approximately 6 subjects with severe hepatic impairment (Child-Pugh C), and approximately 18 matched non-hepatically impaired subjects. Non-hepatically impaired subjects in the control group will be matched to subjects with hepatic impairment based on age (+/- 10 years) and body weight (+/- 20 percent) as measured at screening (Visit 00A). There will be approximately 36 total subjects, adult males and females, 18 to 70 years of age, inclusive. The study will be conducted at 2 sites, study duration is approximately 24 months, and subject participation duration is approximately 5 weeks (including screening). Primary objective: To evaluate the pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Inclusion Criteria for Patients with Hepatic Impairment (Groups 1-3):
- •Subject is able to give voluntary written informed consent before any study related procedure is performed.
- •18-70 years of age, inclusive.
- •Acceptable laboratory values* obtained at screening (within 21 days prior to admission to the confinement/hospital unit) and either at or within 72 hours of admission to the confinement/hospital unit.
- •*Chemistry, complete blood count, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), total bilirubin, alkaline phosphatase, albumin, and urinalysis deemed not clinically significant by the investigator.
- •Hepatic impairment classified as Child-Pugh class A (mild), B (moderate), or C (severe) criteria at screening for Groups 1, 2, or 3, respectively, and documented evidence of hepatic cirrhosis*.
- •*by biopsy, nuclear scan, CT, MRI, ultrasound, or other clinically acceptable methods
- •If female, not of childbearing potential* or agrees to avoid becoming pregnant by using acceptable contraception** during the duration of the study.
- •*Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral oophorectomy or status after hysterectomy.
- •Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral tubal ligation; barrier method (condom) by the male partner (even if vasectomized); hormonal contraceptives; intrauterine contraceptive devices; diaphragm in combination with contraceptive jelly, cream, foam, or spermicide; and abstinence from sexual intercourse with men.
- •If subject is male and capable of reproduction, agrees to avoid fathering a child for three months after dosing by using an acceptable method of birth control*.
- •*In addition to the use of a barrier method (condom) even if vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #5, and abstinence from sexual intercourse with women.
- •If the subject is female, a negative serum pregnancy test at screening and a negative urine pregnancy test at admission to the confinement/hospital unit.
- •Willingness to comply with all protocol requirements.
- •Inclusion Criteria for Non-Hepatically Impaired Controls (Group 4):
- •Subject is able to give voluntary written informed consent before any study related procedure is performed.
- •18-70 years of age, inclusive.
- •Subject is a healthy volunteer as determined by no clinically significant findings from medical history, physical examination, vital signs, and 12-lead ECG as determined by the Site Investigator.
- •Acceptable laboratory values* obtained at screening (within 21 days prior to admission to the confinement/hospital unit) and either at or within 72 hours of admission to the confinement/hospital unit.
- •*Chemistry, complete blood count, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), total bilirubin, alkaline phosphatase, albumin, and urinalysis within the reference range for the test laboratory, unless deemed not clinically significant by the investigator.
- •If female, not of childbearing potential* or agrees to avoid becoming pregnant by using acceptable contraception** during the duration of the study.
- •*Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral oophorectomy or status after hysterectomy.
- •**Females of childbearing potential must agree to use two acceptable methods of contraceptives: bilateral tubal ligation; barrier method (condom) by the male partner (even if vasectomized); hormonal contraceptives; intrauterine contraceptive devices; diaphragm in combination with contraceptive jelly, cream, foam, or spermicide; and abstinence from sexual intercourse with men.
- •If subject is male and capable of reproduction, agrees to avoid fathering a child for three months after dosing by using an acceptable method of birth control*.
- •*In addition to the use of a barrier method (condom) even if vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #5, and abstinence from sexual intercourse with women.
- •If the subject is female, a negative serum pregnancy test at screening and a negative urine pregnancy test at admission to the confinement/hospital unit.
- •Willingness to comply with all protocol requirements.
排除标准
- •Exclusion Criteria for Patients with Hepatic Impairment (Groups 1-3):
- •Hypokalemia (< 3.5mEq/L), severe hypomagnesemia (< 1.1 mg/dL) or severe hypocalcemia (< 7.5 mg/dL).
- •Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 10 times the upper limit of normal.
- •Creatinine clearance < 60 ml/min.
- •Inability to swallow tablets.
- •Presence of any condition or finding* which would jeopardize subject safety, impact study result validity, or diminish the subject's ability to undergo all study procedures and assessments**.
- •*in the opinion of the site investigator
- •**e.g., inability to draw Pharmacokinetics (PK) samples
- •History of fever or documented fever (oral temperature > / = 100.4 degrees F or > / = 38.0 degrees C) in the 48 hours prior to admission to the the confinement/hospital unit.
- •Currently breastfeeding.
- •History of chronic tobacco/nicotine use (> 10 cigarettes per day for 3 months minimum prior to admission).
- •History of clinically significant allergy or severe side effects with nitroimidazoles (e.g., Metronidazole and related substances and azole antifungals or aromatase inhibitors).
- •Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30 days prior to screening.
- •Use of any over the counter (OTC) medication* within 7 days prior to admission to the confinement/hospital unit, unless** the substance would not likely impact the validity of the study results.
- •*including vitamins and herbal supplements, cough and cold medications.
- •**in the opinion of the site investigator
- •Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the confinement/hospital unit, unless** the substance would not likely impact the validity of the study results.
- •except hormonal contraceptives
- •in the opinion of the site investigator NOTE: See list of CYP450 enzyme altering drugs under the concomitant medications section.
- •A positive blood screen for HIV.
- •A positive alcohol breath test (or other suitable test for alcohol) or a urine screen test for drugs of abuse* at screening and at admission to the confinement/hospital unit.
- •*Amphetamines, barbiturates, cocaine metabolites, marijuana, opiates, phencyclidine (PCP).
- •NOTE: Results of the urine screen test can be ignored if in the opinion of the PI the results can be explained by the concomitant medications history.
- •Unwillingness to abstain from engaging in strenuous physical activity (e.g. running, bicycling, weightlifting, competitive sports) during the course of the study.
- •Consumption of grapefruit juice in the 48 hours before admission to the confinement/hospital unit, or the inability to abstain from these until completion of Day
- •A Heart Rate-Corrected QT Interval (Fridericia's Formula) (QTcF) interval > 450 msec (males) or > 450 msec (females) at screening (Visit 00A) or admission to the confinement/hospital unit (Visit 00B) or a history of prolonged QTc interval.
- •A family history* of Long QT Syndrome, premature cardiac death**, or sudden death without a preceding diagnosis of a condition*** that could be causative of sudden death.
- •**due to ischemic heart disease or sudden cardiac death before 55 years of age (men) or 65 years of age (women)
- •***such as known coronary artery disease, congestive heart failure, or terminal cancer
- •Any clinically significant ECG abnormality, in the opinion of the site investigator, at screening and at admission to the confinement/hospital unit.
- •Donation of > 500 mL blood within the 30 days prior to admission to the confinement/hospital unit.
- •Plans to donate blood during the study or up to 14 days after dosing.
- •Persons with a transjugular intrahepatic portosystemic shunt.
- •Exclusion Criteria for Non-Hepatically Impaired Controls (Group 4):
- •Inability to swallow tablets.
- •Presence of any condition or finding* which would jeopardize subject safety, impact study result validity, or diminish the subject's ability to undergo all study procedures and assessments**.
- •*in the opinion of the site investigator
- •**e.g., inability to collect Pharmacokinetics (PK) samples
- •History of fever or documented fever (oral temperature > / = 100.4 degrees F or > / = 38.0 degrees C) in the 48 hours prior to admission to the confinement/hospital unit.
- •Currently breastfeeding.
- •History of chronic tobacco/nicotine use (> 10 cigarettes per day for 3 months minimum prior to admission to the confinement/hospital unit).
- •History of seizures (other than febrile seizures during childhood) or known or suspected Central Nervous System (CNS) disorders that may predispose to seizures.
- •History of clinically significant allergy or severe side effects with nitroimidazoles (e.g., Metronidazole and related substances and azole antifungals or aromatase inhibitors).
- •Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30 days prior to screening.
- •Use of any over the counter (OTC) medication* within 7 days prior to admission to the confinement/hospital unit, unless** the substance would not likely impact the validity of the study results.
- •*including vitamins and herbal supplements, antacids, cough and cold medications.
- •**in the opinion of the site investigator
- •Use of prescription medication except hormonal contraceptives within 30 days prior to admission to the confinement/hospital unit, unless* the substance would not likely impact study result validity.
- •*in the opinion of the site investigator
- •Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the confinement/hospital unit, unless** the substance would not likely impact the validity of the study results.
- 另有 17 项未显示
研究组 & 干预措施
Child-Pugh A (Mild hepatic impairment)
6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1
干预措施: PA-824 (Drug)
Child-Pugh B (Moderate hepatic impairment)
6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1
干预措施: PA-824 (Drug)
Child-Pugh C (Severe hepatic impairment)
6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1
干预措施: PA-824 (Drug)
Non-hepatically impaired controls
18 matched Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1
干预措施: PA-824 (Drug)
结局指标
主要结局
AUC(0-infinity): Area Under the Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points
时间窗: Day 1 to Day 5
AUC(0-infinity) was calculated by noncompartmental analysis using the linear up log down method with the area extrapolated to infinity as Clast/Lambda_z where Clast was the last observed concentration and Lambda_z is the elimination rate constant.
AUC(0-last): Area Under the Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points
时间窗: Day 1 to Day 5
AUC(0-last) Area under the concentration time-curve to the last concentration above the lower limit of quantitation at specified pre-dose and post-dose time points was calculated by noncompartmental analysis using the linear up log down method.
CL/F: Apparent Oral Clearance Calculated From Dose/AUC(0-infinifty) at Specified Pre-dose and Post-dose Time Points
时间窗: Day 1 to Day 5
Apparent oral clearance was calculated by noncompartmental analysis using the formula Dose/AUC(0-infinity).
Cmax: Maximum Pretomanid Concentration at Specified Pre-dose and Post-dose Time Points
时间窗: Day 1 to Day 5
Maximum Pretomanid concentration is the maximum observed drug concentration in blood plasma at specified pre-dose and post-dose timepoints.
t(1/2): Apparent Terminal Elimination Half-life at Specified Pre-dose and Post-dose Time Points
时间窗: Day 1 to Day 5
Apparent terminal half-life at specified pre-dose and post-dose timepoints was estimated by ln(2)/Lambda_z, where Lambda_z is the elimination rate constant.
Tmax: Time of Maximum Pretomanid Concentration at Specified Pre-dose and Post-dose Time Points
时间窗: Day 1 to Day 5
Time of maximum Pretomanid concentration (Tmax) at specified pre-dose and post-dose timepoints.
Vd/F: Apparent Volume of Distribution at Specified Pre-dose and Post-dose Time Points
时间窗: Day 1 to Day 5
Apparent Volume of Distribution at specified pre-dose and post-dose timepoints is the volume that the total amount of administered drug would occupy to provide the same concentration as it currently is in blood plasma divided by the bioavailability. It is calculated by Dose/\[Lambda_z x AUC(0-infinity)\]
次要结局
- Incidence and Severity of Related Adverse Events(Day 1 to Day 12)
- Incidence and Severity of Serious Adverse Events(Day 1 to Day 12)
- Number of Participants With Abnormal ECG Data(Day 12)
- Number of Participants With Abnormal Physical Exam Findings(Day 3, 4, 5 and 12)
- Number of Participants With Abnormal Safety Laboratory Parameters(Day 2, 5, and 12)
- Number of Participants With Abnormal Vital Signs(Days 1, 2, 3, 4, 5, and 12)