A Phase I, Non-Randomized, Open-Label, Single-Dose Study Comparing the Pharmacokinetics, Safety, and Tolerability of Pretomanid Tablets 200 mg in Subjects with Moderate and Severe Hepatic Impairment Relative to Matched Control Subjects with Normal Hepatic Function.
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 3
- 主要终点
- To evaluate the pharmacokinetics (PK) of pretomanid single dose in subjects with moderate and severe hepatic impairment (Child Pugh B and C, respectively) relative to matched control subjects with normal hepatic function
研究概览
简要总结
Pretomanid is a nitroimidazole and is metabolized extensively in the liver (CYP3A4) and it has a low extraction ratio. Hepatic blood flow as well as hepatic functions are compromised in advanced liver disease conditions. Therefore, in comparison to healthy subjects, the pharmacokinetics of pretomanid is likely to be altered in subjects with hepatic impairment. We hypothesize that presence of advanced liver disease will have an impact on the metabolism of pretomanid. The purpose of this study is to evaluate the safety and pharmacokinetics of pretomanid in subjects with underlying liver disease defined as a Child-Pugh class of B (moderate hepatic impairment) or C (severe hepatic impairment). The severity of liver disease is based on five clinical features: 1) total bilirubin level, 2) serum albumin, 3) prothrombin time (measured as the international normalized ratio, INR), 4) the degree of ascites, and 5) the grade of hepatic encephalopathy. The total point score is then used to determine the subject’s Child-Pugh class. Pretomanid will be administered orally, and 200 mg will be the dose.
A single oral dose of pretomanid 200 mg will be taken once. The PK profile studies on oral dosing of pretomanid have been consistent for healthy subjects and subjects with pulmonary TB. Pretomanid is readily absorbed after oral administration and slowly eliminated in plasma. Pretomanid plasma concentrations increased in a dose-related manner after single-dose administration of up to 1000 mg in healthy subjects and subjects with TB. However, at doses above 200 mg/day, the increase was less than dose proportional. With increasing dosages, there is a trend toward increased side effects. Furthermore, efficacy studies have shown equivalent early bacterial activity at dosages ranging from 200 mg to 1200 mg.
The primary purpose of this study is to delineate the effect of hepatic impairment on the plasma PK of pretomanid so as to guide the dosing recommendations for patients with hepatic impairment. The results from this study will enable the development of appropriate dosing recommendations in patients with impaired hepatic function. Therefore, this study will evaluate the PK of pretomanid, following oral administration in subjects with moderate or severe hepatic impairment using Child-Pugh class, (FDA 2003) compared to matched-healthy subjects with normal hepatic function.
研究设计
- 研究类型
- Interventional
入排标准
- 年龄范围
- 18.00 Year(s) 至 70.00 Year(s)（—）
- 性别
- All
入选标准
- •for Subjects with Moderate or Severe Hepatic Impairment Group 1 or 2 1 Males andor nonpregnant nonlactating females aged 18 to 70 years old inclusive 2 Each subject is required to weigh at least 50 kg and have a Body Mass Index BMI value less than or equal to 40 kg per m2 but greater than or equal to 18 kg per m2 3 Hepatically impaired subjects will be classified using Child Pugh System Subjects must have child Pugh B with the score of 7 to 9 moderate hepatic impairment or Child Pugh C with the score of 10 to 15 severe hepatic impairment with known medical history of liver disease with or without a known history of alcohol abuse and previous confirmation of liver cirrhosis by liver biopsy or other medical imaging technique including laparoscopy computed tomography scan magnetic resonance imaging or ultrasonography associated with unambiguous medical history 4 Acceptable laboratory values obtained at screening within 21 days prior to admission to the clinical facility or study center and either at or within 72 hours of admission to the clinical facility or study center 5 A normal or non clinically significant physical examination skin head eyes ears nose and throat thyroid neurological chest and lungs cardiovascular abdomen liver and spleen lymph nodes musculoskeletal and extremities including vital signs sitting blood pressure mm Hg sitting heart rate beats per min and oral body temperature and 12lead ECG as determined by the clinical facility or study center Investigator 6 Adequate venous access in both arms for the collection of a number of blood samples during the study Inclusion Criteria for Non Hepatically Impaired Controls Group 3 1 Healthy Males and or nonpregnant nonlactating females aged 18 to 70 years old inclusive 2 Each subject is required to weigh at least 50 kg and have a Body Mass Index value less than or equal to 40 kg per m2 but greater than or equal to 18 kg per m2 Age 18 to 70 years old inclusive 3 The subjects will be matched to hepatic impaired subjects by age at screening The subject must meet age requirements at the time of signing the initial informed consent and the initial study medication administration 4 Subject is healthy as determined by no clinically significant findings from medical history physical examination skin head eyes ears nose and throat thyroid neurological chest and lungs cardiovascular abdomen liver and spleen lymph nodes musculoskeletal and extremities including vital signs sitting blood pressure mm Hg sitting heart rate beats min and oral body temperature and 12 lead ECG as determined by the clinical facility or study center Investigator 5 Acceptable laboratory values obtained at screening within 21 days prior to admission to the clinical facility or study center and either at or within 72 hours of admission to the clinical facility or study center 6 Adequate venous access in both arms for the collection of a number of blood samples during the study.
排除标准
- •Subject must not be enrolled in the study if they meet any of the following criteria Exclusion Criteria for Subjects with Moderate or Severe Hepatic Impairment Group 1 or 2 1 Institutionalized subjects 2 Subject with hypokalemia lesser than 3.5mEq per L severe hypomagnesemia lesser than 1.1 mg per dL or severe hypocalcemia lesser than 7.5 mg per dL 3 Aspartate aminotransferase AST or alanine transaminase ALT greater than 10 times the upper limit of normal 4 Creatinine clearance lesser than 60 ml per min per 1.73m2 5 Inability to swallow tablets 6 Any condition possibly affecting study drug absorption eg prior bariatric surgery gastrectomy ileal resection NOTE Participants who have undergone cholecystectomy and or appendectomy are eligible for this study as long as the surgery occurred more than 6 months prior to screening 7 Fluctuating or rapidly deteriorating hepatic function as indicated by widely varying or worsening of clinical and or laboratory signs of hepatic impairment 3 months prior to screening or within the screening period or the presence of any condition or finding which would jeopardize subject safety impact study result validity or diminish the subject ability to undergo all study procedures and assessment 8 History of fever or documented fever in the 48 hours prior to admission to the clinical facility or study center 9 History of clinically significant allergy or severe side effects with nitroimidazoles eg metronidazole and related substances and azole antifungals or aromatase inhibitors 10 Receipt of of a study drug vaccine or biologic in a clinical trial within 30 days prior to screening History of seizures other than febrile seizures during childhood or known or suspected CNS disorders that may predispose to seizures 11 Use of any over the counter OTCmedication within 7 days prior to admission to the clinical facility or study center unless the substance would not likely impact the validity of the study results 12 Treatment with CYP3A4 enzyme altering drugs within 7 days prior to admission to the clinical facility or study center unless the substance would not likely impact the validity of the study results 13 QTcF interval greater than 440 msec males or greater than 450 msec females at screening or admission to the clinical facility or study center or a history of prolonged QTc interval 14 History of seizures other than febrile seizures during childhood or known or suspected CNS disorders that may predispose to seizures 15 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 16 Any other clinically significant ECG abnormality in the opinion of the site investigator at screening and admission to the clinical facility or study center 17 Donated blood greater than 500 mL or significant blood loss within the 30 days prior to admission to the clinical facility or study center 18 Planning to donate blood during the study or up to 14 days after dosing 19 Persons with a transjugular intrahepatic portosystemic shunt 20 History of liver transplantation or subjects in the severe hepatic impairment group that are expecting a liver transplant during the study participation period 21 Medical history suggestive of hepatocellular carcinoma HCC with an alpha-fetoprotein AFP level is greater than 50 ng per mL For Non-Hepatically Impaired Controls Group 3 1 Institutionalized subjects 2 Inability to swallow tablets 3 Presence of any condition or finding which would jeopardize subject safety impact study result validity or diminish the subject ability to undergo all study procedures and assessments 4 History of fever or documented fever oral temperature greater than or equal to 100.4 F or greater than or equal to 38 degree celsius in the 48 hours prior to admission to the clinical facility or study center 5 History of clinically significant allergy or severe side effects with nitroimidazoles eg metronidazole and related substances and azole antifungals or aromatase inhibitors 6 Receipt of a study drug vaccine or biologic in a clinical trial within 30 days prior to screening 7 Use of any OTC medication within 7 days prior to admission to the clinical facility study center unless the substance would not likely impact the validity of the study results 8 Treatment with CYP3A4 enzyme altering drugs within 7 days prior to admission to the clinical facility or study center unless the substance would not likely impact the validity of the study results 9 QTcF interval greater than 450 msec males or greater than 450 msec females at screening or admission to the clinical facility or study center or a history of prolonged QTc interval 10 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 11 Any clinically significant ECG abnormality in the opinion of the site investigator at screening and admission to the clinical facility or study center 12 Donated blood greater than 500 mL or had significant blood loss within the 30 days prior to admission to the clinical facility or study center 13 Planning to donate blood during the study or up to 14 days after dosing 14 Pre-existing condition that interferes with normal GI anatomy or motility that could impair the absorption metabolism and or excretion of the IPs inflammatory bowel disease peptic ulcer or pancreatitis 15 Any food allergy intolerance restriction or special diet that in the opinion of the Principal Investigator or Medical Sub Investigator could contraindicate the subject participation in this study.
结局指标
主要结局
To evaluate the pharmacokinetics (PK) of pretomanid single dose in subjects with moderate and severe hepatic impairment (Child Pugh B and C, respectively) relative to matched control subjects with normal hepatic function
时间窗: Blood samples (1 x 6 mL) will be collected in blood collection tubes containing K2EDTA before dosing (pre dose) and at the following times thereafter 1, 2, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose.
次要结局
- To evaluate the safety and tolerability of pretomanid in subjects with moderate and severe hepatic impairment relative to matched control subjects with normal hepatic function.(Vital Signs and Safety will be obtained at screening, and on Day -1 to Day 12.)
研究者
Dr Pradeep Kundapur
Ecron Acunova Limited