A Single Centre, Open Label, One Sequence, Cross-over Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of Single Inhaled Doses of Nemiralisib in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]) of Nemiralisib in Plasma
研究概览
简要总结
Nemiralisib is a potent anti-inflammatory agent for the treatment of chronic obstructive pulmonary disease (COPD) and other inflammatory lung diseases. The Cytochrome P450 3A4 (CYP3A4) is a major route of clearance for nemiralisib. The co-administration of drug therapies, which modulate CYP3A4, may alter the exposure of nemiralisib. Hence, this clinical drug interaction study with itraconazole (a potent CYP3A4 inhibitor) is required. The study will evaluate the PK, safety and tolerability of nemiralisib when administered alone and when administered concomitantly with repeat doses of itraconazole in healthy males and females. Subjects will receive treatment with nemiralisib alone in Period 1 and itraconazole followed by nemiralisib in Period 2 in single sequence crossover manner. Approximately 20 subjects will be enrolled such that approximately 16 evaluable subjects complete the study. Each subject will participate in the study for approximately 7 weeks including screening visit, 2 treatment periods and a follow up visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This will be an open-label study. Hence, there will be no masking.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Subjects must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
- •Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac evaluation.
- •Normal spirometry at Screening (FEV1 and forced vital capacity [FVC] >=80 percent of predicted. Measurements to be taken in triplicate. The highest value of each individual component must be >=80 percent of predicted).
- •A subject with a clinical abnormality or laboratory parameter(s) (except for liver function tests) outside the reference range for the population being studied may be included only if the investigator, in consultation with the medical monitor if needed, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- •Body weight >50 kilograms (kg) and body mass index (BMI) within the range 18.0-35.0 kg per meter square (kg/m^2) (inclusive).
- •Male and/or female: A male subject must agree to use contraception during the treatment period and for at least 10 days after the last dose of study treatment and refrain from donating sperm during this period; a female subject is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP).
- •Capable of giving signed informed consent.
排除标准
- •History or presence of cardiovascular, respiratory (except childhood asthma, which has now remitted), hepatic, renal, gastrointestinal, endocrine, hematological, psychiatric or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
- •Abnormal blood pressure.
- •Liver function test results above the upper limit of normal (ULN).
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •QT interval corrected for heart rate by Fridericia's formula (QTcF) >450 milliseconds (msec).
- •Past or intended use of over-the-counter or prescription medication including herbal medications within 14 days prior to dosing.
- •Participation in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within 90 days.
- •Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
- •Current enrolment or past participation within the last 30 days before signing of consent in this or any other clinical study involving an investigational study treatment or any other type of medical research.
- •Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C antibody test result at screening.
- •Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment.
- •Positive human immunodeficiency virus (HIV) antibody test (according to local policies).
- •Positive drug/alcohol test at screening or on admission (Day -1).
- •Regular use of known drugs of abuse.
- •Regular alcohol consumption within 6 months prior to the study defined as: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 grams (g) of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
- •Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or nicotine-containing products within 6 months of screening, or a total pack year history of >5 pack years. [number of pack years = (number of cigarettes per day/20) x number of years smoked].
- •Sensitivity to any of the study treatments, or components thereof (including lactose and Magnesium Stearate), or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
- •Unwillingness to follow the lifestyle restrictions.
研究组 & 干预措施
Subjects receiving nemiralisib and itraconazole
Eligible subjects will receive a single dose of 100 micrograms (mcg) nemiralisib on Day 1 in Period 1. Subjects will also receive a single dose of 200 milligrams (mg) itraconazole in the morning from Day 1 to Day 10 and single dose of 100 mcg nemiralisib on Day 5, one hour after the dose of itraconazole in Period 2. There will be a washout of at least 14 days between the administration of nemiralisib in Period 1 and Period 2.
干预措施: Nemiralisib (Drug)
Subjects receiving nemiralisib and itraconazole
Eligible subjects will receive a single dose of 100 micrograms (mcg) nemiralisib on Day 1 in Period 1. Subjects will also receive a single dose of 200 milligrams (mg) itraconazole in the morning from Day 1 to Day 10 and single dose of 100 mcg nemiralisib on Day 5, one hour after the dose of itraconazole in Period 2. There will be a washout of at least 14 days between the administration of nemiralisib in Period 1 and Period 2.
干预措施: Itraconazole (Drug)
结局指标
主要结局
Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC [0-t]) of Nemiralisib in Plasma
时间窗: Period 1: Pre-dose, and 5, 30 minutes, 2, 6, 12, 24, 48, 72, 96 and 120 hours post-dose on Day 1. Period 2: Pre-dose, and 5 min, 30 min, 2, 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose on Day 5
Blood samples were collected from participants at indicated time frames after the administration of study treatment to investigate pharmacokinetic parameters of Nemiralisib in both treatment period 1 and 2. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of Nemiralisib in Plasma
时间窗: Period 1: Pre-dose, and 5, 30 minutes, 2, 6, 12, 24, 48, 72, 96 and 120 hours post-dose on Day 1. Period 2: Pre-dose, and 5 min, 30 min, 2, 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose on Day 5
Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate pharmacokinetic parameters of nemiralisib in both treatment period 1 and 2. Pharmacokinetic analysis was conducted using standard non-compartmental methods. Pharmacokinetic population comprised of all participants enrolled in the study who took at least 1 dose of nemiralisib and for whom a nemiralisib pharmacokinetic sample was obtained and analyzed.
Maximum Observed Plasma Concentration (Cmax) of Nemiralisib in Plasma
时间窗: Period 1: Pre-dose, and 5, 30 minutes, 2, 6, 12, 24, 48, 72, 96 and 120 hours post-dose on Day 1. Period 2: Pre-dose, and 5 min, 30 min, 2, 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose on Day 5
Blood samples were collected from participants at indicated time frames after the administration of study treatment to investigate pharmacokinetic parameters of Nemiralisib in both treatment period 1 and 2. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Apparent Terminal Half-life (t1/2) of Nemiralisib in Plasma
时间窗: Period 1: Pre-dose, and 5, 30 minutes, 2, 6, 12, 24, 48, 72, 96 and 120 hours post-dose on Day 1. Period 2: Pre-dose, and 5 min, 30 min, 2, 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose on Day 5
Blood samples were collected from participants at indicated time frames after the administration of study treatment to investigate pharmacokinetic parameters of Nemiralisib in both treatment period 1 and 2. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
Time to Maximum Observed Plasma Concentration (Tmax) of Nemiralisib in Plasma
时间窗: Period 1: Pre-dose, and 5, 30 minutes, 2, 6, 12, 24, 48, 72, 96 and 120 hours post-dose on Day 1. Period 2: Pre-dose, and 5 min, 30 min, 2, 6, 12, 24, 48, 72, 96, 120 and 144 hours post-dose on Day 5
Blood samples were collected at indicated time points after administration of repeated doses of itraconazole along with Nemiralisib. Pharmacokinetic analysis was conducted using standard non-compartmental methods.
次要结局
- Cmax of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2(Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5)
- T1/2 of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2(Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5)
- Number of Participants With Abnormal Spirometry Values(Period 1: Day -1; Period 2: Day 4)
- Change From Baseline in Hemoglobin When Single Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg(Baseline and Day 10)
- Specific Gravity at Indicated Time Points(Days -1, 6 and 10)
- Change From Baseline of Clinical Chemistry Parameters When Nemiralisib 100 mcg When Co-administered With Itraconazole 200 mg Repeated Dose: Alkaline Phosphate, ALT and AST(Baseline, Day 2, 4, 6, 8 and 10)
- Change From Baseline of Total Protein When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered(Baseline and Day 6)
- AUC(0-t) of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2(Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5)
- Tmax of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2(Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5)
- Change From Baseline of Clinical Chemistry Parameters When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered: Calcium, Glucose, Potassium and Sodium(Baseline (Day -1) and Day 6)
- AUC(0-inf) of Itraconazole and Hydroxy Itraconazole When Co-administered With Nemiralisib in Treatment Period 2(Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose (itraconazole) on Day 1; Pre-dose, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose (itraconazole) on Day 5)
- Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)(Up to 35 days)
- Change From Baseline of Clinical Chemistry Parameters When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered: Alkaline Phosphate, Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)(Baseline and Day 6)
- Change From Baseline of Clinical Chemistry Parameters When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered:Bilirubin, Direct Bilirubin and Creatinine(Baseline and Day 6)
- Change From Baseline of Clinical Chemistry Parameters When Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg Repeated Dose: Bilirubin, Direct Bilirubin and Creatinine(Baseline, Day 2, 4, 6, 8 and 10)
- Change From Baseline of Total Protein When Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg Repeated Dose(Baseline, Day 2, 4, 6, 8 and 10)
- Change From Baseline of Clinical Chemistry Parameters When Nemiralisib 100 mcg When Co-administered With Itraconazole 200 mg Repeated Dose: Calcium, Glucose, Potassium and Sodium(Baseline (Day -1), Day 2, 4, 6, 8 and 10)
- Change From Baseline in Hematology Parameters When Single Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg Repeated Dose: Lymphocytes, Neutrophils, Platelets, Basophils, Eosinophils, Monocytes, Erythrocytes and WBC(Baseline and Day 10)
- Change From Baseline in MCV When Single Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg(Baseline and Day 10)
- Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered(Baseline (Day 1, pre-dose) and Day 6)
- Change From Baseline in Temperature When Single Inhaled Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg Repeated Dose(Baseline (Day 1, pre-dose), Days 2, 4, 6, 8 and 10)
- Change From Baseline in Hemoglobin When Single Oral Dose of Nemiralisib 100 mcg Administered(Baseline and Day 6)
- Change From Baseline in Hematology Parameters When Single Oral Dose of Nemiralisib 100 mcg Administered: Lymphocytes, Neutrophils, Platelets, Basophils, Eosinophils, Monocytes, Erythrocytes and White Blood Cells (WBC)(Baseline and Day 6)
- Change From Baseline in Hematocrit When Single Oral Dose of Nemiralisib 100 mcg Administered(Baseline and Day 6)
- Change From Baseline in Erythrocyte Mean Corpuscular Volume (MCV) When Single Oral Dose of Nemiralisib 100 mcg Administered(Baseline and Day 6)
- Change From Baseline in Reticulocyte Percentage When Single Oral Dose of Nemiralisib 100 mcg Administered(Baseline and Day 6)
- Number of Participants With Urine Potential of Hydrogen (pH) at Indicated Time Points(Day -1, 6 and 10)
- Number of Participants With Abnormal Electrocardiogram (ECG) Findings(Period 1: Up to Day 6; Period 2: Up to Day 10)
- Change From Baseline in Pulse Rate When Single Inhaled Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg Repeated Dose(Baseline (Day 1, pre-dose) and Days 2, 4, 6, 8 and 10)
- Change From Baseline in Hematocrit When Single Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg(Baseline and Day 10)
- Change From Baseline in Erythrocyte Mean Corpuscular Hemoglobin (MCH) When Single Oral Dose of Nemiralisib 100 mcg Administered(Baseline and Day 6)
- Change From Baseline in MCH When Single Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg(Baseline and Day 10)
- Number of Participants With Abnormal Urinalysis Parameter(Days -1, 6 and 10)
- Number of Participants With Abnormal Microscopic Examinations: Casts, Epithelial Cells, Erythrocytes and Leukocytes(Day -1)
- Change From Baseline in Reticulocyte Percentage When Single Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg(Baseline and Day 10)
- Change From Baseline in SBP and DBP When Single Inhaled Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg Repeated Dose(Baseline (Day 1, pre-dose) and Days 2, 4, 6, 8 and 10)
- Change From Baseline in Pulse Rate When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered(Baseline (Day 1, pre-dose) and Day 6)
- Change From Baseline in Respiratory Rate When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered(Baseline (Day 1, pre-dose) and Day 6)
- Change From Baseline in Respiratory Rate When Single Inhaled Oral Dose of Nemiralisib 100 mcg Co-administered With Itraconazole 200 mg Repeated Dose(Baseline (Day 1, pre-dose), Days 2, 4, 6, 8 and 10)
- Change From Baseline in Temperature When Single Inhaled Oral Dose of Nemiralisib 100 mcg Administered(Baseline (Day 1, pre-dose) and Day 6)