A Study to Evaluate Pharmacokinetics, Safety and Tolerability of Single and Multiple Intravenous Doses of N-acetylcysteine (NAC) in Chinese Healthy Volunteers

Study Overview
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Brief Summary
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This is a single and multiple dose, single centre, open-label, one-way, pharmacokinetics, safety and tolerability clinical trial of Phase I to be performed in Chinese healthy male and female volunteers. Twenty-four (24) healthy male and female Chinese volunteers will be included in the study. Drop-out subjects will not be replaced. The study has been designed in agreement with the Chinese Technical Guideline on Clinical Pharmacokinetic Research of Chemical Drugs, 18 March 2005 and the European Guideline on the Investigation of Bioequivalence. No randomisation will take place in this study. All the participant will receive the same treatment with the investigational medicinal product (IMP), i.e. NAC, 300 mg/ 3 mL solution for injection.

Official Title
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Phase I Study to Evaluate Pharmacokinetics, Safety and Tolerability of Single and Multiple i.v. Doses of N-acetylcysteine (NAC) in Chinese Healthy Volunteers

Conditions
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Respiratory Tract Disorders

Intervention / Treatment
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* Drug: N-acetylcysteine (NAC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent: signed written informed consent before inclusion in the study Ethnicity, Sex and Age: Chinese males and females, 18-45 year old inclusive Weight: body weight ≥50 kg Body Mass Index: 19-26 kg/m2 inclusive Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-90 bpm, measured after 5 min at rest in the sitting/supine position Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study Nicotine addiction (smoker subjects only): ability to abstain from smoking for the duration of the clinical study Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception: Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 60 calendar days before the screening visit A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 60 calendar days before the screening visit A male sexual partner who agrees to use a male condom with spermicide A sterile sexual partner Women of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. Women of childbearing potential should be willing to adopt abstinence or contraception measures during the study and two weeks post-dose. For all women, pregnancy test result must be negative at screening and day -1. Exclusion Criteria: Electrocardiogram (12-lead ECG in supine position): clinically significant abnormalities Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness, in particular significant laboratory abnormality indicative of hepatic condition (more than 3 times the upper limit) Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine, urologic, metabolic, neurological or psychiatric diseases, as determined by the investigator, that may interfere with the aim of the study; history of carcinoma in situ and malignant disease; active bacterial or viral infection and fever >38°C within 48 h prior to study treatment administration Virology: positive result of HIV, hepatitis B (HBV), hepatitis C (HCV) or Treponema pallidum (TP) assays Surgery: any surgery within 60 calendar days of screening (excluding diagnostic surgery) Medications: medications, including over the counter (OTC) medications, herbal remedies and traditional Chinese remedies for 2 weeks before the start of the study. Hormonal contraceptives for women will be allowed Investigative drug studies: participation in the evaluation of any investigational product for 1 month before this study Blood donation: blood donations for 90 calendar days before this study Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for females and >2 drinks/day for males, defined according to the USDA Dietary Guidelines 2015-2020] caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes/day) Abuse drug test: positive urine abuse drug test at screening or day -1 Alcohol test: positive alcohol breath test at day -1 Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians; consumption of alcohol, grapefruit, products containing grapefruit, or beverages containing xanthines (coffee, tea, soda, coffee with milk, energy drinks) within 48 hours prior to the enrolment Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women Vaccination within 4 weeks of study treatment Other unspecified reasons that, in the opinion of the investigator, make the subject unsuitable for enrolment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: All the subjects enrolled in the study will receive the same treatment with the investigational medicinal product (IMP), i.e. NAC, 300 mg/ 3 mL solution injection as single dose and multiple dose regime. Single dose of IMP will be administered under fasting conditions on day 1 at 08:00 ±1 h. Multiple doses (5) of IMP will be administered twice a day (b.i.d.) on days 4 and 5 at 08:00 ±1 h and 20:00 ±1 h and one dose will be administered on day 6 at 08:00 ±1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose regime of N-acetylcysteine (NAC)<br>On day 1 at 08:00 ±1 hours, one dose of 600 mg of NAC (300 + 300 mg ampoule) will be administered under fasting conditions. | Drug: N-acetylcysteine (NAC)<br>* Two ampoules of IMP (300 + 300 mg) corresponding to a total dose of 600 mg of NAC diluted in 10 mL of NaCl 0.9% sterile saline solution, will be administered by a 5-minute i.v. infusion.<br>|
| Experimental: Multiple dose regime of N-acetylcysteine (NAC)<br>On days 4 and 5 at 08:00 ±1 hours and 20:00 ±1 hours and at 08:00 ±1 on day 6, 5 doses of 600 mg of NAC (300 + 300 mg ampoule) will be administered. | Drug: N-acetylcysteine (NAC)<br>* Two ampoules of IMP (300 + 300 mg) corresponding to a total dose of 600 mg of NAC diluted in 10 mL of NaCl 0.9% sterile saline solution, will be administered by a 5-minute i.v. infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Drug Concentration (Cmax) After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose | 
| Time to Achieve Cmax (Tmax) After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Terminal Elimination Rate Constant (Kel) After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Half-life (t1/2) After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Area Under the Concentration-time Curve (AUC) After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Volume of Distribution (Vd) After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Total Body Clearance (CLt) After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Total Fraction of NAC Dose Excreted in Urine [Fe(0-t)] After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Renal Clearance (CLr) After Single Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Percentage of the AUC(0-inf) Obtained by Extrapolation (%AUCextra) | To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product. | On Day 1 and Day 2-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Plasma Concentration at Steady-state After Multiple Doses of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product. Css_max = maximum NAC plasma concentration at steady-state, Css_min=minimum plasma concentration at steady-state, Css_avg=average NAC plasma concentration at steady-state. | On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Time to Achieve Css_max (tss_max) After Multiple Doses of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product. | On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Area Under the Concentration-time Curve at Steady State After Multiple Doses of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product. AUCss(0-12h)=AUC at steady-state from the last multiple dose to 12 hours post-dose, AUCss(0-t)=AUC at steady-state from the last multiple dose to the last observed concentration time t. | On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Accumulation Ratio After Multiple Doses of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product. | On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Total Amount of NAC Excreted in Urine From the Last Multiple Dose to 32 h at Steady-state [Aess(0-32)] | To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product. | On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 
| Degree of Fluctuation Over One Dosing Interval at Steady-state (DF%) After Multiple Dose of NAC | To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product. Degree of fluctuation over one dosing interval at steady-state is calculated as (Css_max - Css_min)/ Css_av*100 | On Day 4 and Day 5 -At pre-dose. On Day 6 and Day 7-At pre-dose (0) and 5 (at the end of the infusion), 8, 12, 15, 20, 25, 30, 60 minutes and 2, 4, 6, 8, 10, 12, 24 and 32 hours post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | To collect safety and tolerability data after single and multiple dose administration of the investigational product. | From screening to Final Visit/early termination visit (ETV, Day 8) |