Phase I Study to Evaluate Pharmacokinetics, Safety and Tolerability of Single and Multiple i.v. Doses of N-acetylcysteine (NAC) in Chinese Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- N-acetylcysteine (NAC)
- Conditions
- Respiratory Tract Disorders
- Sponsor
- Zambon SpA
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Area Under the Concentration-time Curve (AUC) After Single Dose of NAC
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Single dose regime of N-acetylcysteine (NAC)
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.
Intervention: N-acetylcysteine (NAC)
Multiple dose regime of N-acetylcysteine (NAC)
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.
Intervention: N-acetylcysteine (NAC)
Outcomes
Primary Outcomes
Area Under the Concentration-time Curve (AUC) After Single Dose of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Total Body Clearance (CLt) After Single Dose of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Peak Drug Concentration (Cmax) After Single Dose of NAC
Time Frame: 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
To evaluate pharmacokinetic parameters of NAC in plasma after single administration of the investigational product.
Time to Achieve Cmax (Tmax) After Single Dose of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Half-life (t1/2) After Single Dose of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Volume of Distribution (Vd) After Single Dose of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Percentage of the AUC(0-inf) Obtained by Extrapolation (%AUCextra)
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Terminal Elimination Rate Constant (Kel) After Single Dose of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Area Under the Concentration-time Curve at Steady State After Multiple Doses of NAC
Time Frame: 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.
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.
Accumulation Ratio After Multiple Doses of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Total Fraction of NAC Dose Excreted in Urine [Fe(0-t)] After Single Dose of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Renal Clearance (CLr) After Single Dose of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
Plasma Concentration at Steady-state After Multiple Doses of NAC
Time Frame: 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.
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.
Time to Achieve Css_max (tss_max) After Multiple Doses of NAC
Time Frame: 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.
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
Total Amount of NAC Excreted in Urine From the Last Multiple Dose to 32 h at Steady-state [Aess(0-32)]
Time Frame: 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.
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 (DF%) After Multiple Dose of NAC
Time Frame: 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.
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
Secondary Outcomes
- Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From screening to Final Visit/early termination visit (ETV, Day 8))