Respiratory Tract Disorders
Conditions
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.
Interventions
DRUGN-acetylcysteine (NAC)
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.
Sponsors
Zambon SpA
Study design
Allocation
NON_RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
OTHER
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Informed consent: signed written informed consent before inclusion in the study 2. Ethnicity, Sex and Age: Chinese males and females, 18-45 year old inclusive 3. Weight: body weight ≥50 kg 4. Body Mass Index: 19-26 kg/m2 inclusive 5. 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 6. 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 7. Nicotine addiction (smoker subjects only): ability to abstain from smoking for the duration of the clinical study 8. Contraception and fertility (women only): women of child-bearing potential must be using at least one of the following reliable methods of contraception: 1. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 60 calendar days before the screening visit 2. 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 3. A male sexual partner who agrees to use a male condom with spermicide 4. 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
1. Electrocardiogram (12-lead ECG in supine position): clinically significant abnormalities 2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study 3. 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) 4. 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 5. 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 6. Virology: positive result of HIV, hepatitis B (HBV), hepatitis C (HCV) or Treponema pallidum (TP) assays 7. Surgery: any surgery within 60 calendar days of screening (excluding diagnostic surgery) 8. 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 9. Investigative drug studies: participation in the evaluation of any investigational product for 1 month before this study 10. Blood donation: blood donations for 90 calendar days before this study 11. 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) 12. Abuse drug test: positive urine abuse drug test at screening or day -1 13. Alcohol test: positive alcohol breath test at day -1 14. 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 15. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women 16. Vaccination within 4 weeks of study treatment 17. Other unspecified reasons that, in the opinion of the investigator, make the subject unsuitable for enrolment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Degree of Fluctuation Over One Dosing Interval at Steady-state (DF%) After Multiple Dose of NAC | 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 |
| Total Body Clearance (CLt) After Single Dose of NAC | 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 | 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 | 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 | 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 | 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 (AUC) After Single Dose of NAC | 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 | 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 Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | 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 | 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 | 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) | 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 | 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 | 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. |
| Area Under the Concentration-time Curve at Steady State After Multiple Doses of NAC | 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 | 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)] | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From screening to Final Visit/early termination visit (ETV, Day 8) | To collect safety and tolerability data after single and multiple dose administration of the investigational product. |
Countries
China
Participant flow
Recruitment details
This study was a single center study conducted in China from 11 November 2019 to 18 January 2020. All participants randomized in the study received single and multiple doses of N-acetylcysteine (NAC).
Pre-assignment details
Participants who met the eligibility criteria at the Screening Visit (Day -14 to Day 1) were assigned to receive NAC.
Participants by arm
| Arm | Count |
|---|---|
| Overall - NAC 600 mg All participants were dosed with NAC QD at 08:00 ± 1 hour on Day 1 under fasting conditions, BID at 08:00 ± 1 hour and 20:00 ± 1 hour on Day 4 and Day 5 after one 3-day wash-out, and QD at 08:00 ± 1 hour on Day 6. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Overall - NAC 600 mg |
|---|---|
| Age, Continuous | 30.6 years STANDARD_DEVIATION 5.18 |
| Race/Ethnicity, Customized Chinese | 24 Participants |
| Region of Enrollment China | 24 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 24 |
| other Total, other adverse events | 7 / 24 |
| serious Total, serious adverse events | 0 / 24 |
Outcome results
Primary
Accumulation Ratio After Multiple Doses of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after multiple dose administration of the investigational product.
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Accumulation Ratio After Multiple Doses of NAC | 1.132 Ratio | Geometric Coefficient of Variation 6 |
Primary
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.
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Single Dose - NAC 600mg | Area Under the Concentration-time Curve at Steady State After Multiple Doses of NAC | AUCss(0-t) | 116.6 h*µg/mL | Geometric Coefficient of Variation 15.1 |
| Single Dose - NAC 600mg | Area Under the Concentration-time Curve at Steady State After Multiple Doses of NAC | AUCss(0-12h) | 92.63 h*µg/mL | Geometric Coefficient of Variation 14.1 |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Single Dose - NAC 600mg | Area Under the Concentration-time Curve (AUC) After Single Dose of NAC | AUC from time zero to the last observed concentration time t [AUC(0-t)] | 87.16 h*µg/mL | Geometric Coefficient of Variation 17.4 |
| Single Dose - NAC 600mg | Area Under the Concentration-time Curve (AUC) After Single Dose of NAC | AUC extrapolated to infinity [AUC(0-inf)] | 93.94 h*µg/mL | Geometric Coefficient of Variation 18 |
| Single Dose - NAC 600mg | Area Under the Concentration-time Curve (AUC) After Single Dose of NAC | AUC from time zero to 12 hours post-dose [AUC(0-12h)] | 81.87 h*µg/mL | Geometric Coefficient of Variation 14 |
Primary
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
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Degree of Fluctuation Over One Dosing Interval at Steady-state (DF%) After Multiple Dose of NAC | 1279 percentage | Geometric Coefficient of Variation 30.7 |
Primary
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.
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Half-life (t1/2) After Single Dose of NAC | 7.129 hour | Geometric Coefficient of Variation 56.8 |
Primary
Peak Drug Concentration (Cmax) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single administration of the investigational product.
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
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Peak Drug Concentration (Cmax) After Single Dose of NAC | 83.30 µg/mL | Geometric Coefficient of Variation 30.7 |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Percentage of the AUC(0-inf) Obtained by Extrapolation (%AUCextra) | 6.967 percentage | Geometric Coefficient of Variation 26.8 |
Primary
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.
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Single Dose - NAC 600mg | Plasma Concentration at Steady-state After Multiple Doses of NAC | Css_max | 100.8 µg/mL | Geometric Coefficient of Variation 29.1 |
| Single Dose - NAC 600mg | Plasma Concentration at Steady-state After Multiple Doses of NAC | Css_min | 1.899 µg/mL | Geometric Coefficient of Variation 20.9 |
| Single Dose - NAC 600mg | Plasma Concentration at Steady-state After Multiple Doses of NAC | Css_avg | 7.719 µg/mL | Geometric Coefficient of Variation 14.1 |
Primary
Renal Clearance (CLr) After Single Dose of NAC
To evaluate pharmacokinetic parameters of NAC in plasma after single dose administration of the investigational product.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Renal Clearance (CLr) After Single Dose of NAC | 995.2 mL/h | Geometric Coefficient of Variation 50.2 |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Terminal Elimination Rate Constant (Kel) After Single Dose of NAC | 0.09723 1/hour | Geometric Coefficient of Variation 56.8 |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Dose - NAC 600mg | Time to Achieve Cmax (Tmax) After Single Dose of NAC | 0.083 hours |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Dose - NAC 600mg | Time to Achieve Css_max (tss_max) After Multiple Doses of NAC | 0.083 hour |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | Ae(0-4) | 62750 μg | Geometric Coefficient of Variation 76.4 |
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | Ae(4-8) | 16170 μg | Geometric Coefficient of Variation 55.2 |
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | Ae(8-12) | 3609 μg | Geometric Coefficient of Variation 155 |
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | Ae(12-24) | 1846 μg | Geometric Coefficient of Variation 78 |
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | Ae(24-32) | 1366 μg | Geometric Coefficient of Variation 63.9 |
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | Ae(0-8) | 84020 μg | Geometric Coefficient of Variation 53.4 |
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | Ae(0-12) | 89600 μg | Geometric Coefficient of Variation 50.5 |
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | Ae(0-24) | 92020 μg | Geometric Coefficient of Variation 49.4 |
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine [Ae(0-t)] After Single Dose of NAC | Ae(0-32) | 93490 μg | Geometric Coefficient of Variation 48.5 |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Total Amount of NAC Excreted in Urine From the Last Multiple Dose to 32 h at Steady-state [Aess(0-32)] | 68980 μg | Geometric Coefficient of Variation 68.1 |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Total Body Clearance (CLt) After Single Dose of NAC | 6.387 Liter\hour | Geometric Coefficient of Variation 18 |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Single Dose - NAC 600mg | Total Fraction of NAC Dose Excreted in Urine [Fe(0-t)] After Single Dose of NAC | Fe(0-8) | 0.1400 fraction | Geometric Coefficient of Variation 53.4 |
| Single Dose - NAC 600mg | Total Fraction of NAC Dose Excreted in Urine [Fe(0-t)] After Single Dose of NAC | Fe(0-4) | 0.1046 fraction | Geometric Coefficient of Variation 76.4 |
| Single Dose - NAC 600mg | Total Fraction of NAC Dose Excreted in Urine [Fe(0-t)] After Single Dose of NAC | Fe(0-12) | 0.1493 fraction | Geometric Coefficient of Variation 50.5 |
| Single Dose - NAC 600mg | Total Fraction of NAC Dose Excreted in Urine [Fe(0-t)] After Single Dose of NAC | Fe(0-24) | 0.1534 fraction | Geometric Coefficient of Variation 49.4 |
| Single Dose - NAC 600mg | Total Fraction of NAC Dose Excreted in Urine [Fe(0-t)] After Single Dose of NAC | Fe(0-32) | 0.1558 fraction | Geometric Coefficient of Variation 48.5 |
Primary
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.
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.
Population: Pharmacokinetic (PK) set: all enrolled participants who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned analyses, with no major deviations that might affect the PK results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Single Dose - NAC 600mg | Volume of Distribution (Vd) After Single Dose of NAC | 65.69 litre | Geometric Coefficient of Variation 44.8 |
Secondary
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.
Time frame: From screening to Final Visit/early termination visit (ETV, Day 8)
Population: Safety set: All participants who received at least one dose of investigational medicinal product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Dose - NAC 600mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 7 Participants |
| Single Dose - NAC 600mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE Related to investigational medicinal product | 2 Participants |