no Condition
Conditions
Keywords
healthy volunteers
Brief summary
Study primary Objective: \- To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of N-acetyl-cysteine 600 mg uncoated tablets vs. N-acetyl-cysteine 600 mg film-coated tablets (NAC) in healthy male and female volunteers. Study secondary objectives: * To describe the pharmacokinetic (PK) profile of NAC in plasma after single dose administration of NAC 600 mg uncoated tablets vs. NAC 600 mg film-coated tablets; * to collect safety and tolerability data after single dose administration of NAC 600 mg uncoated tablets vs. NAC 600 mg film-coated tablets.
Detailed description
This is single centre, single dose, open, randomised, cross-over, two-stage bioequivalence study to compare two different oral formulations of NAC. The study has been conducted in healthy volunteers of both genders, in one single dose of both formulations. The initial 48 subjects were sufficient to satisfy the study objectives on the basis of the ad interim preliminary bioequivalence test. The study was then considered as concluded and the second stage did not take place.
Interventions
DRUGN-acetylcysteine
The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.
Sponsors
Zambon SpA
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Informed consent: signed written informed consent before inclusion in the study 2. Sex and age: males and females,18-55 years old, inclusive 3. Body Mass Index (BMI): 18.5-30 kg/m2, inclusive 4. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 50-89 mmHg, heart rate (HR) 50-90 bpm, measured after 5 min of rest in the sitting position 5. 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 6. Contraception and fertility (females only): females of child-bearing potential and with an active sexual life must be using at least one of the following reliable methods of contraception: * Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months 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 2 months before the screening visit * A male sexual partner who agrees to use a male condom with spermicide * A sterile sexual partner Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all female subjects, pregnancy test result must be negative at screening (serum β-HCG test) and day -1 (urine test).
Exclusion criteria
1. Electrocardiogram (ECG 12-leads, 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 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 or neurological diseases that may interfere with the aim of the study 6. Medications: medications, including over the counter (OTC) medications and herbal remedies for 2 weeks before the start of the study. Hormonal contraceptives for females will be allowed 7. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study 8. Blood donation: blood donations for 3 months before this study 9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol \[\>1 drink/day for females and \>2 drinks/day for males, defined according to the USDA Dietary Guidelines 2010\], caffeine (\>5 cups coffee/tea/day) or tobacco abuse (≥6 cigarettes/day) 10. Drug test: positive result at the drug test at screening or day-1 11. Alcohol test: positive alcohol breath test at day -1 12. Diet: abnormal diets (\<1600 or \>3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians 13. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of NAC After Single Dose Administration of Test and Reference | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) | Cmax is the maximum concentration level of the drug reached in plasma. |
| AUC0-t of NAC After Single Dose Administration of Test and Reference | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) | AUC0-t is the Area under the concentration-time curve from time zero to time t, calculated with the linear trapezoidal summation from time 0 to the last measurable data point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| t1/2 of NAC After Single Dose Administration of Test and Reference | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) | Half-life (t1/2) is the time to halve the plasma concentration level of the drug. |
| AUC0-∞ of NAC After Single Dose Administration of Test and Reference | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) | AUC0-∞ is the area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration. |
| Frel of NAC After Single Dose Administration of Test and Reference | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) | Frel is the relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference) |
| Lambda Zeta of NAC After Single Dose Administration of Test and Reference | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) | Lambda zeta is the terminal elimination rate constant. Individual estimate of the terminal elimination rate constant can be calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves. |
| Tmax of NAC After Single Dose Administration of Test and Reference | 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose) | time to achieve the maximum concentration level of the drug in plasma. |
Participant flow
Recruitment details
48 healthy subjects were included in the study, as planned, and received test and reference treatment according to the cross-over design.
Pre-assignment details
Subjects were assigned to a sequence of treatments (TR or RT) according to the randomisation list. Randomisation number was given to the subjects on study day -1, Period 1, and was used to assign the treatment sequence according to the randomisation list. The randomisation list was computer-generated by the Contract Research Organisation (CRO) Biometry Unit, using the PLAN procedure of SAS® version 9.3 (TS1M1) (24). The randomisation list was supplied to the Phase I Unit before study start.
Participants by arm
| Arm | Count |
|---|---|
| Enrolled Subjects Set According to the crossover design, all the enrolled subjects received both NAC formulations based on the randomization schedule. Two single doses of 600 mg of NAC (one with test and one with reference formulation) were administered to each volunteer in two subsequent study periods (morning of day 1), separated by a wash-out interval of at least 5 days. | 48 |
| Total | 48 |
Baseline characteristics
| Characteristic | Enrolled Subjects Set |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants |
| Age, Continuous | 42.6 years STANDARD_DEVIATION 8.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 47 Participants |
| Region of Enrollment Switzerland | 48 participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 48 |
| other Total, other adverse events | 4 / 48 | 2 / 48 |
| serious Total, serious adverse events | 0 / 48 | 0 / 48 |
Outcome results
Primary
AUC0-t of NAC After Single Dose Administration of Test and Reference
AUC0-t is the Area under the concentration-time curve from time zero to time t, calculated with the linear trapezoidal summation from time 0 to the last measurable data point.
Time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test | AUC0-t of NAC After Single Dose Administration of Test and Reference | 10637.87 ng/mL*h | Standard Deviation 3100.94 |
| Reference | AUC0-t of NAC After Single Dose Administration of Test and Reference | 11773.11 ng/mL*h | Standard Deviation 3775.43 |
p-value: 0.004794.12% CI: [85.25, 96.69]ANOVA
Primary
Cmax of NAC After Single Dose Administration of Test and Reference
Cmax is the maximum concentration level of the drug reached in plasma.
Time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test | Cmax of NAC After Single Dose Administration of Test and Reference | 2804.38 ng/mL | Standard Deviation 899.47 |
| Reference | Cmax of NAC After Single Dose Administration of Test and Reference | 3215.63 ng/mL | Standard Deviation 1382.02 |
p-value: 0.013694.12% CI: [82.82, 97.4]ANOVA
Secondary
AUC0-∞ of NAC After Single Dose Administration of Test and Reference
AUC0-∞ is the area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration.
Time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test | AUC0-∞ of NAC After Single Dose Administration of Test and Reference | 12586.17 ng/mL*h | Standard Deviation 3577.24 |
| Reference | AUC0-∞ of NAC After Single Dose Administration of Test and Reference | 13739.43 ng/mL*h | Standard Deviation 4190.59 |
p-value: 0.009594.12% CI: [86.45, 97.61]ANOVA
Secondary
Frel of NAC After Single Dose Administration of Test and Reference
Frel is the relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)
Time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test | Frel of NAC After Single Dose Administration of Test and Reference | 92.82 percentage | Standard Deviation 18.05 |
Secondary
Lambda Zeta of NAC After Single Dose Administration of Test and Reference
Lambda zeta is the terminal elimination rate constant. Individual estimate of the terminal elimination rate constant can be calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.
Time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test | Lambda Zeta of NAC After Single Dose Administration of Test and Reference | 0.05 1/h | Standard Deviation 0.01 |
| Reference | Lambda Zeta of NAC After Single Dose Administration of Test and Reference | 0.05 1/h | Standard Deviation 0.01 |
Secondary
t1/2 of NAC After Single Dose Administration of Test and Reference
Half-life (t1/2) is the time to halve the plasma concentration level of the drug.
Time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test | t1/2 of NAC After Single Dose Administration of Test and Reference | 14.11 hours | Standard Deviation 4.16 |
| Reference | t1/2 of NAC After Single Dose Administration of Test and Reference | 13.59 hours | Standard Deviation 2.69 |
Secondary
Tmax of NAC After Single Dose Administration of Test and Reference
time to achieve the maximum concentration level of the drug in plasma.
Time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Test | Tmax of NAC After Single Dose Administration of Test and Reference | 1.00 hours |
| Reference | Tmax of NAC After Single Dose Administration of Test and Reference | 1.00 hours |
p-value: 0.505Friedman test