Infections, Bacterial
Conditions
Brief summary
This study is prospective, open-label, randomized, crossover, single dose, with 02 treatments, 02 sequences and 02 periods. The volunteers received, in each period, the reference or the test formulation, according to the randomization list, under fasting conditions, in order to evaluate if the reference and test formulations are bioequivalent.
Detailed description
This study is prospective, open-label, randomized, crossover, single dose, with 02 treatments, 02 sequences and 02 periods. The objective is to confirm if two formulations of Amoxicillin trihydrate, in the form powder for oral suspension, are bioequivalent. The test product is Amoxicillin trihydrate - Clamoxyl 500mg/5mL (Glaxo Wellcome Production.) in the form powder for oral suspension and reference product is Amoxil ® 500mg/5mL (GlaxoSmithKline Mexico SA) in the form of powder for oral suspension. Twenty eight healthy volunteers, of both genders, were evaluated. The volunteers received, in each period, the reference or the test formulation, according to the randomization list, under fasting conditions. In each period blood samples are collected in the following times: 0.00 (prior to administration of medication); 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 (after administration of medication). The comparative bioavailability of the two formulations was evaluated based in statistical comparisons of relevant pharmacokinetic parameters, obtained from data of drug concentrations in blood.
Interventions
DRUGAmoxicillin powder for oral suspension (Clamoxyl®) 500mg/5mL
Test formulation
DRUGAmoxil® 500mg/5mL powder for oral suspension
Reference formulation
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Age between 18 and 50 years * Body mass index between 18,5 and 25,0, can vary up to 15% for the upper limit (18,5 and 28,75) * Good health conditions * Obtain signed informed consent
Exclusion criteria
* Results of laboratory tests outside the normal limits, unless they are considered clinically irrelevant * The volunteers who underwent surgery or who were hospitalized for any reason before the start of the study will be reviewed by the physician on admission in the study, observing a period of exclusion of 4 to 8 weeks * Positive test for hepatitis B, hepatitis C or HIV in pre study evaluation * Known hypersensitivity to the study drug or to compounds chemically related * Use of experimental drug or participation in any clinical study within 6 months prior to study initiation * Use of regular medication within 2 weeks prior to study initiation * History of alcohol or drugs abuse or intake of alcohol within 24 hours prior to the period of confinement * Consume of inductive drugs and/or enzymatic inhibitors (CYP450 - hepatic), that are toxic for the organism or presenting long half-life's elimination within 30 days prior to study initiation * Use of MAO and serotonin reuptake inhibitors within 2 weeks prior to study initiation * Volunteers with psychiatric or psychological illness unless they are considered clinically irrelevant by the investigator * History or presence of hepatic, renal or gastrointestinal illness or other condition that interferes on drug's absorption, distribution, excretion or metabolism * History of neurological, endocrine, pulmonary, hematologic, immune, brain, metabolic or cardiovascular illness * Hypo or hypertension of any etiologic that needs pharmacologic treatment * History or clinical case of myocardial infarction, angina and/or heart failure * The volunteer donated or lost 450 mL or more of blood within the 3 months prior to the study initiation * The volunteer has any condition that obstructs his/her participation in the study according the investigator's judgement * Smoking * Positive beta HCG exam for women * Breastfeeding women * Women making use of contraceptive medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve of Plasma Concentration of Drug From Time 0 (Zero) to t (Last Measurable Concentration) (AUC0-t) | Collection points (hours [hrs]): 0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study]) | The area under the plot of plasma concentration of drug against time (non-compartmental method), after drug administration, is defined as the area under the curve (AUC). AUC0-t is calculated from time 0 (prior to administration of medication) to time t (the time of the last quantifiable concentration). AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. ng, nanograms; mL, milliliter. |
| Maximum Observed Concentration of Drug Through Time (Cmax) | Collection points (hrs): 0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study]) | Cmax is defined as the maximum or peak concentration of a drug observed after its administration. Cmax is one of the parameters of particular use in estimating the bioavailability of drugs, by measuring the total amount of drug absorbed. Measurement is obtained directly from the plasma concentration curve of the drug (non-compartmental method). |
| Area Under the Curve of Plasma Concentration of Drug From Time 0 (Zero) Extrapolated to Infinity (AUC0-inf) | Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods (Day 1 of Period 1[Day 1 of study]; Day 1 of Period 2 [Day 15 of study]) | Measurement of AUC0-inf is obtained directly from the plasma concentration curve of drug against time (non-compartmental method). AUC0-inf is calculated from time 0 (prior to administration of medication) extrapolated to infinity, by using the formula AUC0-inf = AUC0-t + Clast/Kel, where Clast is the last measurable concentration, and Kel is the first-order rate constant associated with the terminal portion of the curve. AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. |
| Time of Maximum Observed Concentration (Tmax) | Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods: (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study]) | The time of maximum observed concentration (Tmax) is obtained directly from the plasma concentration curve of the drug by non-compartimental method. Tmax is of particular use in measuring bioavailability, by measuring the time at which the maximum concentration is achieved. |
| Percentage of AUC0-inf That is Due to Extrapolation From the Time of the Last Measurable Concentration to Infinity (AUC%Extrapolation) | Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods: (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study]) | The percentage of AUC0-inf that is due to extrapolation from Tlast to infinity (AUC%Extrapolation) is calculated by using the formula AUC\_%extrapolation = 100\*(AUC0-inf minus AUC0-t)/AUC0-inf. The function of this parameter is to provide information about what percentage of the theoretical curve (AUC0-inf) was possible to determine experimentally (AUC0-t) Therefore, on average, it is expected that the residual area (AUCextrapolation) is not greater than 20%. |
| Terminal Half-life (T1/2_Kel) | Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods: (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study]) | T1/2\_Kel is calculated by using the formula T1/2\_Kel = Ln(2)/Kel.T1/2 is of particular use in measuring bioavailability, by measuring the elimination of the product. |
| First-order Rate Constant Associated With the Terminal Portion of the Curve (Kel) | Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods: (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study]) | This parameter is estimated via linear regression of time versus log concentration. It allows for the obtainment of estimates of T1/2 (T1/2=ln(2)/Kel) considering the schedule and the detection limits defined. |
Countries
Brazil
Participant flow
Pre-assignment details
This is a prospective, open-label, randomized, crossover, single-dose study in which two different treatments (Test Product versus Reference Product) were administered in two sequences in two study periods. The objective was to confirm if two formulations of Amoxicillin trihydrate, in the form of powder for oral suspension, are bioequivalent.
Participants by arm
| Arm | Count |
|---|---|
| Participants Receiving Both Test and Reference Products Participants receiving either test product, Amoxicillin (Clamoxyl) 500 mg/5 mL powder for oral suspension, in Period 1; followed by a 14-day washout period during which no medication was administered; followed by reference product, Amoxil 500 mg/5 mL powder for oral suspension, in Period 2 or reference product in Period 1 and test product inPeriod 2 | 28 |
| Total | 28 |
Baseline characteristics
| Characteristic | Participants Receiving Both Test and Reference Products |
|---|---|
| Age, Continuous | 34.54 Years STANDARD_DEVIATION 7.38 |
| Race/Ethnicity, Customized Black | 4 participants |
| Race/Ethnicity, Customized Mulatto | 14 participants |
| Race/Ethnicity, Customized White | 10 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 14 | 4 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 |
Outcome results
Primary
Area Under the Curve of Plasma Concentration of Drug From Time 0 (Zero) Extrapolated to Infinity (AUC0-inf)
Measurement of AUC0-inf is obtained directly from the plasma concentration curve of drug against time (non-compartmental method). AUC0-inf is calculated from time 0 (prior to administration of medication) extrapolated to infinity, by using the formula AUC0-inf = AUC0-t + Clast/Kel, where Clast is the last measurable concentration, and Kel is the first-order rate constant associated with the terminal portion of the curve. AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption.
Time frame: Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods (Day 1 of Period 1[Day 1 of study]; Day 1 of Period 2 [Day 15 of study])
Population: Entire Study Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Product | Area Under the Curve of Plasma Concentration of Drug From Time 0 (Zero) Extrapolated to Infinity (AUC0-inf) | 36908.392 ng*hr/mL | Standard Deviation 6875.785 |
| Reference Product | Area Under the Curve of Plasma Concentration of Drug From Time 0 (Zero) Extrapolated to Infinity (AUC0-inf) | 40977.755 ng*hr/mL | Standard Deviation 7372.809 |
p-value: 090% CI: [86.96, 93.12]ANOVA
Primary
Area Under the Curve of Plasma Concentration of Drug From Time 0 (Zero) to t (Last Measurable Concentration) (AUC0-t)
The area under the plot of plasma concentration of drug against time (non-compartmental method), after drug administration, is defined as the area under the curve (AUC). AUC0-t is calculated from time 0 (prior to administration of medication) to time t (the time of the last quantifiable concentration). AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. ng, nanograms; mL, milliliter.
Time frame: Collection points (hours [hrs]): 0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study])
Population: Entire Study Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Product | Area Under the Curve of Plasma Concentration of Drug From Time 0 (Zero) to t (Last Measurable Concentration) (AUC0-t) | 36431.460 ng per hour per ml (ng*hr/mL) | Standard Deviation 6806.797 |
| Reference Product | Area Under the Curve of Plasma Concentration of Drug From Time 0 (Zero) to t (Last Measurable Concentration) (AUC0-t) | 40426.451 ng per hour per ml (ng*hr/mL) | Standard Deviation 7279.259 |
p-value: 090% CI: [86.99, 93.17]ANOVA
Primary
First-order Rate Constant Associated With the Terminal Portion of the Curve (Kel)
This parameter is estimated via linear regression of time versus log concentration. It allows for the obtainment of estimates of T1/2 (T1/2=ln(2)/Kel) considering the schedule and the detection limits defined.
Time frame: Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods: (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study])
Population: Entire Study Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Product | First-order Rate Constant Associated With the Terminal Portion of the Curve (Kel) | 0.641 1/hr | Standard Deviation 0.043 |
| Reference Product | First-order Rate Constant Associated With the Terminal Portion of the Curve (Kel) | 0.620 1/hr | Standard Deviation 0.079 |
Primary
Maximum Observed Concentration of Drug Through Time (Cmax)
Cmax is defined as the maximum or peak concentration of a drug observed after its administration. Cmax is one of the parameters of particular use in estimating the bioavailability of drugs, by measuring the total amount of drug absorbed. Measurement is obtained directly from the plasma concentration curve of the drug (non-compartmental method).
Time frame: Collection points (hrs): 0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study])
Population: Entire Study Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Product | Maximum Observed Concentration of Drug Through Time (Cmax) | 13615.929 ng/mL | Standard Deviation 3886.864 |
| Reference Product | Maximum Observed Concentration of Drug Through Time (Cmax) | 15176.107 ng/mL | Standard Deviation 3144.162 |
p-value: 0.001890% CI: [82.55, 93.65]ANOVA
Primary
Percentage of AUC0-inf That is Due to Extrapolation From the Time of the Last Measurable Concentration to Infinity (AUC%Extrapolation)
The percentage of AUC0-inf that is due to extrapolation from Tlast to infinity (AUC%Extrapolation) is calculated by using the formula AUC\_%extrapolation = 100\*(AUC0-inf minus AUC0-t)/AUC0-inf. The function of this parameter is to provide information about what percentage of the theoretical curve (AUC0-inf) was possible to determine experimentally (AUC0-t) Therefore, on average, it is expected that the residual area (AUCextrapolation) is not greater than 20%.
Time frame: Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods: (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study])
Population: Entire Study Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Product | Percentage of AUC0-inf That is Due to Extrapolation From the Time of the Last Measurable Concentration to Infinity (AUC%Extrapolation) | 1.303 percentage | Standard Deviation 0.814 |
| Reference Product | Percentage of AUC0-inf That is Due to Extrapolation From the Time of the Last Measurable Concentration to Infinity (AUC%Extrapolation) | 1.353 percentage | Standard Deviation 0.743 |
Primary
Terminal Half-life (T1/2_Kel)
T1/2\_Kel is calculated by using the formula T1/2\_Kel = Ln(2)/Kel.T1/2 is of particular use in measuring bioavailability, by measuring the elimination of the product.
Time frame: Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods: (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study])
Population: Entire Study Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Product | Terminal Half-life (T1/2_Kel) | 1.085 hr | Standard Deviation 0.071 |
| Reference Product | Terminal Half-life (T1/2_Kel) | 1.137 hr | Standard Deviation 0.155 |
Primary
Time of Maximum Observed Concentration (Tmax)
The time of maximum observed concentration (Tmax) is obtained directly from the plasma concentration curve of the drug by non-compartimental method. Tmax is of particular use in measuring bioavailability, by measuring the time at which the maximum concentration is achieved.
Time frame: Collection points (hrs):0.00; 0.25; 0.50; 0.75; 1.00; 1.25; 1.50; 1.75; 2.00; 2.50; 3.00; 4.00; 5.00; 6.00; 8.00 evaluated in both periods: (Day 1 of Period 1 [Day 1 of study]; Day 1 of Period 2 [Day 15 of study])
Population: Entire Study Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test Product | Time of Maximum Observed Concentration (Tmax) | 1.304 hr | Standard Deviation 0.468 |
| Reference Product | Time of Maximum Observed Concentration (Tmax) | 1.482 hr | Standard Deviation 0.535 |
p-value: 0.33990% CI: [-0.125, 0.375]Wilcoxon (Mann-Whitney)