This is an open-label, randomized, single-center, single-dose, two-treatment, two-sequence, two-period, crossover, comparative study, where each subject will be randomly assigned to the reference or the test formulation in each period of the study (sequences RT or TR), in order to evaluate if both formulations are bioequivalent.
The objective of this study is to establish if two formulations of amoxicillin + clavulanic acid combination are bioequivalent. Also monitoring, registration and evaluation of adverse events will be performed. The test formulation is Clavamox, powder for oral suspension, 400 mg + 57 mg / 5 ml (Pharmtechnology LLC, Belarus). The reference formulation is Augmentin®, powder for oral suspension, 400 mg + 57 mg / 5 ml (GlaxoSmithKline Trading CJSC, Russia). 56 healthy adult volunteers of both genders, with age ranging from 18 to 45 years old, will be divided into two cohorts with equal number of subjects (28). Each subject in a cohort will receive single dose (5 ml containing 400 mg of amoxicillin and 57 mg of clavulanic acid) of the test or the reference formulation with 200 ml of water after an overnight fast of at least 10 hours, according to the pre-defined randomization list, i. e. 14 subjects in each cohort will receive the test product and 14 subjects in each cohort will receive the reference product. Subjects will fast 4 hours after administration of the study drugs during each study period. Standardized meals will be provided in each study period. Water will not be accessible to the subjects 1 hour prior to administration of the study drugs and 2 hours after administration of the study drugs in each period. In each period blood samples will be collected before dosing and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing (total number: 19). The washout period is 7 days. A validated HPLC/MS/MS method will be used to determine plasma concentrations of two analytes (amoxicillin and clavulanic acid). ANOVA will be performed on log-transformed pharmacokinetic parameters Cmax, AUC0-t and 90% confidence interval will be constructed for the ratio of geometric least square means of the test and the reference products, obtained from the log-transformed data. Bioequivalence will be concluded if the ratio estimate as well as its 90% confidence interval for each analyte, both falls within the acceptable range of 80.00% to 125.00% for Cmax and AUC0-t.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
SINGLE
Enrollment
56
Clavamox, Powder for Oral Suspension, 400 mg + 57 mg / 5 ml, manufactured by Pharmtechnology LLC, Belarus
Augmentin®, Powder for Oral Suspension, 400 mg + 57 mg / 5 ml, marketed by CJSC GlaxoSmithKline Trading, Russia
State Autonomous Healthcare Facility of the Yaroslavl Region "Clinical Hospital No. 2"
Yaroslavl, Yaroslavl Oblast, Russia
Cmax of amoxicillin for the test and the reference products
Maximum concentration in plasma among observed concentrations at pre-specified time points
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
AUC0-t of amoxicillin for the test and the reference products
Area under the plasma concentration versus time curve from time 0 to the last measured concentration
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
Cmax of clavulanic acid for the test and the reference products
Maximum concentration in plasma among observed concentrations at pre-specified time points
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
AUC0-t of clavulanic acid for the test and the reference products
Area under the plasma concentration versus time curve from time 0 to the last measured concentration
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
Number of treatment-related adverse events (AE) for the test and the reference products as assessed by guidance predefined in the protocol
An AE is defined as any untoward medical occurrence in a subject administered an investigational product and which does not necessarily have a causal relationship with the treatment. The data from participants who had taken at least one investigational product was analyzed.
Time frame: 17 days
AUC0-∞ of amoxicillin for the test and the reference products
Area under the plasma concentration versus time curve from time 0 to to infinite time
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
AUC0-∞ of clavulanic acid for the test and the reference products
Area under the plasma concentration versus time curve from time 0 to to infinite time
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
Tmax of amoxicillin for the test and the reference products
Time to maximum measured plasma concentration
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
Tmax of clavulanic acid for the test and the reference products
Time to maximum measured plasma concentration
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
T1/2 of amoxicillin for the test and the reference products
Elimination or terminal half-life
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
T1/2 of clavulanic acid for the test and the reference products
Elimination or terminal half-life
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
Kel of amoxicillin for the test and the reference products
Elimination rate constant
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
Kel of clavulanic acid for the test and the reference products
Elimination rate constant
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
AUCresid of amoxicillin for the test and the reference products
Residual area
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
AUCresid of clavulanic acid for the test and the reference products
Residual area
Time frame: Time points: 0,00 (within 30 minutes before dosing) and 0.25, 0.5, 0.75, 1.00, 1.25, 1.5, 1.75, 2.00, 2.33, 2.67, 3.00, 3.5, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00 hours after dosing
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