A Phase 1 interventional study of Fluconazole and Diflucan® in Bioequivalence, sponsored by Pharmtechnology LLC. Completed at 1 site in Canada. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-11-30.
Sponsored by Pharmtechnology LLC · Phase 1, Interventional, and Other
This single dose study is designed in accordance with EMA (the European Medicines Agency) regulatory guidelines, with the aim of characterizing the comparative bioavailability of fluconazole in the two formulations in healthy subjects. As this is a bioequivalence trial where each subject will receive each study treatment in a crossover fashion, a control group is not included. Within the clinical portion of the study each subject will receive a single oral dose of the test and the reference formulation in compliance with the generated randomization code. The primary study endpoints are the pharmacokinetic (PK) parameters Cmax and AUC0-t of fluconazole.
This is a single center, randomized, 2-treatment, 2-period, 2-sequence, crossover, single dose study design, in which 26 healthy adult subjects will receive one of the study treatments during each study period.
The objective of this study is to determine the bioequivalence of two different formulations of fluconazole after a single oral dose administration under fasting conditions. The secondary objective of this study is to determine the safety and tolerability of the Test product compared to the Reference formulation in healthy subjects.
Subject eligibility for this study will be determined at the screening visit and eligible subjects will be admitted to the clinical research unit at least 10 hours prior to drug administration for each study period.
A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving the IP will not be considered as a drop-out and will not be included in the final database. Standbys should be recruited and available to replace any subject who withdraws prior to the first drug administration. On-study drop-outs will not be replaced.
Altasciences will generate the randomization code with a computer program according to the study design, the number of subjects and the sequence of treatment administration. The random allocation of each sequence of treatment administration to each subject will be done in such a way that the study is balanced. Once generated, the randomization code will be final and will not be modified.
For each study period, subjects will receive a single 40 mg oral dose of olmesartan medoxomil (the test or the reference formulation). Study participants will be aware they will receive different formulations of the same drug, without being informed which product (Test or Reference) is being administered.The date and time of each dose will be recorded. For each subject, all scheduled postdose activities and assessments will be performed relative to the time of study drug administration.
Subjects will fast overnight (no food or drink except water), for a minimum of 10 hours prior to dosing. Fasting will continue for at least 4 hours following drug administration, after which a standardized lunch will be served. A supper and a light snack will be served at appropriate times thereafter, but not before 9 hours after dosing.
A total of 22 blood samples will be collected (one tube of 4 mL each) in each study period for PK assessments. The first blood sample will be collected prior to drug administration while the others will be collected up to 120 hours after drug administration.
The analyte to be measured in the present study will be fluconazole. Fluconazole plasma concentrations will be measured according to a validated bioanalytical method.
Subjects are to be discharged from the clinic after the 24-hour postdose PK sample collection, and following medical approval. However, they may be advised to stay at the clinical site for safety reasons, if judged necessary by the physician in charge. Subjects will return to the clinic for blood collections at 48, 72, 96, and 120 hours postdose.
The expected terminal elimination half-life of fluconazole is 34 hours. To avoid any carry-over effect, a wash-out of 21 calendar days is planned between drug administrations.
The decision of which subjects will be included in the PK analysis is to be documented by the pharmacokineticist (or delegate) and approved by the sponsor before the start of the sample analysis by the bioanalytical facility. Subjects who are expected to provide evaluable PK data for both the Test and Reference products (based on viable PK samples) will be included in the PK analysis. Concentration data of the remaining subjects will be presented separately. Subjects who do not complete the sampling schedule of one or more study periods may be included in the PK and statistical analysis and bioequivalence determination for only the PK parameters that are judged not to be affected by the missing sample(s).
The parameter Tmax will be analyzed using a non-parametric approach. Test of fixed period, sequence and treatment effects will be based on the Wilcoxon's rank sum test (Mann-Whitney U-test). When appropriate (e.g. small or sparse sample), the exact version of the test will also be presented. All primary endpoints will be statistically analyzed using an ANOVA model. The fixed factors included in this model will be the subject effect (nested within sequence), the treatment received, the period at which it was given, as well as the sequence in which each treatment is received.
The treatment, sequence and period effects will the evaluated at the 5% significance level. Explanations for significant effects will be provided for log transformed PK parameters.
The 90% confidence interval for the exponential of the difference in LSmeans between the Test and Reference product will be calculated for the ln-transformed parameters (Test to Reference ratio of geometric LSmeans).
Statistical inference of fluconazole will be based on a bioequivalence approach using the following standards:
The safety population will include all subjects who received at least one formulation (Test or Reference). Safety assessments will include physical examination, clinical laboratory test and AE monitoring. Additional safety measurements may be performed at the discretion of the investigator for reasons related to subject safety.
Total study duration: up to 55 days (including screening).
Pharmtechnology LLC is the lead sponsor of 26 studies on the registry; 1 is open to participants now.
Counted across the registry records on this site, refreshed daily.
If female, meets one of the following criteria:
Is of childbearing potential and agrees to use one of the accepted contraceptive regimens from at least 28 days prior to the first study drug administration through to at least 30 days after the last dose of the study drug. An acceptable method of contraception includes one of the following:
Or
Male partner has had a vasectomy less than 6 months prior to dosing, and agrees to use an additional acceptable contraceptive method from the first study drug administration through to at least 30 days after the last dose of the study drug
Or
Exclusion Criteria:
13 subjects assigned to the sequence AB will receive a single 200 mg dose of test product Fluconazole (1 x 200 mg tablet), marked as A in the sequence, in Period 1 and a single 200 mg dose of reference product Diflucan® (1 x 200 mg hard capsule), marked as B in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet or hard capsule must be swallowed whole and must not be chewed or broken.
Drug: Fluconazole · Drug: Diflucan®
13 subjects assigned to the sequence BA will receive a single 200 mg dose of reference product Diflucan® (1 x 200 mg hard capsule), marked as B in the sequence, in Period 1 and test product Fluconazole (1 x 200 mg tablet), marked as A in the sequence, in Period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet or hard capsule must be swallowed whole and must not be chewed or broken.
Drug: Fluconazole · Drug: Diflucan®
Fluconazole is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 200 mg of fluconazole.
Also known as: Test Product
Diflucan® is manufactured by Fareva Amboise, France (MAH: PFIZER PHARMA PFE GmbH, Germany). Each hard capsule contains 200 mg of fluconazole.
Also known as: Reference Product
Maximum observed concentration (Cmax) of fluconazole in plasma after administration of the test and the reference products
Maximum observed concentration in plasma
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
AUC0-T of fluconazole in plasma after administration of the test and the reference products
Cumulative area under the concentration time curve calculated from 0 to TLQC using the linear trapezoidal method, where TLQC represents time of last observed quantifiable concentration
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
AUC0-72 of fluconazole in plasma after administration of the test and the reference products (in case if AUC0-T is less than 80% of AUC0-∞ in more than 20% of the observations, truncated AUC0-72 will be used as primary endpoint instead of AUC0-T)
Cumulative area under the concentration time curve calculated from 0 to 72 hours using the linear trapezoidal method. Nominal time will be used to estimate AUC0-72 using the NCA built-in tool in Phoenix® WinNonlin®. Any actual time that deviates by more than 1 minute from the 72-hour time point will be extrapolated/intrapolated as per Phoenix® WinNonlin®'s built-in formulas.
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
Tmax of fluconazole in plasma after administration of the test and the reference products
Time of maximum observed concentration; if it occurs at more than one time point, Tmax is defined as the first time point with this value
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
TLQC of fluconazole in plasma after administration of the test and the reference products
Time of last observed quantifiable concentration
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
AUC0-∞ of fluconazole in plasma after administration of the test and the reference products
Area under the concentration time curve extrapolated to infinity, calculated as AUC0-t + ĈLQC (the predicted concentration at time TLQC) / λZ (apparent elimination rate constant)
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
Residual area of fluconazole in plasma after administration of the test and the reference products
Extrapolated area (i.e. percentage of AUC0-INF due to extrapolation from TLQC to infinity)
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
Time point where the log-linear elimination phase begins (TLIN) of fluconazole in plasma after administration of the test and the reference products
Time point where the log-linear elimination phase begins
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
λZ of fluconazole in plasma after administration of the test and the reference products
Apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log concentration versus time curve
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
Terminal elimination half-life (Thalf) of fluconazole in plasma after administration of the test and the reference products
Terminal elimination half-life, calculated as ln(2)/λZ
Time frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration
Number of treatment-emergent adverse events for the test and the reference products
The safety population will include all subjects who received at least one dose of the test or the reference product. Any significant changes will be recorded as treatment-emergent adverse events only if they are judged clinically significant by the qualified investigator or delegate.
Time frame: Up to 30 days (after the first drug administration until 3 days following the last blood sample of the study)
Plan to share: No
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Pharmtechnology LLC