The Bioequivalence Study of Two Different Formulations of Candesartan Cilexetil After a Single Oral Dose Administration Under Fasting Conditions
Condition: Bioequivalence
Study type: Interventional
Phase: Phase 1

Summary: 
      This single dose study was designed in accordance with EMA (the European Medicines Agency)
      regulatory guidelines, with the aim of characterizing the bioavailability of candesartan in
      the two formulations in healthy subjects. As this is a bioequivalence trial where each
      subject received each study treatment in a crossover fashion, a control group was not
      included. Within the clinical portion of the study each subject received a single oral dose
      of the test and the reference formulation in compliance with the generated randomization
      code. The primary study endpoints were the pharmacokinetic (PK) parameters Cmax and AUC0-t of
      candesartan.
    

Detailed description: 
      This is a single center, randomized, 2-treatment, 2-period, 2-sequence, crossover, single
      dose study design, in which 40 healthy adult subjects received one of the study treatments
      during each study period.

      The objective of this study was to determine the bioequivalence of two different formulations
      of candesartan after a single oral dose administration under fasting conditions.

      The intra-subject variation following a single dose of candesartan cilexetil appeared to be
      around 28.8% for Cmax and around 24% for AUC0-t. Statistically, given that the expected Test
      to Reference ratio of geometric least-squares means (LSmeans) should fall within 95 and 105%,
      it is estimated that the lowest number of subjects to meet the 80 to 125% bioequivalence
      range with a statistical a priori power of at least 80% is about 36. Therefore, the inclusion
      of 40 subjects should be sufficient to account for the possibility of drop-outs, variations
      around the estimated intra-subject coefficient of variation (CV) and to conclude in favor of
      the hypothesis of bioequivalence with sufficient statistical power.

      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      A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving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 first dose (the test or the reference product) in Period 1 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. Eligible subjects will be randomized to one of two treatment sequences.
      There will be two sequences in the study: AB and BA, where A = the test product, B = the
      reference product (see detailed description of A and B items in Section "Arms and
      Interventions").

      For each study period, subjects will receive a single 32 mg oral dose of candesartan
      cilexetil (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.

      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. Water will be provided as needed until
      1 hour predose. Water will be allowed beginning 1 hour after the administration of the drug.

      A total of 21 blood samples will be collected (one tube of 3 mL each) in each study period
      for pharmacokinetic (PK) assessments.The first blood sample will be collected prior to drug
      administration while the others will be collected up to 48 hours after drug administration.

      Given that the parent compound, candesartan cilexetil, is rapidly and completely converted to
      the pharmacologically active metabolite, candesartan, candesartan cilexetil cannot be
      reliably measured. Therefore, the analyte to be measured in the present study will be
      candesartan. Candesartan plasma concentrations will be measured according to a validated
      bioanalytical method.

      Subjects are to be discharged from the clinic after the 24-hour following drug
      administration. 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 clinical site for
      each of the 2 remaining blood samples.

      The expected terminal elimination half-life observed after a single oral 32 mg dose of
      candesartan cilexetil tablets under fasting conditions is 11.6 hours. To avoid any carry-over
      effect, a wash-out of 7 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).

      Statistical analysis of Tmax will be based on a non-parametric approach. Statistical analysis
      of all other PK parameters will be based on an ANOVA model. Two-sided 90% confidence interval
      of the ratio of geometric LSmeans obtained from the ln-transformed PK parameters will be
      calculated.

      Statistical inference of candesartan will be based on a bioequivalence approach using the
      following standards: the ratio of geometric LSmeans with corresponding 90% confidence
      interval calculated from the exponential of the difference between the Test and the Reference
      for the ln-transformed parameters Cmax and AUC0-t should all be within the 80.00 to 125.00%
      bioequivalence range.

      The safety population will include all subjects who received at least one dose of one of the
      IPs. Safety assessments will include vital signs, clinical laboratory tests and AE
      monitoring. Additional safety measurements may be performed at the discretion of the
      investigator for reasons related to subject safety.The physician in charge will be present at
      the clinical site for at least the first 4 hours following each drug administration and will
      remain available at all times throughout the study.

      Total study duration: up to 38 days (including screening).
    

Intervention name(s): Candesartan Cilexetil 32mg; Atacand® PROTECT
Intervention type(s): Drug; Drug
Intervention description(s): Candesartan Cilexetil is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 32 mg of candesartan cilexetil.; Atacand® PROTECT is manufactured by AstraZeneca GmbH, Germany. Each tablet contains 32 mg of candesartan cilexetil.
Other intervention name(s): The test product; The reference product
Intervention MeSH terms: Candesartan; Candesartan cilexetil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Other
Keywords: Candesartan Cilexetil; Bioequivalence; Atacand PROTECT