Drug-Drug Interaction Study of Voriconazole With Clarithromycin.
Condition: Healthy
Study type: Interventional
Phase: Phase 4

Summary: 
      The current study evaluated the Pharmacokinetic (PK) drug-drug interaction (PK-DDI) of
      voriconazole with clarithromycin in healthy male volunteers. The drug interaction study was
      designed as a single oral dose, open-label, crossover, and randomized trial. In the first
      phase of the study, the principal investigator developed a high-performance-liquid
      chromatography (HPLC) method and validation according to standard ICH guidelines for the
      quantification of voriconazole in the biological matrix. During the second step, Enrolled
      volunteers were divided randomly into group A and group B by the "permuted block
      randomization" technique. Then, voriconazole either alone (2 x 200mg, tab, P/O) or in
      combination with clarithromycin (Voriconazole 2 x 200mg, tab + clarithromycin 500mg, tab,
      P/O) was administered to enrolled volunteers in two sequences. Finally, sample collection was
      carried out and blood samples were collected at specified time periods (i.e., 0.0 (pre-dose),
      0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12, and 24 hours) in EDTA or heparinized tubes
      from the enrolled human volunteers. Further processing of the sample was done for extractions
      and subsequent analysis with the developed analytical method.
    

Detailed description: 
      Study Design and Ethical Approval: The drug interaction study was designed as a single oral
      dose, open-label, randomized, cross-over study of healthy volunteers. The ethical approval of
      the protocol was taken from the Advanced Studies and Research Board (ASRB) of the Pharmacy
      department, Abdul Wali Khan University, Mardan before initiation. This study followed the
      "ethical principles of the Helsinki declaration for medical research involving human
      subjects" and "good clinical practice guidelines". The clinical trial of this study followed
      the guidelines of CONSORT. Written consent was obtained from all included volunteers in the
      DDI study. The study was comprised of two treatment sequences with a two-week washout period

      Randomization and Drug administration: Enrolled volunteers were divided randomly into Group A
      and Group B by the "permuted block randomization" technique. Computed the volunteer data into
      an excel sheet and applied a RAND* function; selected two groups (G-A and G-B) sized, finally
      assigned 6 participants in each study group for two (Voriz (alone) or Voriz + CLRM)
      intervention arms, for the execution of block randomization. A balance (1:1) was acquired
      across both intervention arms through this randomization technique. Treatment drugs were
      administered to enrolled volunteers in two sequences,

      Sequence-I: In the first phase, group-A volunteers on day-1 received oral voriconazole (2 x
      200mg, tab, P/O) while group-B volunteers received oral clarithromycin (500mg, tab, P/O)
      along with voriconazole (2 x 200mg, tab, P/O). A two-week wash-out period was allocated that
      started on day-2 to day-15 for avoiding the carry-over effect.

      Sequence-II: On day-16, the second phase of the trial was conducted in which group-A
      volunteers received voriconazole (2 x 200mg, tab, P/O) along with clarithromycin (500mg, tab,
      P/O) while group-B volunteers received Voriz (2 x 200mg, tab, P/O) only. Voriconazole and
      clarithromycin were administered to the overnight fasted volunteers corresponding to the
      sequences. All volunteers took the medication with a glass of water (250mL). On day-1 and 16
      (treatment days), standard breakfast and lunch were served two and six hours after drug
      administration to all volunteers, respectively.
    

Intervention name(s): Voriconazole 200 mg x 2 Tablets; Clarithromycin 500 mg x 1Tablets
Intervention type(s): Drug; Drug
Intervention description(s): Name of medication of Reference Formulation: Tablets Voriconazole Vfend®, 200 mg by Pfizer, Inc. (USA), (Batch No: 00005505; Mfg. date 09/2016).; Name of medication of Intervention Formulation: Tablet Klaricid, 500 mg by Abbott, Lab Pvt. Ltd. (Karachi, Pakistan), Batch No: 81573XU; Mfg. date 10/2017.
Other intervention name(s): Vfend®; klaricid®
Intervention MeSH terms: Clarithromycin; Voriconazole
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: A single dose, randomized, crossover, open-labeled and two sequence study with a two-week washout period, evaluated the impact of clarithromycin on the pharmacokinetics (PK) profile of voriconazole Pakistani healthy male volunteers.
Masking: None (Open Label)
Primary purpose: Health Services Research
Keywords: Voriconazole (Voriz); Clarithromycin (CLRM); Washout period; Randomized; Pharmacokinetic drug-drug interaction (PK-DDI); Clinical significance