Drug-Drug Interaction Study of Voriconazole With Clarithromycin.

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pharmacokinetic Drug-Drug Interaction Study of Voriconazole With Clarithromycin.

Conditions
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Healthy

Intervention / Treatment
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* Drug: Voriconazole 200 mg x 2 Tablets
* Drug: Clarithromycin 500 mg x 1Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Male Pakistani volunteers in good health aged 18-35 years were enrolled as participants in this study. The selection was based on: A complete detailed medical history, Clinical examination, Voriconazole hypersensitivity test, Evaluation of various biochemical tests like Blood Glucose Level, Hemoglobin (Hb) Level, Serum Glutamic-Pyruvic Transaminase (SGPT) Or Alanine Amino Transferase and Aspartate (ALT and AST, respectively) Level, Urine Test, Albumin to Creatinine Ratio (ACR) Test, Glomerular Filtration Rate (GFR) Level, etc. Exclusion Criteria: Those volunteers were having a history of voriconazole hypersensitivity reaction were excluded from the study. Deviation from normal values in the biochemical test report was excluded from the study. Having any pathology like chronic renal disease, and hepatic impairment was excluded from the study. Having any cardiovascular, gastrointestinal tract, and hematopoietic disorders were excluded from the study. Alcohol addicted, smokers and volunteers who cannot sign the permission consent form were excluded from the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Voriconazole (alone), then Voriconazole + Clarithromycin.<br>On Day-1, Group-A participants first received Voriconazole (alone) (Dose: 400mg, Dosage form: Tablet, Frequency: Once (OD), Duration of administration: Single Dose, Kind of administration: Oral). After a washout period of two weeks. Then, on Day-16 they received Voriconazole (Dose: 400mg, Dosage form: Tablet, Frequency: Once (OD), Duration of administration: Single Dose, Kind of administration: Oral) along with Clarithromycin (Name of medication of Intervention Formulation: Tablet Klaricid, Dose: 500mg, Dosage form: Tablet, Frequency: Once (OD), Duration of administration: Single Dose, Kind of administration: Oral). | Drug: Voriconazole 200 mg x 2 Tablets<br>* Name of medication of Reference Formulation: Tablets Voriconazole Vfend®, 200 mg by Pfizer, Inc. (USA), (Batch No: 00005505; Mfg. date 09/2016).<br>* Other names: Vfend®;Drug: Clarithromycin 500 mg x 1Tablets<br>* Name of medication of Intervention Formulation: Tablet Klaricid, 500 mg by Abbott, Lab Pvt. Ltd. (Karachi, Pakistan), Batch No: 81573XU; Mfg. date 10/2017.<br>* Other names: klaricid®;|
| Experimental: Treatment Voriconazole + Clarithromycin, then Voriconazole (alone).<br>On Day-1, Group-B participants first received Voriconazole (Dose: 400mg, Dosage form: Tablet, Frequency: Once (OD), Duration of administration: Single Dose, Kind of administration: Oral) along with Clarithromycin (Name of medication of Intervention Formulation: Tablet Klaricid, Dose: 500mg, Dosage form: Tablet, Frequency: Once (OD), Duration of administration: Single Dose, Kind of administration: Oral).After a washout period of two weeks. Then, on Day-16 they received Voriconazole (alone) (Dose: 400mg, Dosage form: Tablet, Frequency: Once (OD), Duration of administration: Single Dose, Kind of administration: Oral). | Drug: Voriconazole 200 mg x 2 Tablets<br>* Name of medication of Reference Formulation: Tablets Voriconazole Vfend®, 200 mg by Pfizer, Inc. (USA), (Batch No: 00005505; Mfg. date 09/2016).<br>* Other names: Vfend®;Drug: Clarithromycin 500 mg x 1Tablets<br>* Name of medication of Intervention Formulation: Tablet Klaricid, 500 mg by Abbott, Lab Pvt. Ltd. (Karachi, Pakistan), Batch No: 81573XU; Mfg. date 10/2017.<br>* Other names: klaricid®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration of voriconazole | Determine the Plasma Concentration particularly the Maximum Plasma Concentration (Cmax) of voriconazole either alone or co-administration with clarithromycin. | At Day 1 Pre-dose, 0.5hour, 1hour, 1.5hour, 2hour, 3hour, 4hour, 6hour, 8hour, 12hour, 24hour post-dose and At Day 16 Pre-dose, 0.5hour, 1hour, 1.5hour, 2hour, 3hour, 4hour, 6hour, 8hour, 12hour, 24hour post-dose. | 
| Area under the Plasma Concentration versus Time Curve (AUC) of voriconazole | Determine the Area under the Plasma Concentration versus Time Curve (AUC) of voriconazole either alone or co-administration with clarithromycin. | At Day 1 Pre-dose, 0.5hour, 1hour, 1.5hour, 2hour, 3hour, 4hour, 6hour, 8hour, 12hour, 24hour post-dose and At Day 16 Pre-dose, 0.5hour, 1hour, 1.5hour, 2hour, 3hour, 4hour, 6hour, 8hour, 12hour, 24hour post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Time to Reach (Cmax) of voriconazole (Tmax) | Tmax of voriconazole either alone or co-administration with clarithromycin. | At Day 1 Pre-dose, 0.5hour, 1hour, 1.5hour, 2hour, 3hour, 4hour, 6hour, 8hour, 12hour, 24hour post-dose and At Day 16 Pre-dose, 0.5hour, 1hour, 1.5hour, 2hour, 3hour, 4hour, 6hour, 8hour, 12hour, 24hour post-dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Washout period, Voriconazole (Voriz), Clarithromycin (CLRM), Randomized, Pharmacokinetic drug-drug interaction (PK-DDI), Clinical significance