Voriconazole Blood Level and Liver Metabolizing Enzyme in Taiwanese Patients

The recruitment status of this study is unknown because the information has not been verified recently.
Verified September 2008 by National Taiwan University Hospital.
Recruitment status was  Not yet recruiting
Sponsor:
Collaborator:
National Science Council, Taiwan
Information provided by:
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT00745992
First received: August 31, 2008
Last updated: September 2, 2008
Last verified: September 2008
  Purpose

Voriconazole is an effective antifungal agent and may decrease morbidity and mortality for patients with invasive fungal infections. It is metabolized via liver enzymes. However, these enzymes exhibit different activities in individual patient (genetic polymorphism). Higher proportions of Asians metabolize voriconazole slower than Caucasians and African Americans do. Slower metabolizers may experience dose-associated adverse events more frequently, such as visual disturbances, liver function test abnormalities, and neurological complications. On the other hand, extensive metabolizer or other physiologic conditions may lead to lower blood levels of voriconazole, which may result in treatment failure.

We plan to enroll patient who take voriconazole and examine their liver enzyme activities and blood samples for peak and trough drug levels. We will collect potential factors affecting voriconazole levels, and correlate the levels with the dosing regimen, activity of liver enzyme, occurrence of adverse events, and treatment outcomes. The goal of this study is to determine if monitoring of voriconazole blood levels is necessary in Taiwan.


Condition Intervention
Invasive Fungal Infections
Other: Blood drawn (lab data)

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Voriconazole Therapeutic Drug Monitoring and CYP2C19 Genetic Polymorphisms in Taiwanese Patients

Resource links provided by NLM:


Further study details as provided by National Taiwan University Hospital:

Primary Outcome Measures:
  • Relationship between treatment outcome and voriconazole plasma levels [ Time Frame: continuous observation through treatment course ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Relationship between voriconazole plasma levels and CYP2C19 polymorphism [ Time Frame: 3-5 days after start of IV/PO voriconazole ] [ Designated as safety issue: No ]
  • Relationship between safety and voriconazole plasma levels [ Time Frame: Continuous observation through treatment course ] [ Designated as safety issue: Yes ]

Biospecimen Retention:   Samples With DNA

plasma


Estimated Enrollment: 200
Study Start Date: October 2008
Estimated Study Completion Date: July 2011
Estimated Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Fungal infections
  1. Patients with invasive fungal infections; and
  2. Patients who receive PO or IV voriconazole for more than 3 days
Other: Blood drawn (lab data)
  1. Check drug blood level 3-5 days after start of drug, treatment failure, occurence of adverse events, or clinically indicated
  2. Check genetic polymorphism of liver enzyme 3-5 days after start of drug
Other Names:
  • Plasma concentration
  • Enzyme genetic polymorphism
  • SNP

Detailed Description:

The incidence of opportunistic, invasive fungal infections has dramatically increased over the past two decades and they cause high morbidity and mortality in a variety of patient populations. Voriconazole, a triazole antifungal agent, has shown in vitro activity against many yeasts and a variety of mold and dermatophyte isolates. Voriconazole can be administered either orally or parenterally. It exhibits good oral bioavailability and wide tissue distribution. Voriconazole is extensively metabolized by the hepatic cytochrome P450 isoenzymes, CYP 2C19, CYP 2C9 and CYP 3A4. The affinity of voriconazole is greatest for isoenzyme CYP 2C19 which exhibits genetic polymorphism with 15-20% of Asian populations being poor/slow metabolizers, whereas the prevalence is much lower (3-5%) amongst Caucasians and African Americans. Studies conducted in Caucasian and Japanese healthy subjects have demonstrated that poor metabolizers have, on average, four times higher voriconazole AUC than homozygous extensive metabolisers, while the AUC of heterozygous extensive metabolizers is two times higher than that of homozygous extensive metabolizers. The most commonly reported adverse events associated with voriconazole use include visual disturbances, liver function test abnormalities, and neurological complications. All of them have been reported to be associated with higher plasma concentrations and / or doses. In term of efficacy, an analysis showed a trend toward worse outcomes in patients with voriconazole plasma concentrations < 0.5 μg/mL although this remains controversial. Since Asians have more CYP 2C19 polymorphism, we expect to see more patients with a wider range of voriconazole plasma concentrations than in previous studies in Caucasian patients. Our study will likely provide stronger evidence in explanation of the relationship between voriconazole plasma concentrations and clinical observations.

We plan to enroll patient who take voriconazole and examine their CYP 2C19 genotypes and plasma samples for peak and trough concentrations. We will collect potential confounding factors affecting voriconazole plasma concentrations, and correlate the concentrations with the dosing regimen, presence or absence of CYP 2C19 polymorphism, occurrence of adverse events, and treatment outcomes. The result of this study will be beneficial in clarify the international debate on controversial issue in the voriconazole plasma concentration monitoring. The ultimate goals of this study is to determine if monitoring of voriconazole plasma concentrations is desired in select patient populations or under certain circumstances in Taiwan.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Hospitalization patient or ambulatory patients, Patients with invasive fungal infections, Patients who take PO/IV voricoanzole more than 3 days

Criteria

Inclusion Criteria:

  • Hospitalization patient or ambulatory patients
  • Patients with invasive fungal infections
  • Patients who take PO/IV voriconazole more than 3 days

Exclusion Criteria:

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00745992

Contacts
Contact: Shu-Wen Lin, PharmD, MS 886-2-2312-3456 ext 88408 shuwenlin@ntu.edu.tw
Contact: Fe-Lin L. Wu, Ph.D. 886-2-2312-3456 ext 88389 flwu@ntu.edu.tw

Locations
Taiwan
National Taiwan University Hospital Not yet recruiting
Taipei, Taiwan, 100
Contact: Shu-Wen Lin, PharmD, MS    886-2-2312-3456 ext 88408    shuwenlin@ntu.edu.tw   
Contact: Fe-Lin L. Wu, Ph.D.    886-2-2312-3456 ext 88389    flwu@ntu.edu.tw   
Principal Investigator: Shu-Wen Lin, PharmD, MS         
Sub-Investigator: Fe-Lin L. Wu, Ph.D.         
Sponsors and Collaborators
National Taiwan University Hospital
National Science Council, Taiwan
Investigators
Principal Investigator: Shu-Wen Lin, PharmD, MS Graduate Institute of Clinical Pharmacy, National Taiwan University
  More Information

Publications:
Responsible Party: Shu-Wen Lin, Pharm.D., M.S., Graduate Institute of Clinical Pharmacy, National Taiwan University
ClinicalTrials.gov Identifier: NCT00745992     History of Changes
Other Study ID Numbers: 200801019R, NSC 97-2320-B-002 -016 -MY3
Study First Received: August 31, 2008
Last Updated: September 2, 2008
Health Authority: Taiwan: Institutional Review Board

Keywords provided by National Taiwan University Hospital:
Voriconazole
Antifungal Agents
Invasive fungal infections
Therapeutic drug monitoring
CYP Genetic polymorphism

Additional relevant MeSH terms:
Infection
Mycoses
Voriconazole
14-alpha Demethylase Inhibitors
Anti-Infective Agents
Antifungal Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014