Voriconazole Blood Level and Liver Metabolizing Enzyme in Taiwanese Patients

Voriconazole Therapeutic Drug Monitoring and CYP2C19 Genetic Polymorphisms in Taiwanese Patients

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.

Study Overview

• Status: Completed
• Conditions: Invasive Fungal Infections
• Intervention / Treatment: Other: Blood drawn (lab data)

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.

• Study Type: Observational
• Enrollment (Actual): 200

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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

Description

Inclusion Criteria:

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

Exclusion Criteria:

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Fungal infections; Patients with invasive fungal infections; and; Patients who receive PO or IV voriconazole for more than 3 days	Other: Blood drawn (lab data); Check drug blood level 3-5 days after start of drug, treatment failure, occurence of adverse events, or clinically indicated; Check genetic polymorphism of liver enzyme 3-5 days after start of drug; Other Names: SNP; Plasma concentration; Enzyme genetic polymorphism

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Relationship between treatment outcome and voriconazole plasma levels	continuous observation through treatment course

Secondary Outcome Measures

Outcome Measure	Time Frame
Relationship between voriconazole plasma levels and CYP2C19 polymorphism	3-5 days after start of IV/PO voriconazole
Relationship between safety and voriconazole plasma levels	Continuous observation through treatment course

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Collaborators: National Science Council, Taiwan
• Investigators: Principal Investigator: Shu-Wen Lin, PharmD, MS, Graduate Institute of Clinical Pharmacy, National Taiwan University

Publications and helpful links

General Publications

• Bruggemann RJ, Donnelly JP, Aarnoutse RE, Warris A, Blijlevens NM, Mouton JW, Verweij PE, Burger DM. Therapeutic drug monitoring of voriconazole. Ther Drug Monit. 2008 Aug;30(4):403-11. doi: 10.1097/FTD.0b013e31817b1a95.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: August 31, 2008
• First Submitted That Met QC Criteria: September 2, 2008
• First Posted (Estimate): September 3, 2008

Study Record Updates

• Last Update Posted (Actual): February 10, 2022
• Last Update Submitted That Met QC Criteria: February 8, 2022
• Last Verified: September 1, 2008

More Information

Terms related to this study

• Keywords: Voriconazole; Therapeutic drug monitoring; Antifungal Agents; Invasive fungal infections; CYP Genetic polymorphism
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Invasive Fungal Infections
• Other Study ID Numbers: 200801019R; NSC 97-2320-B-002 -016 -MY3