Voriconazole Trough Plasma Levels : Genetic Polymorphism, Efficacy, Safety in Patients With Hematologic Malignancy

The Correlation of Voriconazole Trough Plasma Levels With Genetic Polymorphism, Efficacy, and Safety Outcomes in Hematologic Malignancy Patients With Invasive Pulmonary Aspergillosis

Multiple factors are associated with a large variability in voriconazole exposure following standard dose administration, such as non-linear saturable pharmacokinetics, drug-drug interactions, liver disease, patient age, and genetic polymorphism of the metabolic enzymes.

Voriconazole is extensively metabolized by the human hepatic enzymes, primarily mediated by CYP2C19. The polymorphisms account for a relatively large portion of inter-individual variance observed in voriconazole plasma concentrations.

However, there are limited data on the relationships between voriconazole blood levels and clinical outcomes or safety in Asian populations.

The purpose of this study is to investigate the relationships of voriconazole blood levels with genetic polymorphism, safety, and clinical outcomes in immunocompromised patients with invasive pulmonary aspergillosis.

Study Overview

• Status: Terminated
• Conditions: Invasive Fungal Infection
• Intervention / Treatment: Drug: voriconazole

Detailed Description

The investigators are trying to establish that routine clinical practice for voriconazole therapeutic drug monitoring can improve the efficacy and safety outcomes.

In Korean patients with hematologic malignancy, the investigators also want to propose the optimal dosing guideline of voriconazole with different genetic polymorphisms.

• Study Type: Observational
• Enrollment (Actual): 10

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center, University of Ulsan College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with hematologic malignancies who were given voriconazole to treat invasive (pulmonary) aspergillosis at Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Description

Inclusion Criteria: all items below

• male or female ≥ 15 years of age
• immunocompromised patients with hematologic disorders
• patients received voriconazole due to treat proven, probable invasive (pulmonary) aspergillosis

Exclusion Criteria:

• severe hepatic dysfunction (t.bil, AST, ALT, ALP > 5 x upper normal limit)
• who experienced hypersensitivity to azoles
• pregnant women

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
1; Patients with hematologic malignancies who were given voriconazole to treat invasive (pulmonary) aspergillosis at Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea	Drug: voriconazole; intravenous, oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful outcome at 12 weeks after voriconazole use	Successful outcome = complete response + partial response Unsuccessful outcome = stable disease + failure of therapy + indeterminate response	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IFI (invasive fungal infection)-related mortality at 12 weeks	IFI (invasive fungal infection)-related mortality at 12 weeks	12 weeks
Successful outcomes at various time points	Successful outcomes at 1 week,2 weeks,4 weeks, and 8 weeks after voriconazole use	1 week, 2 weeks, 4 weeks, and 8 weeks
Non-IFI (invasive fungal infection)-related mortality at 12 weeks	Non-IFI (invasive fungal infection)-related mortality at 12 weeks	12 weeks
breakthrough IFI	breakthrough IFI	12 weeks
Adverse drug reactions	Adverse drug reactions (liver function test impairment, visual disturbance, hallucination, photosensitive rash, renal impairment)	12 weeks

Collaborators and Investigators

• Sponsor: Asan Medical Center

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: June 18, 2010
• First Submitted That Met QC Criteria: June 21, 2010
• First Posted (Estimate): June 22, 2010

Study Record Updates

• Last Update Posted (Estimate): April 10, 2014
• Last Update Submitted That Met QC Criteria: April 9, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: safety; hematologic malignancy; efficacy; voriconazole; invasive pulmonary aspergillosis; genetic polymorphism; therapeutic drug monitoring
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Diseases; Lung Diseases; Neoplasms by Site; Hematologic Diseases; Bacterial Infections and Mycoses; Lung Diseases, Fungal; Aspergillosis; Neoplasms; Hematologic Neoplasms; Mycoses; Invasive Fungal Infections; Pulmonary Aspergillosis; Invasive Pulmonary Aspergillosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Voriconazole
• Other Study ID Numbers: VCZ-IPA-HEM-2010