CYP 2C19 Polymorphism and Voriconazole Trough Concentration in Chinese Adult Patients

Impact of Cytochrome P450 2C19 Genotype Polymorphism on Voriconazole Trough Concentration in Chinese Adult Patients With Invasive Pulmonary Aspergillosis: a Prospective Multicenter Research

To investigate the relationship between cytochrome P450 (CYP) 2C19 genetic polymorphism and the steady-state blood concentration of voriconazole in Chinese patients with invasive pulmonary aspergillosis (IPA), and to assess the effects of voriconazole trough concentration on the prognosis of IPA patients.

Study Overview

• Status: Unknown
• Conditions: Invasive Pulmonary Aspergillosis
• Intervention / Treatment: Drug: Voriconazole

Detailed Description

Each isolate of aspergillosis will be recovered from clinical specimens (sputum, bronchoalveolar lavage fluid, lung biopsy tissue) and the identification of species level will also be performed in Qilu Hospital by using conventional methods (both macroscopic and microscopic characteristics). The aspergillosis strains will be stored in 10 % glycerol broth at -80 °C. The in vitro antifungal susceptibility test of aspergillosis strains to voriconazole will be performed in the Centre for Medical Mycology and Mycoses, First Hospital, Peking University, and the performance will be according to the Clinical and Laboratory Standards Institute (CLSI) standard M38-A2 microdilution methods.

Serum galactomannan (GM) test will be performed twice per week for the first two weeks. A double-sandwich ELISA GM assay was used. A cut-off of optical density index (ODI) >0.5 was taken as positive.

Voriconazole serum levels will be measured on day 4, day 7, day 10, and day 14 (all trough levels). In brief, quantitative analysis of voriconazole was performed using high-performance liquid chromatography coupled with tandem mass spectrometry.

Genotyping of CYP2C19 will be performed using 3 ml of peripheral blood sampled into EDTA (ethylenediaminetetraacetic acid) tubes at day 4. Genomic DNA was extracted from blood leukocytes with the use of a DNA extraction kit. Genotyping was confirmed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. Individuals can be divided into three groups according to the CYP2C19 genotype. Those who inherit two mutant CYP2C19 alleles (*2 and/or *3) have a reduced capacity to metabolize CYP2C19 substrates and are defined as poor metabolizers (PMs). Individuals who are homozygous (*1/*1) for wild-type CYP2C19*1 or 1 wild-type allele and 1 CY¬P2C19*17 have efficient enzymes to metabolize CYP2C19 substrates and are defined as extensive metabolizers (EMs). Subjects who are heterozygous (*1/*2, *1/*3) for wild-type CYP2C19*1 are defined as intermediate metabolizers (IMs)

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

Contacts and Locations

• Study Contact: Name: Shifang Ding, Ph.D.; Phone Number: +86 18560081003; Email: dingshifang@sdu.edu.cn

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250012
      • Qilu hospital
      • Contact: Shifang Ding, Ph.D.; Phone Number: +86 18560081003; Email: dingshifang@sdu.edu.cn
      • Principal Investigator: Shifang Ding, Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with invasive pulmonary aspergillosis and will be treated with voriconazole according to their physician decision

Description

Inclusion Criteria:

• Proven, probable, or possible invasive pulmonary aspergillosis (IPA)
• Acute IPA defined as duration of clinical syndrome of <30 days.
• Treatment with voriconazole
• At least 18 years and older
• Weight >40 kg and ≤120 kg
• Given the informed consent

Exclusion Criteria:

• Patients allergic to azole(s)
• Patients who heve been prescribed voriconazole before
• Positive urine pregnancy test (if female)
• Patients with aspergilloma or chronic aspergillosis ( >1 month duration )
• Anticipated survival of less than 5 days or Karnofsky score <=20

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

invasive pulmonary aspergillosis; Patients with invasive pulmonary aspergillosis and will be treated with voriconazole according to their physician decision in five hospital, Jinan, China

Drug: Voriconazole; Patients with creatinine clearance at least 50 ml/min will be treated with voriconazole by intravenous drip infusion at the dose of 6 mg/kg twice daily on the first day (Day 1) and 4 mg/kg twice daily from day 2 onward. The IV treatment is at least 7 days. Then switch to 200 mg orally twice daily between meals. The total treatment duration is at least 14 days Patients with creatinine clearance <50 ml/min will be treated with oral voriconazole (loading dose of 400 mg twice daily followed by maintenance dose of 200 mg twice daily between meals for at least 14.0 days).; Other Names: Voriconazole Intravenous Solution 200 mg; Voriconazole Tablet 50 mg / Voriconazole Tablet 200 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
voriconazole trough level	one year

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall mortality	one year

Collaborators and Investigators

• Sponsor: dingshifang
• Collaborators: Shandong Provincial Hospital; Qianfoshan Hospital; Jinan Military General Hospital; Jinan Central Hospital; Shandong thorax hospital
• Investigators: Study Chair: Shifang Ding, Ph.D., Qilu Hospital of Shandong University

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Anticipated): June 1, 2015
• Study Completion (Anticipated): June 1, 2015

Study Registration Dates

• First Submitted: March 3, 2014
• First Submitted That Met QC Criteria: March 31, 2014
• First Posted (Estimate): April 1, 2014

Study Record Updates

• Last Update Posted (Estimate): April 1, 2014
• Last Update Submitted That Met QC Criteria: March 31, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: Safety; Efficacy; Voriconazole; Therapeutic drug monitoring; Invasive pulmonary aspergillosis; CYP genetic polymorphism
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections and Mycoses; Mycoses; Invasive Fungal Infections; Lung Diseases, Fungal; Aspergillosis; 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: KYLL-2014(KS)-085