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

NCT ID: NCT02100761

Last Updated: 2014-04-01

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2014-06-30
• Study Completion Date: 2015-06-30

Brief Summary

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.

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)

Conditions

Invasive Pulmonary Aspergillosis

Study Design

• Observational Model Type: CASE_ONLY
• Study Time Perspective: PROSPECTIVE

Study Groups

invasive pulmonary aspergillosis

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

Voriconazole

Intervention Type: DRUG

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).

Interventions

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).

Intervention Type: DRUG

Other Intervention Names

Voriconazole Intravenous Solution 200 mg; Voriconazole Tablet 50 mg / Voriconazole Tablet 200 mg

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shandong Provincial Hospital

OTHER_GOV

Sponsor Role: collaborator

Qianfoshan Hospital

OTHER

Sponsor Role: collaborator

Shandong thorax hospital

UNKNOWN

Sponsor Role: collaborator

Jinan Military General Hospital

OTHER

Sponsor Role: collaborator

Jinan Central Hospital

OTHER

Sponsor Role: collaborator

dingshifang

OTHER

Sponsor Role: lead

Responsible Party

dingshifang

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Shifang Ding, Ph.D.

Role: STUDY_CHAIR

Qilu Hospital of Shandong University

Locations

Qilu Hospital

Jinan, Shandong, China

Countries

China

Central Contacts

Shifang Ding, Ph.D.

Role: CONTACT

dingshifang@sdu.edu.cn

18560081003 ext. +86

Facility Contacts

Shifang Ding, Ph.D.

Role: primary

dingshifang@sdu.edu.cn

18560081003 ext. +86

Other Identifiers

KYLL-2014(KS)-085

Identifier Type: -

Identifier Source: org_study_id