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

Sponsor

dingshifang (Other)

Overall Status

Unknown status

CT.gov ID

NCT02100761

Collaborator

Shandong Provincial Hospital (Other), Qianfoshan Hospital (Other), Shandong thorax hospital (Other), Jinan Military General Hospital (Other), Jinan Central Hospital (Other)

200

Enrollment

Location

Duration (Months)

16.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Invasive Pulmonary Aspergillosis	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 CYP2C191 or 1 wild-type allele and 1 CY¬P2C1917 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 CYP2C191 are defined as intermediate metabolizers (IMs)

Study Design

Study Type:

Observational

Anticipated Enrollment :

200 participants

Observational Model:

Case-Only

Time Perspective:

Prospective

Official Title:

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

Study Start Date :

Jun 1, 2014

Anticipated Primary Completion Date :

Jun 1, 2015

Anticipated Study Completion Date :

Jun 1, 2015

Arms and Interventions

Arm	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

Arm

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