Clinical trial NCT02100761: CYP 2C19 Polymorphism and Voriconazole Trough Concentration in Chinese Adult Patients
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 type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Invasive Pulmonary Aspergillosis
Keywords: Voriconazole
Invasive pulmonary aspergillosis
Therapeutic drug monitoring
CYP genetic polymorphism
Efficacy
Safety
Lead sponsor: Qilu Hospital of Shandong University
Sponsor class: OTHER
Collaborators: name: Shandong Provincial Hospital
name: Qianfoshan Hospital
name: Shandong thorax hospital
name: Jinan Military General Hospital
name: Jinan Central Hospital
First posted: 2014-04-01
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with invasive pulmonary aspergillosis and will be treated with voriconazole according to their physician decision

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)

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

Primary outcomes:
measure: voriconazole trough level
timeFrame: one year
Secondary outcomes:
measure: Overall mortality
timeFrame: one year
Other outcomes:
Locations:
city: Jinan
country: China
facility: Qilu Hospital
state: Shandong
Study officials:
affiliation: Qilu Hospital of Shandong University
name: Shifang Ding, Ph.D.
role: STUDY_CHAIR
References: