Factors on Therapeutic Drug Monitoring and Safety of Voriconazole in Critically Ill Elderly Patients

Factors on Therapeutic Drug Monitoring and Safety of Voriconazole in Critically Ill Elderly Patients: A Prospective Observational Study

This was a prospective clinical study that all voriconazole-treated adult Chinese patients with invasive pulmonary infection admitted to Zhengzhou Central Hospital affiliated to Zhengzhou University from July 2018 to June 2023. The initial voriconazole serum trough concentration, Correlation of various factors, and risk prediction factors for voriconazole serum trough concentration and hepatotoxicity were compared between elderly and non-elderly patients.

Study Overview

• Status: Recruiting
• Conditions: Invasive Fungal Infection
• Intervention / Treatment: Device: other antifungal agents,breathing machine

Detailed Description

A prospective observational study was conducted from July 2018 to June 2023 in Zhengzhou Central Hospital Affiliated to Zhengzhou University. This study was carried out in accordance with the following criteria: (1) patients who met the criteria for diagnosis of IFI, (2) age ≥ 18 years, (3) The duration of VCZ treatment course ≥ 7 days.

Patients were excluded who fulfilled any of the following criteria: (1) Patients who allergic to VCZ, (2) use other anti-fungal drugs during the use of VCZ, (3) do not qualify for blood sampling monitored by blood concentration, (4) pregnant or lactating women, (5) patients who haven't completely and accurately efficacy and safety data, (6) patients who are treated with a combination of liver enzyme inducers and inhibitors (carbamazepine, phenobarbital, phenytoin, cimetidine, rifampin, rifapentine, rifabutin, and so on),(7) patients who are treated with a combination of Paxlovid or Azvudine.

Grouping: Patients were divided into the elderly group (group A, ≥ 60 years) and the non-elderly group (group B, < 60 years) according to ages. All the recruited patients were treated with voriconazole. Voriconazole was intravenously administered 2 times at the loading dose of 6 mg/Kg or orally administered 2 times at the loading dose of 400mg at 12h intervals, followed by a maintenance dose of 4 mg/Kg or 200 mg at 12 h intervals.

• Study Type: Observational
• Enrollment (Estimated): 550

Contacts and Locations

• Study Contact: Name: Zhou Li-juan Zhou Li-juan, master; Phone Number: 13838014946; Email: zhou750423@126.com

Study Locations

• China
  • Henan
    • Zhengzhou, Henan, China, 41
      • Recruiting
      • Zhengzhou Central Hospital affiliated to Zhengzhou University
      • Contact: Zhou Li-juan Zhou Li-juan, master; Phone Number: 13838014946; Email: zhou750423@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All voriconazole-treated adult Henan Chinese Han patients with invasive pulmonary infection were admitted to Zhengzhou Central Hospital affiliated to Zhengzhou University from July 2018 to June 2023.

Description

Inclusion Criteria:

• patients who met the criteria for diagnosis of IFI
• age ≥ 18 years
• The duration of VCZ treatment course ≥ 7 days.

Exclusion Criteria:

• Patients who allergic to VCZ
• use other anti-fungal drugs during the use of VCZ
• do not qualify for blood sampling monitored by blood concentration
• pregnant or lactating women
• patients who haven't completely and accurately efficacy and safety data
• patients who are treated with a combination of liver enzyme inducers and inhibitors(carbamazepine, phenobarbital, phenytoin, cimetidine, rifampin, rifapentine, rifabutin, and so on)
• patients who are treated with a combination of Paxlovid or Azvudine.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group A; the elderly group , the age ≥ 60 years	Device: other antifungal agents,breathing machine; If treatment failure for patients in group A and group B，change other antifungal agents (Amphotericin B for Injection, 25mg, North China Pharmaceutical Co., Ltd or Caspofungin Acetate for lnjection,50mg and 70mg Cancidas®). Mechanical ventilation (EVITA 4, Dräger Medical Equipment (Shanghai) Co.,Ltd) was adopte.Treatment failure was defined as no improvement or worse of clinical symptoms, laboratory data, requiring change of antifungal agents therapy.
Group B; the non-elderly group , the age < 60 years	Device: other antifungal agents,breathing machine; If treatment failure for patients in group A and group B，change other antifungal agents (Amphotericin B for Injection, 25mg, North China Pharmaceutical Co., Ltd or Caspofungin Acetate for lnjection,50mg and 70mg Cancidas®). Mechanical ventilation (EVITA 4, Dräger Medical Equipment (Shanghai) Co.,Ltd) was adopte.Treatment failure was defined as no improvement or worse of clinical symptoms, laboratory data, requiring change of antifungal agents therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum voriconazole trough concentrations	If all patients were administrated by loading dose, voriconazole trough samples were taken immediately 30 minutes before voriconazole administration on the Third day. If all patients were not administrated by loading dose, voriconazole trough samples were taken immediately 30 minutes before voriconazole administration on the sixth day. Blood samples for 2-3 mL were collected in blood-collection tubes without any additives and centrifuged at 3500 rpm for 10min. Serum trough concentrations were determined by a high-performance liquid chromatography method as previously described. A initial steady-state trough concentration blood sample was obtained before dose adjustment for all patients. Each patient received at least one steady-state blood sample. The detections were completed in Translational Medicine Center of Zhengzhou Central Hospital affiliated to Zhengzhou University.	0.5 hour before voriconazole administration on the Third or sixth day.
CYP2C19 Genotyping	CYP2C19 genotype was determined from peripheral blood, which was extracted and stored in an EDTA anticoagulant tube. Real-time fluorescence quantitative PCR (ThermoFisher Applied Biosystems 7500 fast PCR) was performed using a Human CYP2C19 gene detection kit (PCR-fluorescence probe method, Wuhan YZY Medical Science and Technology Co., Ltd, China) following the manufacturer's instructions. Genomic DNA was isolated from whole blood using QIAamp DNA blood kits (Qiagen, Hilden, Germany). According to nomenclature by the Clinical Pharmacogenetics Implementation Consortium (CPIC®), the CYP2C19 genotype was classified as ultrarapid metabolizer (*17/*17), rapid metabolizer (*1/*17), normal metabolizer (*1/*1), intermediate metabolizer (*1/*2, *1/*3, *2/*17, *3/*17), or poor metabolizer (*2/*2, *2/*3, *3/*3).	Unlimited blood drawing time.
The difference of average voriconazole serum trough concentration between group A and group B	The differences were counted between group A and group B by measuring each patient's voriconazole serum trough concentration.	From July 2018 to June 2023
Analysis of factors affecting voriconazole serum trough concentration	A multiple linear stepwise regression analysis was performed by using voriconazole serum trough concentration (Y) as the dependent variable, and sex (x1), age (x2), body weight (x3), VCZ route of administration (x4), CYP2C19 phenotype (x5), the average daily dose (x6), PPIs (x7), methylprednisolone (x8), CRP (x9) , PCT (x10), IL-6 (x11), Albumin (x12), ALP (x13), and TBIL (x14) as independent variables. Linear regression analysis reveals the regression equation and independent risk factors affecting voriconazole serum trough concentration.	From July 2018 to June 2023

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
C-reaction protein (CRP)	It was completed before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy in Zhengzhou city clinical inspection center.	Before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy
Alanine aminotransferase (ALT)	It was completed before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy in Zhengzhou city clinical inspection center.	Before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy
Aspartatrtransaminase (AST)	It was completed before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy in Zhengzhou city clinical inspection center.	Before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy
Gamma-glutamyl transferase(GGT)	It was completed before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy in Zhengzhou city clinical inspection center.	Before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy
Alkaline phosphatase (ALP)	It was completed before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy in Zhengzhou city clinical inspection center.	Before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy
Total bilirubin (TBIL)	It was completed before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy in Zhengzhou city clinical inspection center.	Before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy
procalcitonin(PCT)	It was completed before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy in Zhengzhou city clinical inspection center.	Before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy
interleukin- 6(IL-6)	It was completed before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy in Zhengzhou city clinical inspection center.	before initiation, On the day of blood sample extraction with serum trough concentration, and completion of voriconazole therapy

Collaborators and Investigators

• Sponsor: People's Hospital of Zhengzhou University

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2018
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): March 1, 2024

Study Registration Dates

• First Submitted: November 14, 2023
• First Submitted That Met QC Criteria: November 14, 2023
• First Posted (Actual): November 18, 2023

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Invasive Fungal Infections; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Local; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Antifungal Agents; Clotrimazole; Miconazole
• Other Study ID Numbers: LJzhou

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes