Population Pharmacokinetic Modeling with Inflammatory Covariate Analysis and Neural Network Predictive Modeling of Vancomycin Disposition in Adult ICU Patients: Prospective Observational Clinical Pharmacokinetic Study
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- Development and validation of a two-compartment population
研究概览
简要总结
Vancomycin is a commonly used antibiotic for treating serious bacterial infections in critically ill patients admitted to the Intensive Care Unit (ICU). Giving the right dose of vancomycin is challenging in ICU patients because their body conditions change rapidly due to factors such as altered kidney function, fluid shifts, and inflammation, all of which affect how the drug moves through the body.
This prospective observational study aims to enroll 35 adult ICU patients at AIIMS Bhubaneswar who are receiving standard intravenous vancomycin therapy for suspected or documented Gram-positive infections. Blood samples will be collected at 8 pre-specified time points over the first 48 hours of therapy to measure vancomycin concentrations. Routine inflammatory markers already collected as part of ICU care such as C-reactive protein (CRP), Interleukin-6 (IL-6), and Procalcitonin will be recorded and included in the analysis.
Using these data, a two-compartment population pharmacokinetic (PopPK) model will be developed using nonlinear mixed-effects modeling (nlmixr2 in R) to describe how vancomycin is distributed and cleared from the body, and to identify which patient factors, especially inflammation-related markers, most influence vancomycin drug levels. The study will also compare this traditional PopPK model against an Artificial Intelligence-based approach called Physics-Informed Neural Networks (PINNs) to determine which method better predicts vancomycin concentrations and drug exposure targets.
Computer simulations will be performed to assess the probability of achieving therapeutic targets and to develop ICU-specific dosing guidance charts tailored to a patient’s kidney function and inflammatory status. Vancomycin-associated kidney injury will be monitored as a safety outcome.
No new or experimental drug is being tested. Vancomycin is administered as per standard ICU protocol. This study is purely observational and is intended to improve the precision and safety of vancomycin dosing in critically ill patients in India.
研究设计
- 研究类型
- Observational
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Adult patients aged 18 years or above admitted to medical or central ICU receiving intravenous vancomycin for suspected or documented Gram-positive infection.
- •Minimum anticipated duration of vancomycin therapy of 48 hours or more.
- •Written informed consent obtained from patient or legally authorized representative.
排除标准
- •Pregnant patients.
- •Patients with burns involving more than 20 percent of Body Surface Area (BSA).
- •Patients on Extracorporeal Membrane Oxygenation (ECMO).
- •Patients with known anaphylaxis to vancomycin.
- •Patients requiring renal replacement therapy or dialysis.
结局指标
主要结局
Development and validation of a two-compartment population
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
pharmacokinetic (PopPK) model for vancomycin in adult ICU patients
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
incorporating inflammatory markers as covariates.
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
Primary pharmacokinetic parameters to be estimated:
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
1. Vancomycin Clearance (CL) in L/h
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
2. Central Volume of Distribution (Vc) in L
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
3. Peripheral Volume of Distribution (Vp) in L
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
4. Intercompartmental Clearance (Q) in L/h
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
5. Area Under the Concentration-Time Curve over 24 hours (AUC24)
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
in mg.h/L
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
Inflammatory covariates to be evaluated: C-reactive protein (CRP),
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
Interleukin-6 (IL-6), Procalcitonin, and Fibrinogen.
时间窗: Pharmacokinetic sampling performed over the first 48 hours of | vancomycin therapy. | Day 1: 0.5 hours (mid-infusion), 1 hour (end of infusion), | 2 hours (post-infusion), 6 hours (late distribution phase), | 12 hours (pre-maintenance trough). | Day 2: 24 hours (steady-state trough), 25 hours (steady-state peak), | 30 hours (mid-interval). | Final outcome assessment at end of vancomycin therapy | (up to 7 days).
次要结局
- Comparison of predictive performance of Physics-Informed Neural(Networks (PINNs) and other neural network architectures against traditional population pharmacokinetic (PopPK))
- Probability of target attainment (PTA) for vancomycin AUC24/MIC(ratio of 400 to 600 mg.h/L assessed using Monte Carlo simulations)
- Assessment of vancomycin-associated nephrotoxicity as a safety(outcome, defined as acute kidney injury (AKI) of KDIGO stage 1)
- Comparative evaluation of predictive performance of one-compartment(versus two-compartment pharmacokinetic models for vancomycin using)
研究者
Anand Srinivasan
AIIMS Bhubaneswar