Optimization of Beta-lactam Dosing in Critically Ill Patients With Suspected or Documented Antimicrobial Resistant Gram-Negative Infections With Cystatin-C (OPTIMIZE-GNI)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 161
- 试验地点
- 11
- 主要终点
- Akaike's information criterion (AIC) of cefepime
研究概览
简要总结
This is a Phase 4, interventional, multi-center pharmacokinetics (PK) study in up to 200 adult patients who are residing in an ICU. This study will compare the abilities of Cystatin C (CysC) and CysC-based estimated Glomerular Filtration Rate (eGFR) equations to characterize the PK profiles of meropenem and cefepime relative to Serum Creatinine (SCR), Serum Creatinine based Equation (SCRE), and iohexol in critically ill patients with suspected or documented AMR Gram-negative infections. We hypothesize that CysC and CysC-based eGFR equations will characterize the PK profiles of meropenem and cefepime at the population and individual levels with greater accuracy and precision than SCR and SCREs. Iohexol will be administered to patients enrolled in the study and serve as the reference indicator of measured Glomerular Filtration Rate (mGFR), which is the gold standard assessment of kidney function. We further hypothesize that the predictive performances of CysC and CysC-based eGFR equations in estimating the PK profiles of meropenem and cefepime at the population and individual levels will be comparable to iohexol. Firstly, population PK (PopPK) modeling will be used to develop meropenem and cefepime PopPK models informed by CysC, CysC-based eGFR equations, SCR, and SCREs (renal function biomarkers), and iohexol clearance. Secondly, model diagnostics will then be used to compare the predictive performances of the renal function biomarkers PopPK models for each antibiotic relative to iohexol PopPK model. Lastly, Monte Carlo simulation (MCS) will be used to design PK/ pharmacodynamics (PD) optimized meropenem and cefepime dosing schemes based on the renal function biomarker PopPK model with the best predictive performance for use in the treatment of critically ill adult patients with suspected or documented AMR Gram-negative infections and varying degrees of renal function. The primary objective of this study is to compare the abilities of renal function biomarkers (CysC, CysC-based eGFR equations, SCR, SCREs) relative to iohexol to characterize the PK profiles of meropenem and cefepime in critically ill adult patients with suspected or documented AMR Gram-negative infections.
详细描述
This is a Phase 4, interventional, multi-center pharmacokinetics (PK) study in up to 200 adult patients who are residing in an ICU. This study will compare the abilities of Cystatin C (CysC) and CysC-based estimated Glomerular Filtration Rate (eGFR) equations to characterize the PK profiles of meropenem and cefepime relative to Serum Creatinine (SCR), Serum Creatinine based Equation (SCRE), and iohexol in critically ill patients with suspected or documented AMR Gram-negative infections. We hypothesize that CysC and CysC-based eGFR equations will characterize the PK profiles of meropenem and cefepime at the population and individual levels with greater accuracy and precision than SCR and SCREs. Iohexol will be administered to patients enrolled in the study and serve as the reference indicator of measured Glomerular Filtration Rate (mGFR), which is the gold standard assessment of kidney function. We further hypothesize that the predictive performances of CysC and CysC-based eGFR equations in estimating the PK profiles of meropenem and cefepime at the population and individual levels will be comparable to iohexol. Firstly, population PK (PopPK) modeling will be used to develop meropenem and cefepime PopPK models informed by CysC, CysC-based eGFR equations, SCR, and SCREs (renal function biomarkers), and iohexol clearance. Secondly, model diagnostics will then be used to compare the predictive performances of the renal function biomarkers PopPK models for each antibiotic relative to iohexol PopPK model. Lastly, Monte Carlo simulation (MCS) will be used to design PK/ pharmacodynamics (PD) optimized meropenem and cefepime dosing schemes based on the renal function biomarker PopPK model with the best predictive performance for use in the treatment of critically ill adult patients with suspected or documented AMR Gram-negative infections and varying degrees of renal function. The primary objective of this study is to compare the abilities of renal function biomarkers (CysC, CysC-based eGFR equations, SCR, SCREs) relative to iohexol to characterize the PK profiles of meropenem and cefepime in critically ill adult patients with suspected or documented AMR Gram-negative infections. The secondary objective of this study is to develop PK/PD optimized meropenem and cefepime dosing schemes based on the renal biomarker function PopPK model with the best predictive performance relative to the iohexol PopPK model for critically ill adult patients with suspected or documented AMR Gram-negative infections.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >/=18 years at the time of enrollment.
- •Residing in an ICU.
- •Documented or suspected Antimicrobial Resistant (AMR) Gram-negative infection for which the prospective participant is receiving meropenem or cefepime as part of their clinical management.
- •Expectation that the prospective participant will reside in the ICU and receive meropenem or cefepime for the duration of the study, and that all study procedures will be completed.
- •Expectation that IV access will be sufficient for drug infusion and either IV or arterial access will be sufficient to allow for all protocol-required blood sampling to occur.
- •The prospective participant, or their legally authorized representative (LAR), is able and willing to provide signed informed consent
排除标准
- •Prospective participant has a documented hypersensitivity or allergic reaction to iohexol, any contrast agents, or iodine.
- •Prospective participant has a documented prior history of severe cutaneous reactions to iohexol, any contrast agents, or iodine.
- •Prospective participant received iohexol on the calendar day of enrollment or the expectation that they will receive iohexol for clinical care (i.e., Standard of Care [SOC]) during the study.
- •Prospective participant had a major surgery within one calendar day prior to enrollment.
- •Prospective participant had a recent (within 6 months) burn involving > 25% of total body surface area.
- •Prospective participant had a penetrating injury within one calendar day prior to enrollment.
- •Prospective participant is currently receiving or is expected to receive any type of renal replacement therapy including hemodialysis or extra corporeal membrane oxygenation, during study period.
- •Prospective participant has a documented diagnosis of diabetes with a serum creatinine (SCR) obtained for clinical care purposes (i.e., SOC results) >3 mg/dL during screening.
- •Prospective participant has documented severe thyrotoxicosis as noted in medical records during screening.
- •Prospective participant is homozygous for sickle cell disease as noted in medical history/records.
- •Prospective participant has a documented diagnosis of hepatorenal syndrome as noted in medical records during screening.
- •Prospective participant is anuric* for >/ = 1 calendar day during screening AND has any one of the following documented conditions as noted in medical history/records:
- •Pheochromocytoma
- •Myelomatosis
- •Multiple myeloma
- •Paraproteinemia *Anuria is defined as urine production <100 mL in a calendar day
- •Prospective participant is pregnant or breastfeeding.
- •Prospective participant received or is expected to receive albumin from one calendar day prior to enrollment to end of study period.
- •Prospective participant received or is expected to receive >/= 3 units of any blood product other than platelets from one calendar day prior to enrollment to end of study period.
- •Any condition that, in the judgment of the investigator, precludes participation because it could affect the prospective participant's safety.
研究组 & 干预措施
Arm 1
Adult patients in the ICU receiving either meropenem or cefepime as part of their clinical management will receive one dose of IV iohexol 1500 mgI (5 mL) via slow push administration on Study Days 1 and 2 prior to the start of first or second daily meropenem or cefepime dose. N=200
干预措施: Iohexol (Drug)
结局指标
主要结局
Akaike's information criterion (AIC) of cefepime
时间窗: Days 1-2
For PopPK models
Akaike's information criterion (AIC) of iohexol
时间窗: Days 1-2
For PopPK models
Akaike's information criterion (AIC) of meropenem
时间窗: Days 1-2
For PopPK models
Clearance (Cl) of cefepime
时间窗: Days 1-2
Clearance (Cl) of iohexol
时间窗: Days 1-2
Clearance (Cl) of meropenem
时间窗: Days 1-2
Intercompartment rate constant of cefepime
时间窗: Days 1-2
Intercompartment rate constant of iohexol
时间窗: Days 1-2
Intercompartment rate constant of meropenem
时间窗: Days 1-2
Objective function value (OFV) of cefepime
时间窗: Days 1-2
For PopPK models
Objective function value (OFV) of iohexol
时间窗: Days 1-2
For PopPK models
Objective function value (OFV) of meropenem
时间窗: Days 1-2
For PopPK models
Volume of distribution (Vd) of cefepime
时间窗: Days 1-2
Volume of distribution (Vd) of iohexol
时间窗: Days 1-2
Volume of distribution (Vd) of meropenem
时间窗: Days 1-2
Clearance (Cl)
时间窗: Days 1-2
Composite Euclidean distance score
时间窗: Days 1-2
Summarizes predictive precision, accuracy, and bias of the cefepime or meropenem renal function biomarker population pharmacokinetic (PopPK) model relative to the corresponding iohexol clearance PopPK model using the validation dataset.
Intercompartment rate constant
时间窗: Days 1-2
Volume of distribution (Vd)
时间窗: Days 1-2
次要结局
- Pharmacokinetic/pharmacodynamics (PK/PD) optimized meropenem and cefepime dosing schemes(Days 1-2)