Amikacin Pharmacokinetics to Optimize Dosing Recommendations and Patho(Physiological) Considerations in Neonates With Perinatal Asphyxia Treated With Hypothermia
试验速览
- 阶段
- 不适用
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Maximum Plasma Concentration [Cmax]
研究概览
简要总结
As a part of a project on perinatal clinical pharmacology, the primary aim of the present project is to study amikacin pharmacokinetics (PK) and physiology in asphyxiated neonates treated with therapeutic hypothermia and to provide amikacin dosing recommendations, which will be validated prospectively. For this purpose, we aim to first collect retrospective data on amikacin available in neonates treated with hypothermia in the neonatal intensive care unit (NICU)s in Leuven and Amsterdam, and consequently to propose the dosing regimen to be used in the prospective amikacin PK study at our NICU in University Clinical Center (UCC) Sarajevo. At our NICU we aim to collect amikacin PK observations and other covariates in at least 40 neonates while treated with hypothermia and after re-warming period (a paired analysis), and in asphyxiated neonates not treated with hypothermia (control group).
We hereby will use a stepwise approach, as initially used to develop and to validate an amikacin dosing regimen in preterm and term neonates (De Cock RFW et al., 2012, Smits A et al, 2015).
A 3-step approach will be used, of which different parts will be conducted in different contributing hospitals:
- Retrospective evaluation of amikacin therapeutic drug monitoring (TDM) in asphyxiated neonates treated with hypothermia (University hospital Leuven, VUmc Amsterdam)
- Development of population PK model derived amikacin dosing recommendation
- Prospective PK study with validation of the new dosing regimen (UCC Sarajevo, UCC Tuzla)
详细描述
Step 1: Retrospective evaluation of amikacin TDM in asphyxiated neonates treated with hypothermia (University hospital Leuven, VUmc Amsterdam)
1.1 Study patients All neonates admitted to the NICUs of the VUmc Amsterdam and University hospital Leuven who underwent treatment with hypothermia for perinatal asphyxia and who received amikacin during routine care were considered for inclusion in this retrospective analysis if TDM observations were available. Patients hospitalized between January 2010 and December 2015 were eligible for inclusion. Neonates already included in the Pharmacool trial (de Haan et al BMC Pediatrics 2012), were excluded.
Clinical characteristics at birth [gestational age (GA, weeks), birth bodyweight (grams), Apgar score at 1, 5 and 10 minutes after birth, as well as characteristics at the moment of amikacin TDM [postmenstrual age (PMA, weeks), postnatal age (PNA, days), current bodyweight (grams), concurrent ibuprofen (yes/no) or inotropic drugs (yes/no), respiratory support (i.e. continuous positive airway pressure or mechanical ventilation, yes/no), mechanical ventilation (conventional or high-frequency, yes/no) were retrospectively extracted from the patient files. Additionally, blood culture results at the start of amikacin therapy were collected from the individual laboratory reports. The daily nursing progress reports were used to collect amikacin prescription (dose and interval) data.
1.2 Amikacin dosing regimen
- University hospital Leuven: Up to July 2011, amikacin dosing was based on Langendries JP et al, 1998. Since July 2011, the simplified model-based dosing regimen published by De Cock RFM et al, 2012) was used. Since July 2014, an adapted dosing regimen based on prospective validation is applied (Smits A et al, 2015). In both regimens, the dosing interval was prolonged with 10 hours when ibuprofen was co-administered or when asphyxia was diagnosed/considered by the treating physician.
- Vumc Amsterdam: Up to 24 March 2015 amikacin dosing was 12 mg/kg/dose. Interval (24 hours or 36 hours) was determined based on TDM value and subsequent clearance calculation (see below). From 24 March 2015 amikacin dosing was 15 mg/kg/dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 1 Day（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion criteria for hypothermia group (University Clinical Centre Sarajevo)
- •signed parental informed written consent
- •newborn with GA ≥36 weeks
- •newborn to whom amikacin is administered by intravenous route for clinical indications
- •newborn with perinatal asphyxia treated with hypothermia
- •Inclusion criteria for control group (University Clinical Centre Tuzla)
- •signed parental informed written consent
- •newborn to whom amikacin is administered by intravenous route for clinical indications
- •newborn with GA ≥36 weeks
- •newborn with perinatal asphyxia defined following Bristol hypothermia protocol from 2015
- •Apgar score of ≤5 at 10 minutes after birth OR
- •Continued need for resuscitation, including endotracheal or mask ventilation, at 10 min after birth OR
- •Acidosis defined as either umbilical cord pH or any arterial, venous or capillary pH within 60 min of birth pH<7.00 OR
- •Base deficit ≥-16 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood)
- •Non-inclusion criteria for both groups
- •no parental informed consent
- •the presence of congenital hepatic or renal pathology
- •no central venous or arterial line in situ for non-invasive blood sampling procedures
- •Exclusion criteria for both groups
- •parental informed consent withdrawal
- •the occurrence of clinical reasons to stop blood sampling
排除标准
- 未提供
研究组 & 干预措施
asphyxiated neonates treated with amikacin and hypothermia
Amikacin (Likacin®; 500 mg/2mL vial; Lisapharma S.p.A., Erba, Italy) is given to the neonate, as an IV infusion via umbilical vein over 20 min by use of a syringe-pump (Braun; B. Braun Medical Inc., Bethlehem, PA USA). Infusion is followed by slow 0.5 mL Sodium chloride 0.9% flush.
干预措施: Amikacin (Drug)
asphyxiated neonates treated with amikacin
Amikacin (Likacin®; 500m g/2mL vial; Lisapharma S.p.A., Erba, Italy) is given to the neonate, as an IV infusion via umbilical vein over 20 min by use of a syringe-pump (Braun; B. Braun Medical Inc., Bethlehem, PA USA). Infusion is followed by slow 0.5 mL Sodium chloride 0.9% flush.
干预措施: Amikacin (Drug)
结局指标
主要结局
Maximum Plasma Concentration [Cmax]
时间窗: 5 years
the first plasma concentration measured after the dosing
Minimum Plasma concentration (Ctrough)
时间窗: 5 years
the last plasma concentration measured after the dosing
Area under the plasma concentration versus time curve (AUC)
时间窗: 5 years
Area under the plasma concentration versus time curve calculated based on a trapezoidal rule
Volume of distribution (Vd)
时间窗: 5 years
Volume of distribution of the drug, seen from the early part of the concentration-time curve
Minumum inhibitory concentration (MIC 90)
时间窗: 5 years
concentration of the drug needed to inhibit the growth of 90% of isolates
Creatinine clearance
时间窗: 5 years
clearance of the creatinine calculated by different formulas
Clearance (CL)
时间窗: 5 years
Clearance of the drug, seen from the last part of the concentration-time curve
次要结局
- adverse effects of hypothermia(5 years)
研究者
Sabina Terzic
MD PhD, Assistant professor
University of Sarajevo