Background

Therapeutic hypothermia (TH) is the treatment of choice for neonates diagnosed with perinatal asphyxia (PA). Dosing recommendations of various therapeutic agents including antimicrobials were not specifically available for the neonates undergoing TH.

Methods

A systematic search methodology was used to identify pharmacokinetic (PK) studies of antimicrobials during TH. Antimicrobials with multiple PK studies were identified to create a generalizable PK model. Pharmacometric simulations were performed using the PUMAS software platform to reproduce the results of published studies. A suitable model that could reproduce the results of all other published studies was identified. With the help of a generalizable model, an optimal dosage regimen was designed considering the important covariates of the identified model.

Results

With the systematic search, only gentamicin had multiple PK reports during TH. A generalizable model was identified and the model predictions could match the reported/observed concentrations of publications. Birth weight and serum creatinine were the significant covariates influencing the PK of gentamicin in neonates. A dosage nomogram was designed using pharmacometric simulations to maintain gentamicin concentrations below 10 μg/mL at peak and below 2 μg/mL at trough.

Conclusions

A generalizable PK model for gentamicin during TH in neonates was identified. Using the model, a dosing nomogram for gentamicin was designed.

Impact

• Dosing guidelines for antimicrobials during TH in neonates is lacking.

• This is the first study to identify the generalizable model for gentamicin during TH in neonates.

• Nomogram, proposed in the study, will aid the clinicians to individualize gentamicin dosing regimen for neonates considering the birth weight and serum creatinine.

中文翻译：

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辅助低温治疗新生儿给药方案设计的药理学方法

背景

治疗性低温 (TH) 是诊断为围产期窒息 (PA) 新生儿的首选治疗方法。包括抗微生物剂在内的各种治疗剂的剂量建议并未专门用于接受 TH 的新生儿。

方法

使用系统搜索方法来确定 TH 期间抗菌药物的药代动力学 (PK) 研究。确定了具有多项 PK 研究的抗菌药物，以创建可推广的 PK 模型。使用 PUMAS 软件平台进行药理学模拟，以重现已发表研究的结果。确定了一个可以重现所有其他已发表研究结果的合适模型。在可推广模型的帮助下，考虑到已识别模型的重要协变量，设计了最佳剂量方案。

结果

通过系统搜索，只有庆大霉素在 TH 期间有多个 PK 报告。确定了一个可推广的模型，模型预测可以匹配报告/观察到的出版物浓度。出生体重和血清肌酐是影响新生儿庆大霉素PK的显着协变量。使用药理学模拟设计剂量列线图，以保持庆大霉素浓度峰值低于 10 μg/mL，谷值低于 2 μg/mL。

结论

确定了新生儿 TH 期间庆大霉素的可推广 PK 模型。使用该模型，设计了庆大霉素的剂量列线图。

影响

• 缺乏新生儿 TH 期间抗菌药物的剂量指南。

• 这是第一项确定新生儿 TH 期间庆大霉素可推广模型的研究。

• 研究中提出的列线图将帮助临床医生根据出生体重和血清肌酐对新生儿的庆大霉素给药方案进行个体化。