External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole.
External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole.
复制标题
口服甲氧苄啶和磺胺甲恶唑的两种儿童群体药代动力学模型的外部评价。
DOI：
10.1128/aac.02149-20
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发表时间：
2021
影响因子：
4.9
通讯作者：
BestPharmaceuticalsforChildrenAct—PediatricTrialsNetworkSteeringCommittee
中科院分区：
文献类型：
--
作者：
Wu,YiShuanS;Cohen-Wolkowiez,Michael;Hornik,ChristophP;Gerhart,JacquelineG;Autmizguine,Julie;Cobbaert,Marjan;Gonzalez,Daniel;BestPharmaceuticalsforChildrenAct—PediatricTrialsNetworkSteeringCommittee
抗生素复方甲氧苄啶（TMP）-磺胺甲恶唑（SMX）具有广谱活性，用于治疗多种感染，但儿科药代动力学（PK）数据有限。我们先前发表了基于稀疏机会主义收集的数据（POPS研究）的儿科患者口服TMP-SMX的群体PK（popPK）模型（J. Autmizguine，C.梅洛尼角P. Hornik，S. Dallefeld等人，Antimicrob Agents Chemother 62：e01813-17，2017，https：//doi.org/10.1128/AAC.01813-17）。我们在婴儿和儿童中进行了一项单独的口服TMP-SMX PK研究，采用更传统的PK样本采集，并使用该外部数据集独立开发了新的TMP-SMX popPK模型。POPS数据集和外部数据集分别用于评价两个popPK模型。外部TMP模型的模型和误差结构与POPS TMP模型相同，PK参数的典型值在20%以内。外部SMX模型未将POPS SMX模型中的协变量确定为显著。外部popPK模型预测TMP暴露量较高（POPS数据集的中值过度预测为0.13 mg/L，外部数据集的中值过度预测为0.061 mg/L）和SMX（中位数超预测1.7毫克/升和0.90毫克/升）比POPS TMP（中值预测不足0.016毫克/升和0.39毫克/升）和SMX（中值预测不足1.2毫克/升和14毫克/升）模型。尽管如此，两种模型都支持婴儿和幼儿增加TMP-SMX剂量，以对抗MIC为1 mg/L的耐药病原体，尽管基于外部模型的所需剂量增加较低。(The POPS和外部研究已分别在ClinicalTrials.gov注册，注册号为NCT 01431326和NCT 02475876。）
The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study) (J. Autmizguine, C. Melloni, C. P. Hornik, S. Dallefeld, et al., Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more-traditional PK sample collection and independently developed new popPK models of TMP-SMX using this external data set. The POPS data set and the external data set were each used to evaluate both popPK models. The external TMP model had a model and error structure identical to those of the POPS TMP model, with typical values for PK parameters within 20%. The external SMX model did not identify the covariates in the POPS SMX model as significant. The external popPK models predicted higher exposures to TMP (median overprediction of 0.13 mg/liter for the POPS data set and 0.061 mg/liter for the external data set) and SMX (median overprediction of 1.7 mg/liter and 0.90 mg/liter) than the POPS TMP (median underprediction of 0.016 mg/liter and 0.39 mg/liter) and SMX (median underprediction of 1.2 mg/liter and 14 mg/liter) models. Nonetheless, both models supported TMP-SMX dose increases in infants and young children for resistant pathogens with a MIC of 1 mg/liter, although the required dose increase based on the external model was lower. (The POPS and external studies have been registered at ClinicalTrials.gov under registration no. NCT01431326 and NCT02475876, respectively.)