Bardol Maddlie, Norman Elisabeth, Lagercrantz Hugo, Fellman Vineta, Standing Joseph F
Institute of Child Health, University College London, London, UK.
Pharmetheus AB, Paris, France.
Pediatr Res. 2025 Jan;97(1):239-245. doi: 10.1038/s41390-024-03404-z. Epub 2024 Jul 18.
Fentanyl is commonly administered for procedural pain management in preterm infants, but target concentrations have not yet been defined.
To investigate pharmacokinetics (PK), -dynamics (PD), and -genetics (PG), 25 infants (gestational age 23.3-34.1 weeks) received a fentanyl dose before a skin-breaking procedure (0.5 µg/kg) or tracheal intubation (2 µg/kg). Four pain scales were used as a PD endpoint to evaluate efficacy. The impact of polymorphism in genes encoding enzymes (UGT2B7, CYP3A7, CYP3A4, COMT, CYP2D6, KCNJ6), transporters (SLC22A1, ABCC1, ABCC3) and receptor (OPRM1) on PK parameters was explored.
A two-compartment PK model adequately described the fentanyl concentration. The effects of weight and maturity on the clearance were included as covariates in the model. One genetic variant encoding the ABCC1 transporter (rs111517339 T/TA) and two encoding the ABCC3 transporter (rs11079921 T/C and rs8077268 C/T) had a significant effect on fentanyl elimination that explained 15% of the interindividual variability on the clearance. A proportional odds PK/PD model was used to describe the concentration-effect relationship of fentanyl using the Échelle de douleur et d'inconfort du nouveau-né (EDIN) pain score.
The simulations suggest that an intravenous dose of 2 µg/kg would be appropriate in preterm infants for a clearly painful procedure, such as an intubation.
Design of personalized analgesia with fentanyl for newborn infants should consider maturation and genetic variants of opioid transporters affecting drug elimination. The results indicate that an intravenous dose of 2 μg/kg fentanyl would be suitable before a clearly painful procedure in preterm infants. Genetic variants encoding ABCC1 and ABCC3 transporters increase the clearance of fentanyl, which is a novel finding.
芬太尼常用于早产儿程序性疼痛管理，但尚未确定目标浓度。
为研究药代动力学（PK）、药效动力学（PD）和药物遗传学（PG），25名婴儿（胎龄23.3 - 34.1周）在进行破皮操作（0.5μg/kg）或气管插管（2μg/kg）前接受了芬太尼剂量。使用四种疼痛量表作为PD终点来评估疗效。探讨了编码酶（UGT2B7、CYP3A7、CYP3A4、COMT、CYP2D6、KCNJ6）、转运体（SLC22A1、ABCC1、ABCC3）和受体（OPRM1）的基因多态性对PK参数的影响。
二室PK模型能充分描述芬太尼浓度。体重和成熟度对清除率的影响作为协变量纳入模型。一个编码ABCC1转运体的基因变体（rs111517339 T/TA）和两个编码ABCC3转运体的基因变体（rs11079921 T/C和rs8077268 C/T）对芬太尼消除有显著影响，解释了清除率个体间变异性的15%。使用新生儿疼痛和不适量表（EDIN）疼痛评分，采用比例优势PK/PD模型描述芬太尼的浓度 - 效应关系。
模拟结果表明，对于早产儿进行如插管等明显疼痛的操作，静脉注射2μg/kg的剂量是合适的。
为新生儿设计个性化芬太尼镇痛方案时应考虑成熟度和影响药物消除的阿片类转运体基因变体。结果表明，在早产儿进行明显疼痛操作前，静脉注射2μg/kg芬太尼是合适的。编码ABCC1和ABCC3转运体的基因变体增加了芬太尼的清除率，这是一个新发现。
