Pfiffner Miriam, Berger-Olah Eva, Vonbach Priska, Pfister Marc, Gotta Verena
Hospital Pharmacy, University Children's Hospital Zurich, Zurich, Switzerland.
Emergency Unit, University Children's Hospital Zurich, Zurich, Switzerland.
Front Pediatr. 2022 Mar 2;10:837492. doi: 10.3389/fped.2022.837492. eCollection 2022.
The objective of this pharmacometric (PMX) study was to (i) characterize population pharmacokinetics (PPK) and exposure-pain response associations following intranasal (0.1 mg/kg) or intravenous (IV, 0.05 mg/kg) administration of nalbuphine, with the goal to (ii) evaluate strategies for optimized dosing and timing of painful interventions in infants 1-3 months old.
PPK analysis of nalbuphine serum concentrations, prospectively collected 15, 30, and between 120 and 180 min post-dose, utilizing the software package Monolix. The final PPK model was applied to derive individual time-matched concentration predictions for each pain assessment (Neonatal Infant Pain Score, NIPS) after establishment of venous access and urinary catheterization or lumbar puncture. Drug exposure-pain response simulations were performed to evaluate potential benefits of higher doses with respect to a previously proposed target concentration of 12 mcg/L (efficacy threshold).
Thirty-eight of 52 study subjects receiving nalbuphine had at least one concentration measurement and were included in the pharmacometric analysis. A two-compartment model with allometric scaling was applied to describe population PK data, with intranasal bioavailability estimated to be 41% (95%CI: 26-56%). Model-based simulations showed that the proposed efficacy threshold (12 mcg/L) is expected to be exceeded with an IV dose of 0.05 mg/kg for 6 min, with 0.1 mg/kg for 30 min and with 0.2 mg/kg for 80 min. This efficacy threshold is not achieved with intranasal doses of 0.1 and 0.2 mg/kg, whereas an intranasal dose of 0.4 mg/kg is expected to exceed such threshold for 30 to 100 min.
This PMX study confirmed that bioavailability of intranasal nalbuphine is close to 50%. Exposure-pain response simulations indicated that an intranasal dose of 0.4 mg/kg is required to provide a comparable pain control as achieved with an IV dose of 0.1-0.2 mg/kg. The optimal time window for painful procedures appears to be within the first 30 min after IV administration of 0.1 mg/kg nalbuphine, whereas such procedures should be scheduled 30 min after an intranasal dose of 0.4 mg/kg nalbuphine. Additional clinical studies are warranted to confirm these PMX based recommendations and to further optimize pain management in this vulnerable infant population.
本药物计量学（PMX）研究的目的是：（i）描述纳布啡经鼻（0.1mg/kg）或静脉（IV，0.05mg/kg）给药后的群体药代动力学（PPK）及暴露-疼痛反应关联，目标是（ii）评估1至3个月大婴儿疼痛干预的优化给药策略和时机。
利用Monolix软件包对纳布啡血清浓度进行PPK分析，前瞻性收集给药后15、30以及120至180分钟之间的样本。最终的PPK模型用于在建立静脉通路和插入导尿管或进行腰椎穿刺后，为每次疼痛评估（新生儿婴儿疼痛评分，NIPS）推导个体时间匹配的浓度预测值。进行药物暴露-疼痛反应模拟，以评估相对于先前提出的12μg/L目标浓度（疗效阈值）较高剂量的潜在益处。
52名接受纳布啡治疗的研究对象中有38名至少进行了一次浓度测量，并纳入药物计量学分析。采用具有异速生长比例的二室模型描述群体PK数据，经鼻生物利用度估计为41%（95%CI：26 - 56%）。基于模型的模拟显示，静脉注射0.05mg/kg可在6分钟内超过提议的疗效阈值（12μg/L），0.1mg/kg为30分钟，0.2mg/kg为80分钟。经鼻给药0.1mg/kg和0.2mg/kg未达到该疗效阈值，而经鼻给药0.4mg/kg预计可在30至100分钟内超过该阈值。
本PMX研究证实经鼻纳布啡的生物利用度接近50%。暴露-疼痛反应模拟表明，需要经鼻给药0.4mg/kg才能提供与静脉注射0.1 - 0.2mg/kg相当的疼痛控制。静脉注射0.1mg/kg纳布啡后，疼痛操作的最佳时间窗似乎在前30分钟内，而经鼻给药0.4mg/kg纳布啡后，此类操作应安排在30分钟后。需要进一步的临床研究来证实这些基于PMX的建议，并进一步优化这一脆弱婴儿群体的疼痛管理。
