Lam Kevin, Mondick John T, Peltz Gary, Wu Manhong, Kraft Walter K
Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
A2-Ai, Ann Arbor, Michigan, USA.
Clin Transl Sci. 2025 Feb;18(2):e70147. doi: 10.1111/cts.70147.
Ondansetron is an anti-emetic 5-HT3 receptor antagonist being investigated for treating neonatal opioid withdrawal syndrome (NOWS). Sparse PK data were analyzed from a multicenter, double-blind clinical trial with 98 mother/neonate dyads. Pregnant women with opioid use disorder were randomized to receive either placebo or ondansetron 8 mg intravenously within 4 h of delivery. Neonates born to mothers who were randomized to ondansetron received 0.07 mg/kg orally once every 24 h for up to five doses. Using current PK data, model parameters from a two-compartmental structural model from the literature (i.e., a priori model) were updated with the Metropolis-Hastings Markov-chain Monte Carlo estimation algorithm in NONMEM. The updated Bayesian model indicated a slower absorption rate (KA) but no differences in model parameters (CL, V, V2, Q) after including body weight and postmenstrual age. Sensitivity analyses on CL prior revealed statistical improvement favoring larger body weights, but not changes in postmenstrual age. However, further model development using larger body weights did not illustrate superior performance through visual inspection of diagnostic plots. Overall, a cumulative AUC of at least 1000 ng*h/mL appears to be the threshold for reductions in symptom severity. Exposure-response analyses suggest the total number of doses to be the primary driver for efficacy with respect to AUC, which reasonably aligns with the literature. Overall, it is suggested that at least three doses of the current oral ondansetron regimen are required to reduce symptom severity in neonates.
昂丹司琼是一种抗呕吐的5-羟色胺3（5-HT3）受体拮抗剂，目前正用于新生儿阿片类药物戒断综合征（NOWS）的治疗研究。我们从一项包含98对母婴的多中心双盲临床试验中分析了稀疏的药代动力学（PK）数据。患有阿片类药物使用障碍的孕妇在分娩后4小时内被随机分配接受安慰剂或静脉注射8毫克昂丹司琼。随机接受昂丹司琼治疗的母亲所生的新生儿每24小时口服0.07毫克/千克，最多服用五剂。利用当前的PK数据，采用文献中两室结构模型（即先验模型）的模型参数，在NONMEM中通过Metropolis-Hastings马尔可夫链蒙特卡罗估计算法进行更新。更新后的贝叶斯模型显示吸收速率（KA）较慢，但在纳入体重和月经后年龄后，模型参数（清除率CL、分布容积V、中央室分布容积V2、转运速率常数Q）没有差异。对CL先验值的敏感性分析显示，体重较大时在统计学上有改善，但月经后年龄没有变化。然而，通过对诊断图的目视检查，使用更大体重进行进一步的模型开发并没有显示出更好的数据表现。总体而言，至少1000纳克·小时/毫升的累积曲线下面积（AUC）似乎是症状严重程度降低的阈值。暴露-反应分析表明，就AUC而言，给药总剂量是疗效的主要驱动因素，这与文献报道合理相符。总体而言，建议至少使用三剂目前的口服昂丹司琼方案来减轻新生儿的症状严重程度。
