Oregon Health & Science University, Portland, OR, USA.
Rocky Mountain Poison and Drug Center, Denver, CO, USA.
Clin Toxicol (Phila). 2022 Oct;60(10):1113-1121. doi: 10.1080/15563650.2022.2114361. Epub 2022 Sep 15.
The introduction of delayed release formulations of acetaminophen (APAP) has created concern about the role of formulation in overdose. We examined the APAP overdose pharmacokinetic (PK) profiles to assess the role of dose, coingestants and formulation: immediate release (IR), extended release (ER), and modified release (MR) on APAP pharmacokinetic measures.
We collected by-subject APAP PK data: subject description, timed blood APAP concentrations, dose, and coingestants. We sought both overdose and randomized controlled trials (RCTs) for supratherapeutic doses involving ER or MR formulations. Data analysis and simulation used the non-linear mixed-effects modeling program NONMEM-version 7.4.
The final dataset comprised 3,033 [APAP] from 356 subjects and 15 sources including 3 RCTs (179 subjects receiving IR, 122 ER, 65 MR). The final population PK (PopPK) model was a linear 2-compartment model with first-order (oral) absorption. Covariate relationships included: APAP absorption rate and bioavailability decreased with increased oral dose ( < 0.00005) for all 3 formulations (MR > ER > IR). Post hoc analyses showed opioid coingestant increased exposure (area under the curve, AUC) by factor of 1.6. Simulations of 100 g vs 10 g doses for IR, ER and MR showed overdose of the ER formulation exhibits slower absorption and lower , overall exposure (AUC) is less than 80% of an equivalent dose of IR acetaminophen. The overall exposure for the MR formulation is less than 70% of an equivalent dose of IR.
Acetaminophen ER and MR formulations have slower absorption and decreased bioavailability leading to a lower and later than the IR formulation. These results have potential clinical implications because delayed absorption could confound use of the Rumack-Matthew nomogram by underestimating the severity of ingestion early in the course of treatment.
醋氨酚（APAP）延迟释放制剂的引入引起了人们对制剂在用药过量中的作用的关注。我们检查了 APAP 用药过量药代动力学（PK）谱，以评估剂量、共服药物和制剂（即：普通释放（IR）、延长释放（ER）和改良释放（MR））对 APAP 药代动力学指标的作用。
我们通过个体收集 APAP PK 数据：个体描述、定时血液 APAP 浓度、剂量和共服药物。我们寻找涉及 ER 或 MR 制剂的超治疗剂量的用药过量和随机对照试验（RCT）。数据分析和模拟使用非线性混合效应建模程序 NONMEM 版本 7.4。
最终数据集包含来自 356 名患者和 15 个来源的 3033 个 [APAP]，其中包括 3 个 RCT（179 名患者接受 IR，122 名患者接受 ER，65 名患者接受 MR）。最终的群体 PK（PopPK）模型是一个具有一级（口服）吸收的线性 2 室模型。协变量关系包括：对于所有 3 种制剂（MR > ER > IR），APAP 吸收速率和生物利用度随口服剂量的增加而降低（ < 0.00005）。事后分析表明，阿片类药物共服药物使暴露（曲线下面积，AUC）增加了 1.6 倍。对于 IR、ER 和 MR 的 100 g 与 10 g 剂量的模拟显示，ER 制剂的用药过量表现出较慢的吸收和较低的 AUC，总暴露（AUC）低于 IR 乙酰氨基酚等效剂量的 80%。MR 制剂的总暴露低于 IR 乙酰氨基酚等效剂量的 70%。
醋氨酚 ER 和 MR 制剂的吸收较慢，生物利用度降低，导致与 IR 制剂相比，AUC 较低且出现较晚。这些结果具有潜在的临床意义，因为延迟吸收可能会通过在治疗早期低估摄入的严重程度而低估 Rumack-Matthew 列线图的使用。
