Sunovion Pharmaceuticals Inc, Fort Lee, New Jersey, USA.
Ann Arbor Pharmacometrics Group, Inc, Ann Arbor, Michigan, USA.
Clin Transl Sci. 2021 Jul;14(4):1464-1475. doi: 10.1111/cts.13008. Epub 2021 May 2.
Apomorphine is an on-demand treatment of "OFF" episodes in patients with Parkinson's disease (PD). A joint parent-metabolite population pharmacokinetic (PK) model characterized apomorphine and apomorphine-sulfate following administration of apomorphine sublingual film (APL) and two formulations of subcutaneous apomorphine. Overall, 2485 samples from 87 healthy subjects and 71 patients with PD and "OFF" episodes were analyzed using nonlinear mixed-effects modeling. Apomorphine PK was adequately described by a two-compartment model with first-order transit absorption via both routes of administration and first-order metabolism to apomorphine-sulfate with one-compartment disposition and first-order elimination. Bioavailability of apomorphine sublingual film was ~ 18% relative to subcutaneous apomorphine. Among covariates tested, only body weight had a large effect on apomorphine exposure (maximum plasma concentration and area under the concentration-time curve [AUC ]), with greater weight resulting in lower exposure. Model-predicted apomorphine exposure was similar between apomorphine sublingual film 30 mg and subcutaneous apomorphine 5 mg (median AUC , 66.7 ng•h/mL, geometric mean ratio of 0.99; 90% confidence interval [CI], 0.96-1.03) and was comparable between apomorphine sublingual film 35 mg and subcutaneous apomorphine 6 mg (median AUC , 75.4 and 80.0 ng•h/mL, respectively; geometric mean ratio of 0.94; 90% CI, 0.90-0.97) administered every 2 h for a maximum of 5 doses per day. In a typical patient with PD, predicted apomorphine exposure increased with increasing doses of apomorphine sublingual film; however, the increase was less than dose proportional. Similar apomorphine exposure was predicted in patients with mild renal impairment versus normal renal function. PK properties of apomorphine sublingual film support its administration for a wide range of patients with PD and "OFF" episodes, regardless of demographic and clinical characteristics.
阿扑吗啡是一种按需治疗帕金森病（PD）患者“OFF”期的药物。一项联合母体-代谢物群体药代动力学（PK）模型，对舌下膜给药的阿扑吗啡和两种皮下阿扑吗啡制剂的阿扑吗啡和阿扑吗啡硫酸盐进行了特征描述。总共分析了 87 名健康受试者和 71 名 PD 伴“OFF”期患者的 2485 个样本，采用非线性混合效应模型进行分析。阿扑吗啡 PK 可以通过两种给药途径的一级转运吸收和一级代谢为阿扑吗啡硫酸盐的两室模型来很好地描述，而阿扑吗啡硫酸盐的一室分布和一级消除。舌下膜给药的阿扑吗啡相对皮下阿扑吗啡的生物利用度约为 18%。在测试的协变量中，只有体重对阿扑吗啡暴露量（最大血浆浓度和浓度-时间曲线下面积[AUC]）有较大影响，体重越大，暴露量越低。模型预测的阿扑吗啡暴露量在阿扑吗啡舌下膜 30mg 和皮下阿扑吗啡 5mg 之间相似（AUC中位数，66.7ng·h/mL，几何均数比为 0.99；90%置信区间[CI]，0.96-1.03），在阿扑吗啡舌下膜 35mg 和皮下阿扑吗啡 6mg 之间也相似（AUC中位数，75.4ng·h/mL 和 80.0ng·h/mL，几何均数比为 0.94；90%CI，0.90-0.97），每天最多 5 剂，每 2 小时给药一次。在一名典型的 PD 患者中，随着阿扑吗啡舌下膜剂量的增加，预测的阿扑吗啡暴露量增加；然而，增加量小于剂量比例。在轻度肾功能不全和正常肾功能的患者中，预测的阿扑吗啡暴露量相似。阿扑吗啡舌下膜的 PK 特性支持其在广泛的 PD 伴“OFF”期患者中使用，无论患者的人口统计学和临床特征如何。
