Halozyme Therapeutics, Inc, San Diego, California.
Halozyme Therapeutics, Inc, San Diego, California.
Clin Ther. 2014 Feb 1;36(2):211-24. doi: 10.1016/j.clinthera.2013.12.013. Epub 2014 Jan 31.
Subcutaneous ondansetron facilitated by recombinant human hyaluronidase PH20 (rHuPH20) is an alternative for treating nausea/vomiting in patients who cannot receive ondansetron by other routes of administration.
Based on preclinical results in minipigs, a Phase I study was designed to assess the tolerability and pharmacokinetic properties of subcutaneous ondansetron + rHuPH20 compared with intramuscular, intravenous, or oral ondansetron monotherapy in healthy volunteers.
In a crossover design, 3 minipigs were dosed with subcutaneous ondansetron 0.08 mg/kg + rHuPH20, or as intramuscular or intravenous monotherapy, for the evaluation of plasma ondansetron concentrations and local tolerability. In a randomized, open-label, 4-way crossover study, subjects received a randomized sequence of SC ondansetron 4 mg + rHuPH20, or ondansetron monotherapy IM (4 mg), IV (4 mg), or PO (8 mg), over 4 daily visits. Study participants included healthy volunteers aged 19 to 65 years with adequate venous access in both upper extremities and no history of QT-interval prolongation. Primary tolerability end points (administration-site observations, systemic adverse events [AEs], and subject-assessed pain) were assessed, and pharmacokinetic parameters (AUC, Cmax, Tmax, t½) were computed to compare relative rate and extent of systemic exposure. Results were described using summary statistics, and bioequivalence was determined with a linear mixed-effects model.
In the preclinical study, no adverse events or significant local reactions were observed. The Cmax (45.8 ng/mL at 0.08 hour) with subcutaneous administration + rHuPH20 was 83% greater and was achieved 68% faster than with intramuscular administration (Cmax = 25 ng/mL at 0.25 hour). In the clinical study, a total of 12 subjects (7 women, 5 men; white majority; mean age, 44.8) were randomized. The majority of AEs were at the injection site, mild in severity, and transient. After subcutaneous administration of ondansetron + rHuPH20, geometric mean Cmax was 35% higher than with intramuscular ondansetron, 43% lower than with intravenous ondansetron, and 126% higher than with oral ondansetron (corrected for dose). Bioequivalence tests demonstrated that systemic exposure after subcutaneous administration was similar to that after intramuscular or intravenous administration and significantly greater than that after oral administration.
Subcutaneous ondansetron + rHuPH20 was generally well-tolerated. Subcutaneous dosing resulted in an extent of systemic exposure similar to that with intramuscular or intravenous dosing and greater than that with oral administration, and may be an option for clinical administration of ondansetron. ClinicalTrials.gov identifier: NCT01572012.
通过重组人透明质酸酶 PH20（rHuPH20）辅助的皮下昂丹司琼是治疗不能通过其他途径给予昂丹司琼的患者恶心/呕吐的替代方法。
基于小型猪的临床前研究结果，一项 I 期研究旨在评估健康志愿者中皮下昂丹司琼+ rHuPH20 与肌内、静脉或口服昂丹司琼单药治疗的耐受性和药代动力学特性。
在交叉设计中，3 只小型猪接受皮下昂丹司琼 0.08mg/kg+ rHuPH20 治疗，或作为肌内或静脉单药治疗，以评估血浆昂丹司琼浓度和局部耐受性。在一项随机、开放标签、4 向交叉研究中，受试者接受了随机顺序的 SC 昂丹司琼 4mg+ rHuPH20 或昂丹司琼单药肌内（4mg）、静脉（4mg）或口服（8mg）治疗，共 4 天。研究参与者包括年龄在 19 至 65 岁之间、上肢有足够静脉通路且无 QT 间期延长史的健康志愿者。主要耐受性终点（给药部位观察、全身不良事件 [AE]和受试者评估的疼痛）进行评估，并计算药代动力学参数（AUC、Cmax、Tmax、t½）以比较全身暴露的相对速率和程度。结果使用总结统计数据描述，并使用线性混合效应模型确定生物等效性。
在临床前研究中，未观察到不良事件或明显的局部反应。皮下给药+ rHuPH20 的 Cmax（0.08 小时时为 45.8ng/mL）比肌内给药高 83%（Cmax=0.25 小时时为 25ng/mL），且达峰时间快 68%。在临床研究中，共有 12 名受试者（7 名女性，5 名男性；以白人为主；平均年龄 44.8 岁）被随机分组。大多数不良事件发生在注射部位，程度轻微且为一过性。皮下给予昂丹司琼+ rHuPH20 后，几何平均 Cmax 比肌内昂丹司琼高 35%，比静脉昂丹司琼低 43%，比口服昂丹司琼高 126%（校正剂量）。生物等效性检验表明，皮下给药后的全身暴露与肌内或静脉给药后的全身暴露相似，且明显高于口服给药后的全身暴露。
皮下昂丹司琼+ rHuPH20 一般耐受性良好。皮下给药导致的全身暴露程度与肌内或静脉给药相似，大于口服给药，可能是昂丹司琼临床给药的一种选择。临床试验注册：NCT01572012。
