Medical City Childrens Hospital, Dallas, Texas 75230, USA.
Clin Pharmacokinet. 2011 Jun;50(6):405-14. doi: 10.2165/11587030-000000000-00000.
Immunoglobulin replacement is a standard therapy for patients with primary immunodeficiencies. Subcutaneous administration of immunoglobulin offers more constant IgG levels than intravenous administration and simplifies administration for some patients. Use of L-proline as an excipient contributes to the stability of highly concentrated IgG preparations. The aims of the present study were to evaluate the pharmacokinetics of IgPro20 (Hizentra®), a new 20% subcutaneous IgG solution, and compare the area under the serum concentration-time curve (AUC) with that of a similar intravenous 10% IgG solution (IgPro10; Privigen®). At the request of the US FDA, an algorithm for determining IgG trough level ratios (TLRs) was developed in order to provide physicians with a practical tool for monitoring doses during steady-state IgPro20 therapy.
This was a prospective, open-label, multicentre, single-arm, phase III clinical trial conducted in the US. The study was performed in a primary-care setting. Eligible patients were males or females aged 6-75 years with a primary immunodeficiency (common variable immunodeficiency or X-linked agammaglobulinaemia) who had received regular treatment with IgPro10 for at least 3 months prior to entering this study and had achieved serum trough concentration (C(trough)) values ≥5 g/L. IgPro20 was administered subcutaneously once weekly at initial doses equivalent to 130% of patients' previous doses, based on the results obtained in a Vivaglobin® study and due to an FDA request. After run-in, each patient's dose was adjusted to achieve an AUC comparable to that achieved with IgPro10 administered intravenously.
Eighteen patients completed the study. Mean IgPro20 : IgPro10 dose ratio (dose adjustment coefficient) was 1.53 (range 1.26-1.87). The resulting mean AUCs were 105.6 g · day/L for IgPro20 versus 103.2 g · day/L for IgPro10 (geometric mean ratio 1.002; lower one-sided 95% confidence limit [CL] 0.951). Thus, the primary endpoint of the study was met, as this result exceeded the pre-specified criterion of the lower one-sided 95% CL of ≥0.8 for non-inferiority. At these AUCs, which were considered equivalent, the mean IgPro20 : IgPro10 TLR, determined by the developed algorithm, was 1.29 (range 1.18-1.73). Titres of specific antibodies tested were well above respective product specifications, suggesting that protection against infection would be effective.
Steady-state AUCs with subcutaneous IgPro20 and intravenous IgPro10 were equivalent. Mean dose adjustment coefficient and mean TLR can be used for initial dose conversion without risk of under-protection but vary too widely to be considered measures of equivalence. Trial registration number (clinicaltrials.gov): NCT00419341.
免疫球蛋白替代疗法是治疗原发性免疫缺陷症患者的标准疗法。与静脉给药相比，皮下给药可使 IgG 水平更稳定，并且使某些患者的给药更简便。使用 L-脯氨酸作为赋形剂有助于提高高浓度 IgG 制剂的稳定性。本研究的目的是评估新型 20%皮下 IgG 溶液 IgPro20（Hizentra®）的药代动力学，并比较其血清浓度-时间曲线下面积（AUC）与类似的静脉内 10% IgG 溶液（IgPro10；Privigen®）的 AUC。应美国 FDA 的要求，开发了一种 IgG 谷浓度比值（TLR）测定算法，以便为医生在 IgPro20 稳态治疗期间监测剂量提供一种实用工具。
这是一项在美国进行的前瞻性、开放性、多中心、单臂、III 期临床试验。该研究在初级保健环境中进行。符合条件的患者为年龄 6-75 岁的男性或女性，患有原发性免疫缺陷症（普通变异性免疫缺陷或 X 连锁无丙种球蛋白血症），在入组前至少接受过 3 个月的 IgPro10 常规治疗，且血清谷浓度（C(trough)）值≥5 g/L。根据 Vivaglobin®研究结果，并应 FDA 的要求，皮下给予 IgPro20 初始剂量，相当于患者先前剂量的 130%。在洗脱期后，根据 AUC 结果调整每位患者的剂量，使其与静脉内给予 IgPro10 相当。
18 名患者完成了研究。IgPro20：IgPro10 剂量比（剂量调整系数）的均值为 1.53（范围 1.26-1.87）。由此产生的 AUC 均值分别为 IgPro20 的 105.6 g·day/L 和 IgPro10 的 103.2 g·day/L（几何均数比 1.002；下限单侧 95%置信区间[CL]0.951）。因此，研究的主要终点达到，因为这一结果超过了非劣效性的下限单侧 95%CL 下限≥0.8 的预设标准。在这些被认为等效的 AUC 下，通过开发的算法确定的 IgPro20：IgPro10 TLR 的均值为 1.29（范围 1.18-1.73）。经测试的特异性抗体效价均远高于各自的产品规格，表明抗感染的保护作用将是有效的。
皮下给予 IgPro20 和静脉内给予 IgPro10 的稳态 AUC 是等效的。平均剂量调整系数和平均 TLR 可用于初始剂量转换，而不会有保护不足的风险，但变化范围太广，不能作为等效性的衡量标准。试验注册号（clinicaltrials.gov）：NCT00419341。
