From the Department of Pharmacology (F.B., E.E.), University of Gothenburg; Neurology (F.B.), Sahlgrenska University Hospital, Göteborg; Department of Pharmaceutical Biosciences (M.E.), Uppsala University; Pharm Assist Sweden AB (M.E.), Uppsala; Department of Neuroscience (D.N.), Uppsala University; Department of Clinical Neurosciences (A.J., P.S.), Karolinska Institutet (A.J., P.S.), Solna; Department of Biomedical and Clinical Sciences (F.L., N.D.), Linköping University (F.L., N.D.); Neurology (P.O.), Department of Clinical Sciences, Lund University; CTC Clinical Trial Consultants AB (F.H.), Uppsala; and Dizlin Pharmaceuticals (L.B.) Gothenburg, Sweden.
Neurology. 2022 Sep 5;99(10):e965-e976. doi: 10.1212/WNL.0000000000200804.
Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson disease. The primary objective of this trial was to investigate whether continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady-state plasma concentrations of levodopa that are equivalent in magnitude, and noninferior in variability, to those obtained with LCIG in patients with advanced Parkinson disease.
A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved LCIG in a randomized, 3-period crossover, open-label, multicenter trial. Formulations were infused for 16 hours to patients with Parkinson disease who were using LCIG as their regular treatment. Patients were recruited from several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and noninferior variability of DIZ101 and DIZ102 vs LCIG with respect to levodopa plasma concentrations.
With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits compared with LCIG in the 18 participants who received all treatments. Although the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Owing to poor uptake of LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n = 20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient.
It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa-containing solution.
ClinicalTrials.gov identifier: NCT03419806. Registration first posted on February 5, 2018, first patient enrolled on February 16, 2018.
肠内左旋多巴/卡比多巴凝胶输注（LCIG）在晚期帕金森病中的疗效优于口服治疗。本试验的主要目的是研究连续皮下或静脉输注持续缓冲酸性左旋多巴/卡比多巴溶液是否能产生与 LCIG 相当的稳态左旋多巴血浆浓度，并且在晚期帕金森病患者中的变异性非劣效于 LCIG。
在一项随机、三周期交叉、开放标签、多中心试验中，比较了一种连续缓冲的浓酸性左旋多巴/卡比多巴（8:1）溶液（DIZ101）静脉内（DIZ101）或皮下（DIZ102）给药与已批准的 LCIG。将制剂输注给正在使用 LCIG 作为常规治疗的帕金森病患者 16 小时。患者从几个大学神经病学诊所招募，但都到同一个 I 期单位接受治疗。报告了药代动力学变量和安全性，包括皮肤耐受性。主要终点是 DIZ101 和 DIZ102 与 LCIG 相比，在左旋多巴血浆浓度方面的生物等效性和变异性非劣效性。
在调整剂量以估计生物利用度后，18 名接受所有治疗的参与者中，DIZ101 和 DIZ102 产生的左旋多巴血浆水平在标准生物等效性范围内与 LCIG 相当。虽然 DIZ102 的左旋多巴生物利用度完全，但 LCIG 的生物利用度为 80%。DIZ102 皮下给药达到治疗浓度与 LCIG 一样快，并且在整个输注过程中保持稳定。由于 LCIG 的吸收不良，DIZ101 和 DIZ102 与 LCIG 相比，血浆中的卡比多巴水平更高。所有接受任何治疗的个体（n=20）均纳入安全性和耐受性评估。输注部位的反应轻微且短暂。
通过对皮下给予的酸性左旋多巴/卡比多巴溶液进行持续缓冲，可以快速达到高且稳定的左旋多巴浓度。
ClinicalTrials.gov 标识符：NCT03419806。首次注册于 2018 年 2 月 5 日，首次患者入组于 2018 年 2 月 16 日。
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