Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
J Control Release. 2022 May;345:101-107. doi: 10.1016/j.jconrel.2022.03.005. Epub 2022 Mar 4.
The Port Delivery System with ranibizumab (PDS) consists of an implant that is a permanent, indwelling drug delivery device that can be refilled through a self-sealing septum and is designed to continuously release a customized formulation of ranibizumab into the vitreous by passive diffusion through a porous titanium release control element. Target release rates of ranibizumab via the implant used in studies of the PDS in patients with neovascular age-related macular degeneration were selected based on clinical and pharmacokinetic (PK) data from previously conducted intravitreal ranibizumab injection studies. In-vitro testing was performed to verify release rates with a range of ranibizumab concentrations before the phase II Ladder (NCT02510794) and phase III Archway (NCT03677934) trials of the PDS. Implants were filled with ranibizumab and were regularly transferred to new buffer-containing tubes to represent ocular ranibizumab clearance and release kinetics. Ranibizumab concentrations were measured and release rates calculated. Release rate data were fit to an exponential model and compared with expected release kinetics of diffusion. Release profiles of the implant releasing ranibizumab at concentrations of 10 mg/mL, 40 mg/mL, and 100 mg/mL were determined in the pre-phase II in-vitro studies. At day 3.5, mean (SD) ranibizumab release rates were 1.75 (0.07), 6.42 (0.35), and 16.69 (0.67) μg/d for PDS 10 mg/mL, 40 mg/mL, and 100 mg/mL, respectively. At month 6, mean (SD) release rates were 1.68 (0.05) and 4.16 (0.05) μg/d for PDS 40 mg/mL and 100 mg/mL, respectively. Measured release rates were within 90% of theoretical release rates during the course of drug release. PDS 100 mg/mL released 73% (SD, 1.92) of drug by month 6. In the pre-phase III in-vitro studies, mean (SD) release rates with PDS 100 mg/mL were 17.97 (0.90), 4.44 (0.11), and 2.45 (0.08) μg/d at 3.5 days, 6 months, and 9 months, respectively. Cumulative release (SD) was 73% (1.92) by month 6 and 87% (1.88) by month 9. The sustained, continuous, and reproducible release from the PDS observed in the in-vitro studies was also observed in Ladder and Archway. In conclusion, in-vitro studies were a powerful tool for characterizing and verifying ranibizumab release from the PDS implant and supported clinical evaluation of the PDS. PDS 100 mg/mL, which was associated with the longest therapeutic-level delivery of ranibizumab among the concentrations tested, was selected for evaluation in the pivotal phase III Archway trial.
玻璃体内药物输送系统（PDS）与雷珠单抗联合使用，其输送装置为永久性植入物，是一种可通过自密封隔膜进行再填充的药物持续释放装置，设计用于通过多孔钛释放控制元件通过被动扩散将定制的雷珠单抗配方持续释放到玻璃体中。在新生血管性年龄相关性黄斑变性患者中进行的 PDS 研究中，用于研究的植入物的雷珠单抗目标释放率是基于先前进行的玻璃体内雷珠单抗注射研究的临床和药代动力学（PK）数据选择的。在进行 II 期 Ladder（NCT02510794）和 III 期 Archway（NCT03677934）试验之前，进行了体外测试以验证各种雷珠单抗浓度下的释放率。用雷珠单抗填充植入物，并定期转移到新的含有缓冲液的管中，以代表眼部雷珠单抗清除和释放动力学。测量雷珠单抗浓度并计算释放率。释放率数据拟合到指数模型，并与扩散的预期释放动力学进行比较。在预 II 期的体外研究中确定了以 10mg/mL、40mg/mL 和 100mg/mL 浓度释放雷珠单抗的植入物的释放曲线。在第 3.5 天，PDS 10mg/mL、40mg/mL 和 100mg/mL 的平均（SD）雷珠单抗释放率分别为 1.75（0.07）、6.42（0.35）和 16.69（0.67）μg/d。在第 6 个月时，PDS 40mg/mL 和 100mg/mL 的平均（SD）释放率分别为 1.68（0.05）和 4.16（0.05）μg/d。在药物释放过程中，测量的释放率在理论释放率的 90%以内。在第 6 个月时，PDS 100mg/mL 释放了 73%（SD，1.92）的药物。在预 III 期的体外研究中，PDS 100mg/mL 在第 3.5 天、第 6 个月和第 9 个月的平均（SD）释放率分别为 17.97（0.90）、4.44（0.11）和 2.45（0.08）μg/d。在第 6 个月时，累积释放（SD）为 73%（1.92），第 9 个月时为 87%（1.88）。在体外研究中观察到的 PDS 的持续、连续和可重复的释放也在 Ladder 和 Archway 中观察到。总之，体外研究是表征和验证 PDS 植入物中雷珠单抗释放的有力工具，并支持了 PDS 的临床评估。在测试的浓度中，PDS 100mg/mL 与最长的雷珠单抗治疗水平输送相关，因此被选为关键的 III 期 Archway 试验评估。
