Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Nuclear Medicine, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Eur J Nucl Med Mol Imaging. 2024 Feb;51(3):820-827. doi: 10.1007/s00259-023-06463-2. Epub 2023 Oct 16.
Clear evidence regarding the effect of reduced tumour accumulation in later peptide receptor radionuclide therapy (PRRT) cycles is lacking. Therefore, we aimed to quantify potential cycle effects for patients treated with [Lu]Lu-HA-DOTATATE using a population pharmacokinetic (PK) modelling approach.
A population PK model was developed using imaging data from 48 patients who received multiple cycles of [Lu]Lu-HA-DOTATATE. The five-compartment model included a central, kidney, spleen, tumour and lumped rest compartment. Tumour volume and continued use of long-acting somatostatin analogues (SSAs) were tested as covariates in the model. In addition, the presence of a cycle effect was evaluated by relating the uptake rate in a specific cycle as a fraction of the (tumour or organ) uptake rate in the first cycle.
The final PK model adequately captured observed radioactivity accumulation in kidney, spleen and tumour. A higher tumour volume was identified to increase the tumour uptake rate, where a twofold increase in tumour volume resulted in a 2.3-fold higher uptake rate. Also, continued use of long-acting SSAs significantly reduced the spleen uptake rate (68.4% uptake compared to SSA withdrawal (10.5% RSE)). Lastly, a cycle effect was significantly identified, where tumour uptake rate decreased to 86.9% (5.3% RSE) in the second cycle and even further to 79.7% (5.6% RSE) and 77.6% (6.2% RSE) in the third and fourth cycle, respectively, compared to cycle one.
Using a population PK modelling approach, the cycle effect of reduced tumour uptake in subsequent PRRT cycles was quantified. Our findings implied that downregulation of target receptors is probably not the major cause of the cycle effect, due to a plateau in the decrease of tumour uptake in the fourth cycle.
在后续肽受体放射性核素治疗（PRRT）周期中，肿瘤积聚减少的效果尚缺乏明确证据。因此，我们旨在采用群体药代动力学（PK）建模方法，量化接受[Lu]Lu-HA-DOTATATE 治疗的患者的潜在周期效应。
使用 48 名接受多次[Lu]Lu-HA-DOTATATE 治疗的患者的影像学数据，开发了一个群体 PK 模型。该五室模型包括中央室、肾脏、脾脏、肿瘤和汇总剩余室。肿瘤体积和长效生长抑素类似物（SSA）的持续使用被测试为模型中的协变量。此外，通过将特定周期的摄取率与第一周期的（肿瘤或器官）摄取率的分数相关联，评估了周期效应的存在。
最终的 PK 模型充分捕捉了肾脏、脾脏和肿瘤中观察到的放射性物质积累。发现肿瘤体积越大，肿瘤摄取率越高，肿瘤体积增加两倍导致摄取率增加 2.3 倍。此外，长效 SSA 的持续使用显著降低了脾脏摄取率（与 SSA 停药相比，摄取率为 68.4%（10.5% RSE））。最后，显著确定了周期效应，与第一周期相比，肿瘤摄取率在第二周期下降至 86.9%（5.3% RSE），在第三周期甚至进一步下降至 79.7%（5.6% RSE）和第四周期下降至 77.6%（6.2% RSE）。
使用群体 PK 建模方法，量化了后续 PRRT 周期中肿瘤摄取减少的周期效应。我们的研究结果表明，由于肿瘤摄取率在第四周期趋于平稳，靶受体的下调可能不是周期效应的主要原因。
