Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.
Br J Clin Pharmacol. 2022 Jan;88(1):323-335. doi: 10.1111/bcp.14971. Epub 2021 Jul 19.
In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn's disease (CD) on ustekinumab achieved endoscopic response and 10.9% of patients achieved endoscopic remission at week (w)44. We aimed to evaluate the impact of alternative ustekinumab dosage regimens on endoscopic outcomes based on population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis.
Real-world data were obtained from 83 patients with moderate-to-severe CD (95% biological-refractory) enrolled in a prospective cohort study receiving intravenous ustekinumab (~6 mg/kg) followed by every eight-week (q8w) subcutaneous maintenance therapy (90 mg). Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fecal calprotectin (fCal), and a logistic regression outcome model linking fCal to endoscopic outcomes.
Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1800 μg/g to 694 μg/g (EC ). The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1800 μg/g to 214 μg/g (EC ). Simulation-based comparison of q8w and q4w maintenance dosing regimens predicted 16.7% and 22.2% endoscopic response rates, respectively. Endoscopic remission rates were estimated to be 4.2% on q8w dosing and 6.7% on q4w dosing.
The developed models can guide clinical trial design and support model-informed dose optimization (stratified or individualized dosing) to improve endoscopic outcomes.
在 UNITI 内镜子研究中，接受乌司奴单抗治疗的克罗恩病（CD）患者中仅有 17.4%达到内镜缓解，44 周时仅有 10.9%达到内镜缓解。我们旨在根据群体药代动力学-药效学（popPK-PD）建模和模拟分析，评估替代乌司奴单抗剂量方案对内镜结局的影响。
从接受静脉注射乌司奴单抗（~6mg/kg）后每 8 周（q8w）接受皮下维持治疗（90mg）的 83 例中重度 CD（95%生物难治性）患者前瞻性队列研究中获得真实世界数据。开发了三个连续的模型：一个将乌司奴单抗剂量与乌司奴单抗暴露联系起来的两室 popPK 模型，一个描述乌司奴单抗暴露对粪便钙卫蛋白（fCal）影响的间接反应 popPK-PD 模型，以及一个将 fCal 与内镜结局联系起来的逻辑回归结局模型。
乌司奴单抗清除率随血清白蛋白降低和体重增加而增加。fCal 随乌司奴单抗暴露量的增加而降低。在 w8 时 fCal 从 1800μg/g 降至 694μg/g（EC）时，w24 的内镜缓解率从 10.0%增加到 17.9%。在 w8 时 fCal 从 1800μg/g 降至 214μg/g（EC）时，w24 的内镜缓解率从 2.1%增加到 10.0%。基于模拟的 q8w 和 q4w 维持剂量方案比较预测内镜缓解率分别为 16.7%和 22.2%。估计 q8w 给药的内镜缓解率为 4.2%，q4w 给药的内镜缓解率为 6.7%。
所开发的模型可以指导临床试验设计，并支持模型指导的剂量优化（分层或个体化剂量），以改善内镜结局。
