Scholarlink

<p>The study presents a comprehensive evaluation of physiologically-based pharmacokinetic (PBPK) modeling for Proteolysis Targeting Chimeras (PROTACs), using ARV-110 (Bavdegalutamide) as a case example. We sought to develop a PBPK model that accurately predicts the human pharmacokinetics (PK) of ARV-110 and began with a bottom-up approach to predict ARV-110 PK in mice and rats using available ADME and physicochemical data. Owing to the observed <i>in vitro</i>-<i>in vivo</i> extrapolation (IVIVE) gaps in clearance, the published <i>in vivo</i> data was used for refinement, resulting in a middle-out PBPK model bridging this discrepancy. PBPK predictions were extrapolated to human and validated against observed clinical PK for single and multiple doses in healthy volunteers and cancer patients revealing IVIVE gaps for human clearance. Similar to rodents, a middle-out modeling approach was then used to refine the human PBPK prediction. This model effectively captured plasma drug concentration–time profiles reported for preclinical and clinical studies, including studies involving impact of food and drug-drug interactions with itraconazole and esomeprazole. All observed human concentrations were within 5th and 95th percentile of predictions and PK parameters were within two-fold of the observed <i>in vivo</i> data. Following administration of a single dose (280&#xa0;mg) of ARV-110, the observed vs. predicted AUC<sub>0-inf</sub> for high fat, medium fat and low fat studies were 13563.0 vs. 7646.0&#xa0;ng.h/ml, 4358.0 <i>vs</i>. 4618.3&#xa0;ng.h/ml and 1919.0 vs. 1403.3&#xa0;ng.h/ml. This work provides a translational PBPK framework for predicting human oral PK of PROTACs and emphasizes challenges in generating robust preclinical data to enhance prediction accuracy.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

PBPK Modelling of PROTACs: Learnings from ARV-110 as a Case Example

  • 期刊论文

  • 发表日期：

    2026年3月27日

查看全文
  • Farzaneh Salem,
  • Ali Tabatabaeian Nimavardi,
  • Abhishek Srivastava,
  • Katharina Krollik,
  • Andreas Reichel,
  • David Cebrian,
  • Kunal S. Taskar,
  • James W. T. Yates,
  • Caroline Rynn,
  • Heide Marika Duevel

摘要

The study presents a comprehensive evaluation of physiologically-based pharmacokinetic (PBPK) modeling for Proteolysis Targeting Chimeras (PROTACs), using ARV-110 (Bavdegalutamide) as a case example. We sought to develop a PBPK model that accurately predicts the human pharmacokinetics (PK) of ARV-110 and began with a bottom-up approach to predict ARV-110 PK in mice and rats using available ADME and physicochemical data. Owing to the observed in vitro-in vivo extrapolation (IVIVE) gaps in clearance, the published in vivo data was used for refinement, resulting in a middle-out PBPK model bridging this discrepancy. PBPK predictions were extrapolated to human and validated against observed clinical PK for single and multiple doses in healthy volunteers and cancer patients revealing IVIVE gaps for human clearance. Similar to rodents, a middle-out modeling approach was then used to refine the human PBPK prediction. This model effectively captured plasma drug concentration–time profiles reported for preclinical and clinical studies, including studies involving impact of food and drug-drug interactions with itraconazole and esomeprazole. All observed human concentrations were within 5th and 95th percentile of predictions and PK parameters were within two-fold of the observed in vivo data. Following administration of a single dose (280 mg) of ARV-110, the observed vs. predicted AUC0-inf for high fat, medium fat and low fat studies were 13563.0 vs. 7646.0 ng.h/ml, 4358.0 vs. 4618.3 ng.h/ml and 1919.0 vs. 1403.3 ng.h/ml. This work provides a translational PBPK framework for predicting human oral PK of PROTACs and emphasizes challenges in generating robust preclinical data to enhance prediction accuracy.

Graphical Abstract