Utility of a Bayesian Mathematical Model to Predict the Impact of Immunogenicity on Pharmacokinetics of Therapeutic Proteins

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• 作者：Steven Kathman Jr. ; Theingi M. Thway ; Lei Zhou ; Stephanie Lee…
• 刊名：The AAPS Journal
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：18
• 期：2
• 页码：424-431
• 全文大小：760 KB
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• 作者单位：Steven Kathman Jr. (1)
  Theingi M. Thway (2)
  Lei Zhou (1)
  Stephanie Lee (3)
  Steven Yu (2)
  Mark Ma (2)
  Naren Chirmule (3)
  Vibha Jawa (3)
  
  1. Global Biostatistical Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California, 91320, USA
  2. Pharmacokinetic and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California, 91320, USA
  3. Clinical Immunology, Medical Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California, 91320, USA
  
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Biotechnology; Pharmacy;
• 出版者：Springer US
• ISSN：1550-7416

文摘

The impact of an anti-drug antibody (ADA) response on pharmacokinetic (PK) of a therapeutic protein (TP) requires an in-depth understanding of both PK parameters and ADA characteristics. The ADA and PK bioanalytical assays have technical limitations due to high circulating levels of TP and ADA, respectively, hence, significantly hindering the interpretation of this assessment. The goal of this study was to develop a population-based modeling and simulation approach that can identify a more relevant PK parameter associated with ADA-mediated clearance. The concentration-time data from a single dose PK study using five monoclonal antibodies were modeled using a non-compartmental analysis (NCA), one-compartmental, and two-compartmental Michaelis-Menten kinetic model (MMK). A novel PK parameter termed change in clearance time of the TP (α) derived from the MMK model could predict variations in α much earlier than the time points when ADA could be bioanalytically detectable. The model could also identify subjects that might have been potentially identified as false negative due to interference of TP with ADA detection. While NCA and one-compartment models can estimate loss of exposures, and changes in clearance, the two-compartment model provides this additional ability to predict that loss of exposure by means of α. Modeling data from this study showed that the two-compartment model along with the conventional modeling approaches can help predict the impact of ADA response in the absence of relevant ADA data.