Semi-mechanistic Multiple-Analyte Pharmacokinetic Model for an Antibody-Drug-Conjugate in Cynomolgus Monkeys

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• 作者：Dan Lu ; Jin Yan Jin ; Sandhya Girish ; Priya Agarwal ; Dongwei Li…
• 关键词：antibody ; drug conjugate ; integrated modeling ; multiple analytes ; pharmacokinetics
• 刊名：Pharmaceutical Research
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：32
• 期：6
• 页码：1907-1919
• 全文大小：867 KB
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• 作者单位：Dan Lu (1)
  Jin Yan Jin (1)
  Sandhya Girish (1)
  Priya Agarwal (1)
  Dongwei Li (2)
  Saileta Prabhu (2)
  Randall C. Dere (3)
  Ola M. Saad (3)
  Denise Nazzal (3)
  Neelima Koppada (3)
  Saroja Ramanujan (2)
  Chee M. Ng (4) (5)
  
  1. Department of Clinical Pharmacology, Genentech, Inc, 1 DNA Way, South San Francisco, California, 94080, USA
  2. Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc, South San Francisco, California, USA
  3. Department of Bioanalytical Sciences, Genentech, Inc, South San Francisco, California, USA
  4. Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  5. Children’s Hospital of Philadelphia, CTRB Building Room 4010, 3501 Civic Center Blvd, Philadelphia, Pennsylvania, 19104, USA
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Pharmacy
  Biochemistry
  Medical Law
  Biomedical Engineering
  
• 出版者：Springer Netherlands
• ISSN：1573-904X

文摘

Purpose A semi-mechanistic multiple-analyte population pharmacokinetics (PK) model was developed to describe the complex relationship between the different analytes of monomethyl auristatin E (MMAE) containing antibody-drug conjugates (ADCs) and to provide insight regarding the major pathways of conjugate elimination and unconjugated MMAE release in vivo. Methods For an anti-CD79b-MMAE ADC the PK of total antibody (Tab), conjugate (evaluated as antibody conjugated MMAE or acMMAE), and unconjugated MMAE were quantified in cynomolgus monkeys for single (0.3, 1, or 3?mg/kg), and multiple doses (3 or 5?mg/kg, every-three-weeks for 4 doses). The PK data of MMAE in cynomolgus monkeys, after intravenous administration of MMAE at single doses (0.03 or 0.063?mg/kg), was included in the analysis. A semi-mechanistic model was developed and parameter estimates were obtained by simultaneously fitting the model to all PK data using a hybrid ITS-MCPEM method. Results The final model well described the observed Tab, acMMAE and unconjugated MMAE concentration-time profiles. Analysis suggested that conjugate is lost via both proteolytic degradation and deconjugation, while unconjugated MMAE in systemic circulation appears to be mainly released via proteolytic degradation of the conjugate. Conclusions Our model improves the understanding of ADC catabolism, which may provide useful insights when designing future ADCs.