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Journal of Chinese Pharmaceutical Sciences ›› 2018, Vol. 27 ›› Issue (11): 767-776.DOI: 10.5246/jcps.2018.11.077

• Original articles • Previous Articles     Next Articles

Simulation-based simplification of target-mediated drug disposition model of denosumab

Yu Fu1, Ye Yao1, Peiming Ma2, Xuan Zhou2, Wei Lu1, Tianyan Zhou1*   

  1. 1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
    2. GSK Research and Development, Shanghai 201203, China
  • Received:2018-05-15 Revised:2018-05-29 Online:2018-11-28 Published:2018-09-30
  • Contact: Tel.: +86-010-82801717, E-mail: tianyanzhou@bjmu.edu.cn

Abstract:

Target-mediated drug disposition (TMDD) model is one of the main modeling theories for studying nonlinear pharmacokinetics (PK) of monoclonal antibodies. However, there are too many parameters in full TMDD model to be estimated based on limited clinical data, leading to instability of the final model. In the present study, we analyzed the predictive ability and applicability of a simplified quasi-steady state (QSS) model with the assumption that the total target concentration was a constant parameter during treatment with monoclonal antibody in clinical data modeling. Based on the parameters of a published TMDD model of denosumab, simulations were performed at population and individual levels. Then, a simplified TMDD model, QSS model, was used to examine the effects of hypotheses, in which the total receptor concentration was constant or variable on model fit and stability of parameter estimation. Both simulations at the population level and model fit results of simulated individual data showed that at the therapeutic doses, the total receptor concentration had little influence on changes in drug concentration, and the model with constant total receptor concentration had the same predictive power. The validated hypothesis could be applied to clinical trial design and selection of the optimal PK model in the development of monoclonal antibodies.

Key words: Target-mediated drug disposition model, Monoclonal antibody, Nonlinear pharmacokinetics, Denosumab, Simulation

CLC Number: 

Supporting:

 

Figure S1. Goodness-of-fit plots of Rtot constant model. (A) Simulated observation vs. individual predicted concentration; (B) Observed vs. population predicted concentration; (C) Conditional weighted residual error vs. population predicted concentration; (D) Conditional weighted residual error vs. time after dose.
 

 

Figure S2. Goodness-of-fit plots of Rtot variable model. (A) Simulated observation vs. individual predicted concentration; (B) Observed vs. population predicted concentration; (C) Conditional weighted residual error vs. population predicted concentration; (D) Conditional weighted residual error vs. time after dose.
 

 

Figure S3. Goodness-of-fit plot of two-compartment model. (A) Simulated observation vs. individual predicted concentration; (B) Observed vs. population predicted concentration; (C) Conditional weighted residual error vs. population predicted concentration; (D) Conditional weighted residual error vs. time after dose.