MPBPK-TMDD models for mAbs: alternative models, comparison, and identifiability issues
The aim of the present study was to evaluate model identifiability when minimal physiologically-based pharmacokinetic (mPBPK) models are integrated with target mediated drug disposition (TMDD) models in the tissue compartment. Three quasi-steady-state (QSS) approximations of TMDD dynamics were explored: on (a) antibody-target complex, (b) free target, and (c) free antibody concentrations in tissue. The effects of the QSS approximations were assessed via simulations, taking as reference the mPBPK-TMDD model with no simplifications. Approximation (a) did not affect model-derived concentrations, while with the inclusion of approximation (b) or (c), target concentration profiles alone, or both drug and target concentration profiles respectively deviated from the reference model profiles. A local sensitivity analysis was performed, highlighting the potential importance of sampling in the terminal pharmacokinetic phase and of collecting target concentration data. The a priori and a posteriori identifiability of the mPBPK-TMDD models were investigated under different experimental scenarios and designs. The reference model and QSS approximation (a) on antibody-target complex were both found to be a priori identifiable in all scenarios, while under the further inclusion of QSS approximation (b) target concentration data were needed for a priori identifiability to be preserved. The property could not be assessed for the model including all three QSS approximations. A posteriori identifiability issues were detected for all models, although improvement was observed when appropriate sampling and dose range were selected. In conclusion, this work provides a theoretical framework for the assessment of key properties of mathematical models before their experimental application. Attention should be paid when applying integrated mPBPK-TMDD models, as identifiability issues do exist, especially when rich study designs are not feasible.
KeywordsMonoclonal antibodies Minimal physiologically-based pharmacokinetics Target mediated drug disposition Identifiability Study design
Funding for this analysis was provided by GlaxoSmithKline.
Compliance with ethical standards
Conflict of interest
Peiming Ma, Monica Simeoni, and Stefano Zamuner are employed by GlaxoSmithKline and hold company stocks.
- 23.Mezzalana E, Lavezzi SM, Zamuner S, De Nicolao G, Ma P, Simeoni M (2015) Integrating target mediated drug disposition (TMDD) into a minimal physiologically based modelling framework: evaluation of different quasi-steady-state approximations. In: PAGE 24, Abstr 3598, Hersonissos, Greece. www.page-meeting.org/?abstract=3598
- 27.Hastie T, Tibshirani R, Friedman J (2008) The elements of statistical learning. Springer, New York, pp 265–267Google Scholar