Pharmacometric Modelling of Biologic Medicinal Products

Andrew Hooker, Siv Jönsson, Mats Karlsson

Biological medicinal products are becoming an important contributor in the treatment of many diseases, e.g. multiple sclerosis, rheumatoid arthritis, cancer, psoriasis. Characterization of biologics benefit from pharma­cometric modelling, since they exhibit complex disposition characteristics, quite different to the processes and pathways utilized for small molecules, e.g. monoclonal antibodies exhibit target mediated drug disposition (TMDD).

Available TMDD models describe the formation of one complex (a dimer), but in reality further complexes may be formed (trimers, hexamers, etc.), as described for IgE and omalizumab. We aim to explore and develop alternative TMDD models for the interaction between a target and drug, taking into account formation of different complexes. Furthermore, to explore study design options for studies in different stages of drug develop­ment, optimal design methodology is applied to TMDD models.

A complicating factor for biologics is the occurrence of antidrug antibodies (ADA), which may affect the pharmacokinetic and efficacy features. The identification of ADAs is usually confounded by the presence of the drug itself and therefore the result from an analysis is that ADA is present, absent or unknown (missing information). Thus, there is a need to develop adequate methods to incorporate the ADA information in pharmacometric models. Currently, we are using mixed hidden Markov models (MHMM) to model the underlying unobservable ADA states (see Pharmacodynamic modelling of discrete outcomes).