Target-mediated drug disposition model: relationships with indirect response models and application to population PK–PD analysis
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The paper focuses on approximations of the target-mediated drug disposition (TMDD) model as applied to pharmacodynamic (target kinetics) modeling. The TMDD equation for the total target concentration is shown to coincide with the indirect response model with stimulation or inhibition of elimination. This correspondence allows estimation of pharmacodynamic TMDD parameters and unobservable free target concentrations using indirect-response models. The ability of the TMDD model and its approximations to estimate the unobservable free target concentration is investigated by simulation. Pharmacokinetic parameters used for simulations were parameters typical for monoclonal antibodies. TMDD binding and target turnover parameters were similar to those estimated for omalizumab. Free drug and total target concentrations were measured. The simulated population PK–PD study demonstrated that for drugs with TMDD, indirect-response models are in fact mechanistic models that can be used to estimate TMDD model parameters and unobservable free target concentrations that are important for pharmacodynamic modeling.
KeywordsIndirect-response models Michaelis–Menten approximation Nonlinear pharmacokinetics Pharmacodynamics Quasi-steady-state approximation Target-mediated drug disposition
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