Selection between Michaelis–Menten and target-mediated drug disposition pharmacokinetic models
Target-mediated drug disposition (TMDD) models have been applied to describe the pharmacokinetics of drugs whose distribution and/or clearance are affected by its target due to high binding affinity and limited capacity. The Michaelis–Menten (M–M) model has also been frequently used to describe the pharmacokinetics of such drugs. The purpose of this study is to investigate conditions for equivalence between M–M and TMDD pharmacokinetic models and provide guidelines for selection between these two approaches. Theoretical derivations were used to determine conditions under which M–M and TMDD pharmacokinetic models are equivalent. Computer simulations and model fitting were conducted to demonstrate these conditions. Typical M–M and TMDD profiles were simulated based on literature data for an anti-CD4 monoclonal antibody (TRX1) and phenytoin administered intravenously. Both models were fitted to data and goodness of fit criteria were evaluated for model selection. A case study of recombinant human erythropoietin was conducted to qualify results. A rapid binding TMDD model is equivalent to the M–M model if total target density R tot is constant, and R tot K D /(K D + C) 2 ≪ 1 where K D represents the dissociation constant and C is the free drug concentration. Under these conditions, M–M parameters are defined as: V max = k int R tot V c and K m = K D where k int represents an internalization rate constant, and V c is the volume of the central compartment. R tot is constant if and only if k int = k deg, where k deg is a degradation rate constant. If the TMDD model predictions are not sensitive to k int or k deg parameters, the condition of R tot K D /(K D + C) 2 ≪ 1 alone can preserve the equivalence between rapid binding TMDD and M–M models. The model selection process for drugs that exhibit TMDD should involve a full mechanistic model as well as reduced models. The best model should adequately describe the data and have a minimal set of parameters estimated with acceptable precision.
KeywordsMichaels–Menten Target-mediated drug disposition Nonlinear pharmacokinetics Erythropoietin
This study was supported by Grant 57980 from the National Institute of General Medical Sciences, National Institutes of Health.
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