A TRACER INTERACTION METHOD FOR NONLINEAR PHARMACOKINETICS ANALYSIS -APPLICATION TO EVALUATION OF NONLINEAR ELIMINATION

A drug tracer is most commonly applied to get information about the ph armacokinetics (PK) of a drug that is not confounded by an endogenousl y produced drug or an unknown drug input. An equally important use of tracers that has not been fully recognized is their use in the study o f nonlinear PK behavior. In the present study a system analysis is app lied to examine the interaction between drug molecules characteristic and intrinsic to any nonlinear process which enables the nonlinearity to be identified and modeled using a drug tracer. The proposed Tracer Interaction Methodology (TIM) forms a general developmental framework for novel methods for examining nonlinear phenomena. Such methods ave potentially much more sensitive and accurate than previous methods not exploiting the tracer principle. The methodology proposed is demonstr ated in a simulation study and with real data in a specific implementa tion aimed at determining the Michaelis-Menten (MM) parameters of nonl inear drug elimination while accounting for drug distribution effects. The simulation study establishes that the TIM-based, MM parameter eva luation produces substantially more accurate parameter estimates than a nontracer (NT) conventional method. In test simulations the accuracy of the TIM was in many cases an order of magnitude better than the NT method without evidence of bias. The TIM-based, MM parameter estimati on methodology proposed is ideally suitable for dynamic, non-steady-st ate conditions. Thus, it offers greater applicability and avoids the m any problems specific to steady state evaluations previously proposed. TIM is demonstrated in an evaluation of the nonlinear elimination beh avior of erythropoietin, a process that likely takes place via recepto r-based endocytosis. Due to its high sensitivity, accuracy, and intrin sic nonlinearity the TIM may be suitable for in-vivo studies of recept or binding of the many biotechnology produced peptide drugs and endoge nous compounds displaying receptor-mediated elimination.