Analysis of errors due to assigned model constants in pharmacokinetic calculations based on functional optimization.
Mathematical models in pharmacokinetic studies frequently include, in addition to model parameters that are estimated from experimental data, model constants that are directly measured or derived from standardized, anthropometric formulae. Although these assigned constants are usually considered as error-free, uncertainties in their values affect the estimation precision of the remaining model parameters as well as the reliability of other derived quantities such as predictions of drug concentration levels or prescriptions of drug dosage. The present paper addresses the problem of quantifying the effects of errors in assigned model constants on the outcome of pharmacokinetic calculations. The error analysis is performed starting from the general assumption that the optimization of some objective function, such as encountered in parameter estimation, is involved. The proposed approach is based on the linearization of theoretical conditions that must be satisfied by the optimal solution of the problems. It requires quite complex mathematical calculations which can be however performed automatically by specific software based on symbolic computer algebra. Examples of applications are reported showing the usefulness of this kind of error analysis, in particular for detecting potentially critical error sources in the modeling of physiological systems and for suggesting improvements to experimental protocols for increasing the confidence in diagnostic and therapeutic decisions.
Thomaseth
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Institute of Systems Science and Biomedical Engineering (LADSEB-CNR), Padova, Italy.
D000284:Administration, Oral; D016001:Confidence Intervals; D005947:Glucose / Q000008:administration & dosage / Q000493:pharmacokinetics; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000493:pharmacokinetics; D000078790:Insulin Secretion; D015233:Models, Statistical; D008962:Models, Theoretical; D010599:Pharmacokinetics; D015203:Reproducibility of Results
D007328:Insulin; D005947:Glucose