Toxicokinetics, nonlinearities

Nonlinearity in toxicokinetics can be assessed by comparing relevant parameters, e.g., AUC, after different dose levels, or after single and repeated exposure. Dose dependency may be indicative of saturation of enzymes involved in the metabolism of the compound. An increase of AUC after repeated exposure as compared to single exposure may be an indication for inhibition of metabolism. A decrease in AUC may be an indication for induction of metabohsm. 

Carrier, G., R.C. Brunet, and J. Brodeur. 1995. Modeling of the toxicokinetics of polychlorinated dibenzo-p-dioxins and dibenzofurans in mammalians, including humans. I. Nonlinear distribution of PCDD/PCDF body burden between liver and adipose tissues. Toxicol. Appl. Pharmacol. 131(2) 253-266. 

The pharmacokinetic evaluation of biopharmaceuticals is generally simplified by the usual metabolism of products to small peptides and to amino acids, and thus classical biotransformation and metabolism studies are rarely necessary. Routine studies to assess mass balance are not useful. However, both single- and multiple-dose toxicokinetic data are essential in safety pharmacology asessments, and these can be complicated by two factors (1) biphasic clearance with a saturable, initial, receptor-dependent clearance phase, which may cause nonlinearity in dose-exposure relationships and doseresponses [14] and (2) antibody production against an antigenic biopharmaceutical that can alter clearance or activity in more chronic repeat-dose safety studies in the preclinical model. 

Preclinical pharmacokinetic (PK) studies provide information useful for supporting efficacy and safety evaluation studies in animals, preclinical and clinical study designs, dosing regimen development, and interpretation of toxicity data. These studies provide PK data that may be useful in dose escalation in healthy volunteers and patients. Toxicokinetics is a major component of toxicology studies. It enables the investigation of the relationship between drug dose and measured concentration, primarily the establishment of the dose proportionahty and hnearity or nonlinearity in pharmacokinetics. 

Other Aspects of Toxicokinetics. Other aspects of toxicokinetics also have the potential for nonlinearities, but are linear at doses approaching zero. Nonlinearities may occur in the transport of a chemical into a cell, by either diffusion or active transport. Diffusion is a linear function of chemical concentration, and active transport at doses approaching zero is a linear function of chemical concentration, unless the expression of the transport molecule is induced. Nonlinearities may occur at higher doses, if the transport mechanism is saturated. 

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