Dose-dependent kinetics

A drug exhibits first order elimination if plasma concentrations of drug do NOT saturate the primary elimination mechanism(s) for that drug. Therefore, if drug concentration goes up, the rate of elimination goes up (rate of elimination is equal to the elimination rate constant multiplied by concentration) and if the concentration goes down, the rate of elimination goes down.

A drug exhibits zero-order elimination if plasma concentrations of drug DO saturate the primary elimination mechanism(s) for that drug. In those cases, a constant amount of drug is eliminated in unit time, rather than a constant proportion of remaining drug (and therefore a decreasing amount of drug per minute, over time), in unit time.

When increasing the dose of a drug within the therapeutic range causes plasma concentrations of the drug to go from a point where elimination is not saturated to a point where elimination is (more or less) saturated, then that drug is said to display dose-dependent kinetics. At lower therapeutic doses, the drug is cleared with first-order kinetics, but as the dose rate is increased, elimination transitions to a zero-order process as the eliminating mechanism becomes saturated. The consequence of this type of behaviour is that in a repeated dosing regimen, where doubling the dosing rate would typically double the steady state concentration of the drug, with a drug that displays dose-dependent kinetics, doubling the dosing rate might increase the steady state concentration by more (and possibly far more) than would normally be expected. An example of a drug that behaves in this way is the anticonvulsant, phenytoin.

Dose-dependent kinetic behaviour is also observed when higher therapeutic doses of a drug saturate plasma protein binding sites, so that any subsequently-administered drug is entirely present as “unbound drug”. As such, at low therapeutic doses, the ratio of free:bound drug remains relatively constant as the dose rate is changed, but as the dosing rate is increased and plasma proteins reach saturation, the free:bound ratio increases markedly with further increases in dose rate. Since it is the unbound fraction of the administered dose that is free to move between compartments, distribute to tissues and have a pharmacological effect (or cause side-effects), the magnitude of the response (and the likelihood of side-effects) increase to a far greater degree than might have been expected based upon the size of the change in dosing rate. An example of a drug that behaves in this way is the anticonvulsant, sodium valproate.