Nonlinear Pharmacokinetics
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In most cases, at therapeutic doses, the change in the amount of drug in the body or the change in its plasma concentration due to absorption, distribution, binding, metabolism or excretion, is proportional to its dose, whether administered as a single dose or as multiple doses.
Nonlinear
Pharmacokinetics
In most cases, at therapeutic doses, the change in
the amount of drug in the body or the change in its plasma concentration due to
absorption, distribution, binding, metabolism or excretion, is proportional to
its dose, whether administered as a single dose or as multiple doses. In such
situations, the rate processes are said to follow first-order or linear
kinetics and all semilog plots of C versus t for different doses, when
corrected for dose administered, are superimposable. This is called as principle of superposition. The
important pharmacokinetic parameters viz.
F, Ka, KE, Vd, ClR and ClH
which describe the time-course of a drug in the body remain unaffected by the
dose i.e. the pharmacokinetics is dose-independent.
In some instances, the rate process of a drug’s
ADME are dependent upon carrier or enzymes that are substrate-specific, have
definite capacities, and susceptible to saturation at high drug concentration.
In such cases, an essentially first-order kinetics transform into a mixture of
first-order and zero-order rate processes and the pharmacokinetic parameters change
with the size of the administered dose. The pharmacokinetics of such drugs are
said to be dose-dependent. Other
terms synonymous with it are mixed-order,
nonlinear and capacity-limited kinetics. Drugs exhibiting such a kinetic profile
are sources of variability in
pharmacological response.
There are several tests to detect nonlinearity in pharmacokinetics but the simplest
ones are –
1. Determination of steady-state plasma concentration at different doses. If the steady-state
concentrations are directly proportional to the dose, then linearity in the
kinetics exists. Such proportionality is not observable when there is
nonlinearity.
2. Determination of some of the important pharmacokinetic parameters such as fraction bioavailable,
elimination half-life or total systemic clearance at different doses of the
drug. Any change in these parameters which are usually constant, is indicative
of nonlinearity.
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