Pharmacokinetics V

Time Course of Drug Plasma Levels
During Repeated Dosing
When a drug is administered at regular
intervals over a prolonged period, the
rise and fall of drug concentration in
blood will be determined by the relationship
between the half-life of elimination
and the time interval between
doses. If the drug amount administered
in each dose has been eliminated before
the next dose is applied, repeated intake
at constant intervals will result in similar
plasma levels. If intake occurs before
the preceding dose has been eliminated
completely, the next dose will add on to
the residual amount still present in the
body, i.e., the drug accumulates. The
shorter the dosing interval relative to
the elimination half-life, the larger will
be the residual amount of drug to which
the next dose is added and the more extensively
will the drug accumulate in
the body. However, at a given dosing
frequency, the drug does not accumulate
infinitely and a steady state (Css) or
accumulation equilibrium is eventually
reached. This is so because the activity
of elimination processes is concentration-
dependent. The higher the drug
concentration rises, the greater is the
amount eliminated per unit of time. After
several doses, the concentration will
have climbed to a level at which the
amounts eliminated and taken in per
unit of time become equal, i.e., a steady
state is reached. Within this concentration
range, the plasma level will continue
to rise (peak) and fall (trough) as dosing
is continued at a regular interval.
The height of the steady state (Css) depends
upon the amount administered
per dosing interval and the
clearance (Cltot)