Pharmacokinetics (PK) and Pharmacodynamics (PD) of Antimalarial Drugs
Pp. 95-148 (54)
Qigui Li and Mark R. Hickman
Most of the antimalarial drugs available on market were introduced in an era
prior to the introduction of more modern practices of dose design based on principles of
pharmacodynamics (PD) and pharmacokinetics (PK). Antimalarial dose regimens have
been derived by empirical means rather than based on PK/PD models to maximize
efficacy. These analyses factor in a wide variety of PK/PD parameters to include drug
half-life, drug exposure levels, and times, drug metabolism, drug tissue volume of
distribution and clearance, and PK inter-individual variations derived from animal
model experiments and clinical trials in man. The relationships of drug half-life to
antimalarial efficacy and resistance, dosing regimens to antimalarial efficacy and
toxicity, and drug peak concentration to rapid antimalarial effects are defined in this
chapter. There are significant advantages associated with defining the PK and PD
characteristics of novel antimalarial drugs precisely which includes devising better
methods of assessing therapeutic response. A clear definition of required PK and PD
properties will also help with the design of drug regimens for dosing antimalarial drugs.
The dose to be administered, the duration of dosing, and the frequency of dosing, can be
modeled to help predict treatment cures and failures. Ultimately, a well-planned dose
regimen of an antimalarial combination therapy will aid in slowing the emergence of
parasite drug resistance. Antimalarial drugs are administered therapeutically in doses
that result in patient blood concentrations far beyond the levels required for maximum
effect. To evaluate a usable antimalarial drug, the maximum antimalarial effect
observed differs when examining the varied responses between individuals. Thus,
defining in vivo therapeutic levels requires analyzing associations between drug levels
(PK inputs) and the risk of recurrent parasitemia, recrudescence, and re-infection (PD
inputs) which provides important data to both develop and refine antimalarial
monotherapy and combination therapies.
Artemisinins, drug exposure level, drug exposure time, drug peak
concentration, drug therapy, half-life, pharmacodynamics (PD), pharmacokinetics
(PK), pharmacokinetics and pharmacodynamics (PK/PD), rapid action, toxicity.
Walter Reed Army Institute of Research USA.