The mass-action law, the equilibrium law, and the absolute reaction rate
theory have all had an impact on the mathematical modeling of biological interactions,
and these fundamental discoveries are the foundation for PK/PD modeling. These
physicochemical approaches are very useful tools to help understand mathematically the
interaction of drugs and combinations with biological systems. Theories have been
developed that can be applied to understand a variety of biological applications based
on these laws. Accordingly, the algorithms for computer- based analysis and simulation
based on these principles been created. Modeling and simulation are important elements
in decision making by regulatory agencies affecting both industry and the public. PK
models exist to assemble all of the data derived from both nonclinical and clinical
studies that have been performed in the drug development process, which provides a
means to guide future studies with predictive models. Physiologically based PK (PBPK)
models differ from classic PK models due to their incorporation of specific tissue
compartments associated with exposure, biotransformation, toxicity, and clearance that
are all connected through the flow of blood. The objective of PK/PD modeling as
applied to antimalarial drug development is to develop and apply models to characterize
pharmacokinetic parameters reflecting the concentration of drug over time and the
pharmacodynamic relationships, which describe the effect of drugs with respect to drug
concentration. PK modeling elements describe the distribution and clearance kinetics of
a drug at the macro level. Adding a PD component to this model adds a drug effect
element to characterize drug combination in vivo. These models can assist in choosing
appropriate combination partner drugs or alternate first-line treatments for treatment of
malaria in a given transmission setting, which may be relevant to malaria eradication
efforts.
Keywords: Antimalarial policies, computerized simulation and analysis, drug
combination, efficacy, mathematical modeling, model, modeling, modeling theory,
PBPK/PD modeling, PD modeling, PK modeling, PK/PD modeling, resistance.