Population Pharmacokinetic–Pharmacodynamic (PK/PD) Modeling of Anti-infective Agents and Its Applications to Individualized Therapy

Abstract

This chapter describes the general principles of population pharmacokinetic-pharmacodynamic (PK/PD) modeling and its application to optimization of antibiotic dosing. Parametric and nonparametric pharmacokinetic modeling approaches are discussed. Population modeling will identify central tendency of PK/PD parameter estimates, quantify between and within patient variability, and identify clinically useful covariates. Population modeling has become an important component of quantitative model-based drug development. In addition, PK/PD models can be important extensions of therapeutic drug management in infectious diseases. The concept of population model-based individualized antimicrobial therapy is described. With the availability of population modeling for obtaining PK parameter estimates, the focus has shifted to quantifying the antimicrobial effect and linking kinetics to drug effects. Mathematical models that link drug exposure (PK) with PD indices that correlate with microbiological and clinical outcomes will provide us with a better rationale for proper dose selection of antimicrobial therapy in different patient populations.

Stochastic Process Pharmacodynamics: Dose Timing in Neonatal Gentamicin Therapy as an Example

“…Time dependent averages are typically computed by integrating coupled nonlinear first order ordinary differential equations [reviewed, e.g., in (4)]. Inter-individual variability (IIV) is usually addressed by assuming that some of the parameters in the differential equations are described by appropriate statistical distributions for a patient population [reviewed in (5)]. …”