Pharmacokinetic/pharmacodynamic integration in drug development and dosage-regimen optimization for veterinary medicine

Abstract

Pharmacokinetic (PK)/pharmacodynamic (PD) modeling is a scientific tool to help developers select a rational dosage regimen for confirmatory clinical testing. This article describes some of the limitations associated with traditional dose-titration designs (parallel and crossover designs) for determining an appropriate dosage regimen. It also explains how a PK/PD model integrates the PK model (describing the relationship between dose, systemic drug concentrations, and time) with the PD model (describing the relationship between systemic drug concentration and the effect vs time profile) and a statistical model (particularly, the intra- and interindividual variability of PK and/or PD origin). Of equal importance is the utility of these models for promoting rational drug selection on the basis of effectiveness and selectivity. PK/PD modeling can be executed using various approaches, such as direct versus indirect response models and parametric versus nonparametric models. PK/PD concepts can be applied to individual dose optimization. Examples of the application of PK/PD approaches in veterinary drug development are provided, with particular emphasis given to nonsteroidal anti-inflammatory drugs. The limits of PK/PD approaches include the development of appropriate models, the validity of surrogate endpoints, and the acceptance of these models in a regulatory environment.

Paw Inflammation Model in Dogs for Preclinical Pharmacokinetic/Pharmacodynamic Investigations of Nonsteroidal Anti-Inflammatory Drugs

“…We showed that the plasma concentration corresponding to our estimated in vivo IC 50A value would ensure, in a canine ex vivo whole-blood assay, an inhibition of approximately 80% for body temperature and 90% for the other end points of the COX-2 isoenzyme. These results are consistent with what we observed for several other NSAIDs (i.e., that an inhibition close to 90% of the COX-2 isoenzyme is predictive of clinical efficacy) (Toutain, 2002). Thus, the kaolin model could be relevant for in vitro (ex vivo) to in vivo extrapolations.…”

Generic Vancomycin Products Fail In Vivo despite Being Pharmaceutical Equivalents of the Innovator

“…Each primary PDP has its own biological meaning under the Hill model: E max quantifies the efficacy of the antibiotic, ED 50 is an approximate measure of potency, and N describes the affinity of the drug's API for binding its molecular target in the bacterial cell. Secondary PDP represent the exact potency of the antibiotic (28,38): the doses (mg/kg per day) required in vivo to reach a net bacteriostatic effect (BD) or to kill the first log (1LKD). To calculate secondary PDP, the net bacterial growth in the absence of therapy (G ϭ CFU/g h24 Ϫ CFU/g h0 ) replaces E in equation 1 when the antibiotic action prevents bacterial growth (BD) or when it kills the first log of organisms (1LKD):…”

Pharmacokinetic – Pharmacodynamic Considerations for Bovine Mastitis Treatment

“…Conversely, the more shallows the curve, the greater the relationships between the rates of bacterial kill versus the ATM drug concentration. This relationship can be described using a sigmoidal Emax model, also known as the Hill model, which can be described as follows (Toutain, 2002):…”