Research

Antimicrobial breakpoint estimation accounting for variability in pharmacokinetics

Goue Denis Gohore Bi¹ , Jun Li^2,3 and Fahima Nekka^1,2,4

¹  Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada

²  Centre de Recherche Mathématiques, Université de Montréal, Montréal, Québec, Canada

³  Pharsight, Montréal, Québec, Canada

⁴  Groupe de recherche universitaire sur le médicament (GRUM), Université de Montréal, Montréal, Québec, Canada

author email corresponding author email

Theoretical Biology and Medical Modelling 2009, 6:10doi:10.1186/1742-4682-6-10

Published:	26 June 2009

Abstract

Background

Pharmacokinetic and pharmacodynamic (PK/PD) indices are increasingly being used in the microbiological field to assess the efficacy of a dosing regimen. In contrast to methods using MIC, PK/PD-based methods reflect in vivo conditions and are more predictive of efficacy. Unfortunately, they entail the use of one PK-derived value such as AUC or Cmax and may thus lead to biased efficiency information when the variability is large. The aim of the present work was to evaluate the efficacy of a treatment by adjusting classical breakpoint estimation methods to the situation of variable PK profiles.

Methods and results

We propose a logical generalisation of the usual AUC methods by introducing the concept of "efficiency" for a PK profile, which involves the efficacy function as a weight. We formulated these methods for both classes of concentration- and time-dependent antibiotics. Using drug models and in silico approaches, we provide a theoretical basis for characterizing the efficiency of a PK profile under in vivo conditions. We also used the particular case of variable drug intake to assess the effect of the variable PK profiles generated and to analyse the implications for breakpoint estimation.

Conclusion

Compared to traditional methods, our weighted AUC approach gives a more powerful PK/PD link and reveals, through examples, interesting issues about the uniqueness of therapeutic outcome indices and antibiotic resistance problems.