PK / PD模型下的细菌生长动力学Therapy
This document presents a SimBiology model characterizing the pharmacokinetic/pharmacodynamic (PK/PD) relationship of antimicrobial agents as described in the article,"Semi-mechanistic Model for Assessment of Activity of Antibacterial Agents from Time-Kill Curve Experiments”by Nielsen et al [1].
Model Description
In 2007, Nielson et al [1] proposed an integrated PK/PD model to characterize the effect of antibacterial drugs on bacterial growth kinetics in time-kill curve studies. Time-kill curve experiments involve exposing anin vitrobacterial inoculum to a fixed antibiotic dose and monitoring bacterial activity over time. The authors described thein vitrodrug kinetics using a one-compartment model with linear elimination (kdeg) to account for drug degradation due to compound instability. The authors also included a second compartment,Biophase, to incorporate potential pharmacologic delay. Input and output to the Biophase compartment were described as a first order processes (ke). The dotted line indicates that theDrugin theCentralcompartment is both a reactant and product in the input process; this models the assumption that the presence of theBiophasecompartment does not affect the mass balance.
For the bacterial growth model, it was assumed that the bacterial system is comprised of 2 subpopulations –GrowingandResting. All the processes in the bacterial dynamics model – growth (kgrowth), the reversible transformation between sub-populations (ksrandkrs) and decay (kdeath) – were modeled as first-order processes. It was assumed that only the cells in the growing phase are drug-susceptible. The inhibitory effect of the antibiotic was build into the decay rate (kdeath+Effect) of theGrowingpopulation. The pharmacodynamic effect was modeled using a sigmoidal Emax model:
where Ce is theDrugconcentration in theBiophasecompartment, E_max represents the maximal achievable antibiotic effect, EC50 is the drug concentration that induces 50% of the maximum effect, and ? is the hill coefficient.
References
[1] Nielsen, E. I., A. Viberg, E. Lowdin, O. Cars, M. O. Karlsson, and M. Sandstrom (2007) Semimechanistic pharmacokinetic/pharmacodynamic model for assessment of activity of antibacterial agents from time-kill curve experiments. Antimicrobial Agents and Chemotherapy. 51:128-136.
