Mechanism-based pharmacokinetic–pharmacodynamic modeling of antimicrobial drug effects

Abstract

Mathematical modeling of drug effects maximizes the information gained from an experiment, provides further insight into the mechanisms of drug effects, and allows for simulations in order to design studies or even to derive clinical treatment strategies. We reviewed modeling of antimicrobial drug effects and show that most of the published mathematical models can be derived from one common mechanism-based PK-PD model premised on cell growth and cell killing processes. The general sigmoid Emax model applies to cell killing and the various parameters can be related to common pharmacodynamics, which enabled us to synthesize and compare the different parameter estimates for a total of 24 antimicrobial drugs from published literature. Furthermore, the common model allows the parameters of these models to be related to the MIC and to a common set of PK-PD indices. Theoretically, a high Hill coefficient and a low maximum kill rate indicate so-called time-dependent antimicrobial effects, whereas a low Hill coefficient and a high maximum kill rate indicate so-called concentration-dependent effects, as illustrated in the garenoxacin and meropenem examples. Finally, a new equation predicting the time to microorganism eradication after repeated drug doses was derived that is based on the area under the kill-rate curve.

Quantifying Subpopulation Synergy for Antibiotic Combinations via Mechanism-Based Modeling and a Sequential Dosing Design

“…Models with one, two, or three preexisting populations with different susceptibilities to the respective antibiotic were considered similarly to previously described models (8,14,19,22,(25)(26)(27)(28)(29)(30). The susceptibility of each population was estimated via a specific rate of bacterial killing by the respective antibiotic (Fig.…”

The Impact of Pharmacokinetic Mismatched Antimalarial Drug Combinations on the Emergence and Spread of Drug Resistant Parasites

“…Previous models demonstrating the benefits of ACT in delaying the onset of resistance largely assumed parasites are either completely sensitive to the drug, or else completely resistant [52]. This is an overly simplistic approach to modeling drug resistance, and knowledge of PK/PD mechanisms can guide development of more realistic models of drug resistance [53]. While PK profiles describe the disposition of drugs by the human body, PD parameters actually measure how drugs act on the parasite.…”

Review on Pharmacokinetics and Pharmacodynamics and the Aging Kidney

“…Conversely, the widely known need for higher furosemide or torasemide dosages can be explained by a higher CE 50 required to produce a diuretic effect in renal impairment. The emergence of bacterial or viral resistance to anti-infective drugs corresponds to a higher minimal inhibitory concentration that is closely related to a higher CE 50 (56). Thus, a higher concentration is needed to stop bacterial or viral growth, as shown with fluoroquinolones or with threshold trough concentrations of antiviral drugs (44).…”

“…Conversely, prolongation of the interval (Tau) in proportion to the T 1 ⁄2 might be critical for antiinfectives with a time-dependent action (antivirals, betalactams) because concentrations should not fall below a threshold value that is required for a specific time to maintain the minimum effect (56).…”