Animal models in the pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents
Graphical abstract
Introduction
The pharmacology of antimicrobial therapy can be divided into two distinct components. The first of these components is pharmacokinetics (PK), which examine how the body handle drugs, including absorption, distribution, metabolism and elimination, the other component is pharmacodynamics (PD), which examine the relationship between drug PK, a measure of in vitro potency (usually the minimum inhibitory concentration [MIC]), and the treatment outcome (usually efficacy or sometimes drug toxicity). The time course of antimicrobial activity is a reflection of the interrelationship between PK and PD. PK/PD relationships are vital in facilitating the translation of microbiological activity into clinical situations and ensuring that antibiotics achieve a successful outcome. A large number of studies have indicated that antibiotics can be divided into two major groups (Fig. 1): those that exhibit concentration-dependent killing and prolonged persistent effects (e.g. aminoglycosides, fluoroquinolones), for which the area under the concentration-time curve (AUC) and peak concentration in relation to the MIC of the organism causing the infections (AUC/MIC and Cmax/MIC, respectively) are the major PK/PD indices correlating with efficacy; the other group is those antibiotics that exhibit time-dependent killing and minimal-to-moderate persistent effects (e.g. Beta-lactam and macrolide classes), the time (expressed as a percentage of the dosing interval) that drug concentration exceed the MIC (%T > MIC) is the major parameter determining efficacy. To identify the PK/PD indices most closely associated with efficacy, dose-fractionation studies are used. In such studies, the same total drug exposure is administered using different dosing intervals, for instance, a dose might be delivered as 100 mg once daily or in 4 equally divided doses throughout the day, regardless of dosing interval, each regimen would have identical AUC0–24/MIC values, but different %T>MIC and Cmax/MIC values. However in clinical trials, usually only 1 dose and 1 doing interval are studied, making discrimination of the PK/PD linked measured difficult, therefore, we usually rely on animal infection models to determine the PK/PD index (also called PK/PD parameter) and target (i.e. the magnitudes of exposure required to gain certain PD endpoints, e.g. stasis or 1 log killing of pathogens in animals, or 90% chance of clinical effectiveness) that is linked to efficacy. Importantly, available PK/PD data derived from infected patients have shown remarkable concordance between the PK/PD in patients and from animal data.1 This means that, in many circumstances, we can translate the PK/PD profile from animal models to effective treatment regimens in humans.
Infections caused by antibiotic-resistant bacteria have increased rapidly and new antimicrobial agents are urgently needed. However, the paucity of new antibiotics in the drug discovery pipeline is presenting a significant unmet global need.2 In antibiotic discovery and development, PK/PD evaluation in animal infection models play an essential role in designing the optimal dosing regimen and planning clinical trials, both of which are extremely costly. Identification of PK/PD relationships using animal models in an early discovery stage can lower the attrition rate and provide a tool to enable rational go or no-go decision making. Additionally, for drugs developed to ameliorate or prevent serious or life-threatening infections, when human efficacy studies are not ethical and clinical trials are not feasible, animal models are especially important, FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies.3
For these animal models, there are several variables that are taken into consideration. These can include host-specific variables such as the animal species, route of infection, infection site, immune status, end organ/tissue sampling and optimal endpoint measure. Pathogen-specific variables include the genus/species, inoculum size, virulence, and drug-susceptibility. Finally, therapeutic variables include route of drug administration, timing of therapy, dose level, frequency of administration, penetration to the site of infection, metabolism and/or elimination, and duration of therapy. This list of variables may seem challenging; however, carefully controlled animal model studies are the cornerstone of PK/PD therapeutic evaluations that lead to dosing regimen optimization, limiting drug-related toxicity, guiding therapeutic drug monitoring, and setting of drug susceptibility breakpoints. The aim of this paper is to outline these key factors in animal PK/PD models.
Section snippets
Pharmacokinetic considerations
Pharmacokinetic (PK) measurements are necessary to ensure an anti-infective agent will be present at sufficient concentrations and microbiologically active at a given site of infection in a mammalian host. The PK characteristics, such as area under the drug concentration curve (AUC) or elimination half-life, of some antibiotics can vary significantly according to the route of administration, formulation, animal species, age, body condition, gender, and physiological status, all of which
Immune suppression in the animal model
Animal models of anti-infective therapy often utilize immune suppression. There are several reasons for this model design. First, an un-confounded evaluation of antimicrobial effect can be performed if the immune system is removed or significantly inhibited from affecting the outcome. Therefore, one will get a more robust drug-effect evaluation by removing confounders that will artificially enhance antimicrobial efficacy. Secondly, many animals are inherently resistant to microbes that are
Common animal infection models for antimicrobial PK/PD study
Various different animal models have been used for experimental antibacterial PK/PD study. A description of the most commonly used models is provided in this review. In general, mice and rats are the preferred experimental animals because of their low cost and ease of handling. Virulent bacterial strains are used to develop infections. A high inoculum, immunocompromised animals,57 and/or adjuvants58, 59 (like mucin or formalin60) may be required to produce progressive infection. The time to
Antimicrobial PK/PD modeling
In antibiotic development, PK/PD indices are intended to normalize the drug exposure relative to the in vitro susceptibilityof the respective pathogen.193 Once the optimal PK/PD index and target is identified and validated for a new compound, it can be used to optimize the dosing regimen and determination of preliminary susceptibility breakpoints.
Practically, there are a number of key experimental elements in antimicrobial PK/PD studies. First, one must determine the dose range to study for
Conclusion
Developing safe and effective dosing regimens is a significant challenge in antibiotic development, which can be achieved by the integration of PK and PD information in preclinical experimental models. Hence, accurate and predictive animal infection PK/PD models are an extremely powerful tool which can streamline the drug development process and optimize therapeutic effect. In this review, we summarized the factors that can affect animal model PK/PD studies of antimicrobial agents and the
Acknowledgement
Miao Zhao is financially supported by China Scholarship Council.
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