Elsevier

Bioorganic & Medicinal Chemistry

Volume 24, Issue 24, 15 December 2016, Pages 6390-6400
Bioorganic & Medicinal Chemistry

Animal models in the pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents

https://doi.org/10.1016/j.bmc.2016.11.008Get rights and content

Abstract

Animal infection models in the pharmacokinetic/pharmacodynamic (PK/PD) evaluation of antimicrobial therapy serve an important role in preclinical assessments of new antibiotics, dosing optimization for those that are clinically approved, and setting or confirming susceptibility breakpoints. The goal of animal model studies is to mimic the infectious diseases seen in humans to allow for robust PK/PD studies to find the optimal drug exposures that lead to therapeutic success. The PK/PD index and target drug exposures obtained in validated animal infection models are critical components in optimizing dosing regimen design in order to maximize efficacy while minimize the cost and duration of clinical trials. This review outlines the key components in animal infection models which have been used extensively in antibiotic discovery and development including PK/PD analyses.

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 AUC024/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.

References (194)

  • K.M. Giacomini et al.

    Evaluation of methods for producing renal dysfunction in rats

    J Pharm Sci

    (1981)
  • I. Thonus et al.

    Tissue cage infusion: a technique for the acheivement of prolonged steady state in experimental animals

    J Pharmacol Methods

    (1979)
  • P. Marzola et al.

    Comparison between MRI, microbiology and histology in evaluation of antibiotics in a murine model of thigh infection

    MAGMA

    (1999)
  • E. Mutlu Yilmaz et al.

    Efficacy of tigecycline/colistin combination in a pneumonia model caused by extensively drug-resistant Acinetobacter baumannii

    Int J Antimicrob Agents

    (2012)
  • J.Y. Song et al.

    Efficacy of monotherapy and combined antibiotic therapy for carbapenem-resistant Acinetobacter baumannii pneumonia in an immunosuppressed mouse model

    Int J Antimicrob Agents

    (2009)
  • H.J. Tang et al.

    Comparative evaluation of intratracheal colistimethate sodium, imipenem, and meropenem in BALB/c mice with carbapenem-resistant Acinetobacter baumannii pneumonia

    Int J Infect Dis: IJID

    (2012)
  • F. Docobo-Perez et al.

    Efficacies of colistin and tigecycline in mice with experimental pneumonia due to NDM-1-producing strains of Klebsiella pneumoniae and Escherichia coli

    Int J Antimicrob Agents

    (2012)
  • Paul G. Ambrose et al.

    Pharmacokinetics-pharmacodynamics of antimicrobial therapy it’s not just for mice anymore

    Clin Infect Dis

    (2007)
  • H.W. Boucher et al.

    Infectious Diseases Society of A: 10 × ’20 progress–development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America

    Clin Infect Dis

    (2013)
  • Services DoHaH: Product Development Under the Animal Rule Guidance for Industry. In. Edited by Administration FaD;...
  • C. Lopez-Cadenas et al.

    Enrofloxacin: pharmacokinetics and metabolism in domestic animal species

    Curr Drug Metab

    (2013)
  • J.W. Mouton et al.

    Tissue concentrations: do we ever learn?

    J Antimicrob Chemother

    (2008)
  • D. Gonzalez et al.

    Importance of relating efficacy measures to unbound drug concentrations for anti-infective agents

    Clin Microbiol Rev

    (2013)
  • C.H. Ballow et al.

    Pharmacokinetics of oral azithromycin in serum, urine, polymorphonuclear leucocytes and inflammatory vs non-inflammatory skin blisters in healthy volunteers

    Clin Drug Investig

    (1998)
  • J.J. Schentag et al.

    Tissue-directed pharmacokinetics

    Am J Med

    (1991)
  • A. Lardner

    The effects of extracellular pH on immune function

    J Leukoc Biol

    (2001)
  • O. Burkhardt et al.

    Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration

    J Antimicrob Chemother

    (2007)
  • J.A. Roberts et al.

    The clinical relevance of plasma protein binding changes

    Clin Pharmacokinet

    (2013)
  • P.G. Ambrose et al.

    Pharmacokinetic-pharmacodynamic considerations in the design of hospital-acquired or ventilator-associated bacterial pneumonia studies: look before you leap!

    Clin Infect Dis

    (2010)
  • A. Louie et al.

    In vivo pharmacodynamics of torezolid phosphate (TR-701), a new oxazolidinone antibiotic, against methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains in a mouse thigh infection model

    Antimicrob Agents Chemother

    (2011)
  • A.J. Lepak et al.

    Comparative pharmacodynamics of the new oxazolidinone tedizolid phosphate and linezolid in a neutropenic murine Staphylococcus aureus pneumonia model

    Antimicrob Agents Chemother

    (2012)
  • J. Redington et al.

    Role of antimicrobial pharmacokinetics and pharmacodynamics in surgical prophylaxis

    Rev Infect Dis

    (1991)
  • M. Muller et al.

    Issues in pharmacokinetics and pharmacodynamics of anti-infective agents: distribution in tissue

    Antimicrob Agents Chemother

    (2004)
  • T.H. Tsai

    Pharmacokinetics of pefloxacin and its interaction with cyclosporin A, a P-glycoprotein modulator, in rat blood, brain and bile, using simultaneous microdialysis

    Br J Pharmacol

    (2001)
  • J. Waga et al.

    Intravitreal concentrations of some drugs administered with microdialysis

    Acta Ophthalmol Scand

    (1997)
  • C.S. Chaurasia et al.

    AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives

    Pharm Res

    (2007)
  • A.U. Gerber et al.

    Antibiotic therapy of infections due to Pseudomonas aeruginosa in normal and granulocytopenic mice: comparison of murine and human pharmacokinetics

    J Infect Dis

    (1986)
  • B. Vogelman et al.

    Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model

    J Infect Dis

    (1988)
  • T. Bruzzese et al.

    Pharmacokinetics and tissue distribution of rifametane, a new 3-azinomethyl-rifamycin derivative, in several animal species

    Arzneimittelforschung

    (2000)
  • D.M. MacCallum et al.

    Influence of grapefruit juice on itraconazole plasma levels in mice and guinea pigs

    J Antimicrob Chemother

    (2002)
  • N.J. Onufrak et al.

    Pharmacokinetic and pharmacodynamic principles of anti-infective dosing

    Clin Ther

    (2016)
  • D.P. Krontz et al.

    Effect of meningitis and probenecid on the penetration of vancomycin into cerebrospinal fluid in rabbits

    Antimicrob Agents Chemother

    (1980)
  • R.A. Keel et al.

    Pharmacokinetics and pulmonary disposition of tedizolid and linezolid in a murine pneumonia model under variable conditions

    Antimicrob Agents Chemother

    (2012)
  • E. Morita et al.

    Comparison of the pharmacokinetics of five beta-lactam antibiotics between neonatal and adult rats

    Dev Pharmacol Ther

    (1990)
  • A. Boulamery et al.

    Population pharmacokinetics of ertapenem in juvenile and old rats

    Fundam Clin Pharmacol

    (2014)
  • H. Thadepalli et al.

    Efficacy of trovafloxacin for treatment of experimental Bacteroides infection in young and senescent mice

    Antimicrob Agents Chemother

    (1997)
  • B.J. Cusack et al.

    Age-related pharmacokinetics of daunorubicin and daunorubicinol following intravenous bolus daunorubicin administration in the rat

    Cancer Chemother Pharmacol

    (1997)
  • D.N. McMartin et al.

    Effect of aging on gentamicin nephrotoxicity and pharmacokinetics in rats

    Res Commun Chem Pathol Pharmacol

    (1982)
  • A. Maiza et al.

    Variability in the renal clearance of cephalexin in experimental renal failure

    J Pharmacokinet Biopharm

    (1993)
  • D. Andes et al.

    In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations

    Antimicrob Agents Chemother

    (1998)
  • Cited by (0)

    View full text