What In Vitro Models of Infection Can and Cannot Do
What In Vitro Models of Infection Can and Cannot Do
The science of pharmacodynamics analyzes the relationship between an antimicrobial's bactericidal effects and its pharmacokinetics. Ideally, randomized and well-controlled clinical trials are the best way to determine pharmacodynamic properties. However, in vitro models that recapitulate in vivo drug clearance profiles represent an increasingly important technology for carrying out pharmacodynamic studies in a more cost-effective, timely, and easily controlled fashion. Although in vitro pharmacodynamic models cannot incorporate all variables seen in vivo, they do provide valuable information for the drug development process and the determination of optimal dosing regimens.
The answers to four questions govern the choice and administration of any antibacterial agent. First, does the selected agent display good bactericidal activity against the infecting pathogen(s)? Second, is the antibacterial agent safe? Third, is the dosing regimen effective at limiting the development of resistance? Finally, does the dosing regimen maximize the eradication of pathogen? The final question, focusing on the strengths and weaknesses of in vitro modeling in the analysis of dosing regimens, is examined in this article. Although in vitro models may be able to help assess the toxicity of drugs, this issue will not be addressed here.
Obviously, the best method for analyzing the efficacy of a specific dosing regimen is a controlled clinical trial in humans. In addition to being expensive, however, clinical trials are slow, tend to evaluate relatively small numbers of patients, and are hampered by ethical consid-erations that limit the ability to vary dosing too broadly. Animal studies partially circumvent these problems, but differences in pharmaco-kinetic parameters in many animal species versus humans make their evaluation problematic.
As a result, in vivo approaches have been supplemented since the 1960s with models of infection that are carried out in vitro. Although clearly having disadvantages, in vitro systems have many attractive features not shared by in vivo approaches. For instance, in vitro systems are relatively inexpensive, can be more easily controlled than in vivo studies, can be evaluated over a wider range of dosing regimens, can easily evaluate activity of antibacterial agents against a wider variety of bacterial species, and can more accurately mimic bacterial exposure to antimicrobials in humans than many animal models. Thus, while in vitro models cannot replace in vivo studies, they clearly have significant utility.
The science of pharmacodynamics analyzes the relationship between an antimicrobial's bactericidal effects and its pharmacokinetics. Ideally, randomized and well-controlled clinical trials are the best way to determine pharmacodynamic properties. However, in vitro models that recapitulate in vivo drug clearance profiles represent an increasingly important technology for carrying out pharmacodynamic studies in a more cost-effective, timely, and easily controlled fashion. Although in vitro pharmacodynamic models cannot incorporate all variables seen in vivo, they do provide valuable information for the drug development process and the determination of optimal dosing regimens.
The answers to four questions govern the choice and administration of any antibacterial agent. First, does the selected agent display good bactericidal activity against the infecting pathogen(s)? Second, is the antibacterial agent safe? Third, is the dosing regimen effective at limiting the development of resistance? Finally, does the dosing regimen maximize the eradication of pathogen? The final question, focusing on the strengths and weaknesses of in vitro modeling in the analysis of dosing regimens, is examined in this article. Although in vitro models may be able to help assess the toxicity of drugs, this issue will not be addressed here.
Obviously, the best method for analyzing the efficacy of a specific dosing regimen is a controlled clinical trial in humans. In addition to being expensive, however, clinical trials are slow, tend to evaluate relatively small numbers of patients, and are hampered by ethical consid-erations that limit the ability to vary dosing too broadly. Animal studies partially circumvent these problems, but differences in pharmaco-kinetic parameters in many animal species versus humans make their evaluation problematic.
As a result, in vivo approaches have been supplemented since the 1960s with models of infection that are carried out in vitro. Although clearly having disadvantages, in vitro systems have many attractive features not shared by in vivo approaches. For instance, in vitro systems are relatively inexpensive, can be more easily controlled than in vivo studies, can be evaluated over a wider range of dosing regimens, can easily evaluate activity of antibacterial agents against a wider variety of bacterial species, and can more accurately mimic bacterial exposure to antimicrobials in humans than many animal models. Thus, while in vitro models cannot replace in vivo studies, they clearly have significant utility.
