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Pharmacokinetics I: PK-PD Approach, the Case of Antibiotic Drug Development

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Clinical Pharmacology: Current Topics and Case Studies

Abstract

The therapeutic efficacy of antibiotics is very dependent not only on the drug itself but also on whether there is enough drug concentration at the site of infection for a sufficient amount of time that would stop the development of bacterial resistance and on the susceptibility and severity of the infection. Therapeutic success of therapy is also dependent on the physiological characteristics of the host, including disease state, age, comorbidity, and other factors that are highly variable in the clinical setting. Understanding how these factors or covariates affect antibiotic disposition and their pharmacological effects as well as the relationship between drug concentration in the body at the site of infection and the drug effect on the bacterial pathogen is part of the general concepts of pharmacokinetics (PK) and pharmacodynamics (PD). By using PK-PD principles and linking specific PK exposure parameters to microbiological outcomes, clinicians have designed better dosing strategies for specific classes of antibiotics. By evaluating how covariates affect the drug disposition in specific patient population, dosing regimens can be designed for that population to achieve an optimal therapeutic goal. We examined PK-PD principles that characterize antibiotic activities, experimental designs to characterize pharmacodynamic properties of antimicrobial agents, modeling and simulation approach for translation from in vitro time-kill and animal infection models to human efficacy, and dosing strategies in special populations including critically ill, renal-impaired, obese, geriatric, and pediatric patients, as well as Bayesian approach to individualize dosing regimens based on the sampled drug concentration in a therapeutic drug-monitoring setting. The model-based approach can also streamline the drug development process and support decision-making with greater confidence. These decisions include but not limited to planning clinical trials and developing optimal dosing strategies, and these crucial steps in the drug development process can be costly if the wrong decisions are made. From the perspective of clinical practice, the modeling and simulation approach can provide a more precise medicine to the patients and improve the healthcare outcome. By utilizing all the information available, from in vitro studies, animal models, clinical trials, and patient characteristics, the goal is to maximize the benefits to the patients through evidence-based medicine and practice.

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  1. Department of Pharmaceutics, College of Pharmacy, University of Florida, 1345 Center Drive, Room P3-20, 100494, Gainesville, FL, 32610, USA

    Sherwin K. B. Sy & Hartmut Derendorf PhD

  2. Programa de Pós-Graduação em Bioestatística, Universidade Estadual de Maringá, Av. Colombo, 5790, Bloco E-90, Campus Universitário, CEP 87020-900, Maringá, PR, Brazil

    Sherwin K. B. Sy

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    Markus Müller

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Sy, S.K.B., Derendorf, H. (2016). Pharmacokinetics I: PK-PD Approach, the Case of Antibiotic Drug Development. In: Müller, M. (eds) Clinical Pharmacology: Current Topics and Case Studies. Springer, Cham. https://doi.org/10.1007/978-3-319-27347-1_13

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