Pharmacodynamics and the Impact on Antiinfective Drug Development (antibacterials, antifungals, antivirals)

A workshop co-sponsored by ISAP and CDER (Center for Dug Evaluation and Research [FDA])

• Pre-meeting introduction (goals and objectives)
• Post-meeting conclusions (these will be posted after review by the sponsors; please call again).

ISAP presidential address (Paul M. Tulkens, Brussels, Belgium) Introduction (George L. Drusano, Albany, NY) Use of In Vitro models for preclinical pharmacodynamic modeling(Mike N. Dudley, Mountain View, CA) Animal models: Use in the Evaluation of Anti-Infective Agents (Wiliam A. Craig,  Madison, WI) Setting MIC and disk diffusion interpretive criteria for antibacterials (Sousan S. Altaie, Rockville, MD) The significance of the distribution of pharmacokinetic and pharmacodynamic variability in determining clinical outcomes (He Sun, Rockville, MD) Prediction of antimicrobial therapy outcome: a tree-based modeling approach(Funmilayo Ajayi, Rockville, MD) The role of PK/PD in the assessment of antivirals (Prabhu Rajagopalan, Rockville, MD) Look at the Data, Model the Behavior (Meyer Katzper, Rockville, MD) Pharmacodynamics in Clinical Trials: A Tool-Based Approach (George L. Drusano, Albany, NY) PK/PD Approach and Drug Development: Utility and Regulatory Implications(Kofi Kumi, Rockville, MD) Development of PK/PD relationships: implications for FDA Modernization Act and  the pediatric regulations (Carl.C. Peck, Georgetown, DC) The Clinical Division Heads respond...(Gary Chikami, Mark Goldberger, Heidi Jolson, Rockville, MD) Round-Table (G.L. Drusano, moderator; Paul M. Tulkens, Albert T. Sheldon, Sousan S. Altaie, Lawrence J. Lesko, Philip M. Colangelo, Robert J.Hopkins, Jeffrey S. Murray,  Alexander T. Rakowsky, Arthur Atkinson, William A. Craig, Carl C. Peck, David Foster, Michael N. Dudley, Roger Echols, Lynne Smiley)

Over the last ten years, our understanding of the pharmacodynamics of antiinfective chemotherapy has markedly improved.  This understanding has occured with in vitro models of infection, animal models, and, most recently, clinical trial data.  The latter has been due to advances in mathematics, making sophisticated data analysis tools readily available to investigators.  The combination of in vitro modelling, proper design of animal model experiments, and the willingness to obtain sparse pharmacokinetic information on patients in clinical trials allows an in depth understanding of which aspects of drug exposure are most closely linked to therapeutic outcome as well as to toxicity.  By providing such information to clinicians, drug therapy can achieve the goal of maximal therapeutic effect while engendering the lowest probability of encountering a drug exposure-related adverse event.

    The goal of this workshop is to bring to the reviewers current information and thoughts about in vitro model systems, animal model systems, and clinical trial analysis which link drug exposure to outcomes for anti-bacterials, anti-fungals and anti-virals.  The wokshop will focus on the interrelationship between pharmacokinetics and pharmacodynamics in determining dosing regimens to achieve optimal efficacy of antiinfective agents.  The basic principles to be discussed will also have applications to the optimal dosing of other classes of drugs.

    The relationship between in vitro susceptibility test results, information derived from human pharmacokinetics and pharmacodynamics studies, from animal models, and from clinical study results will focus on how the microbiologist can use this information to set meaningful breakpoints for the labeling of antiinfective agents.  In addition, discussions on post-antibiotic effect (in vitro and in vivo), post-antibiotic leukocytes effects, synergy and antagonism, intracellular killing, etc... will focus on how this information also can be used to help set the breakpoints and dosing regimens for antiinfectives.

    The focus of the programme is on the practical.  That is, how to employ each of these methodologies throughout the drug discovery and development process to speed drug development and to provide informations to clinicians through the package insert so that maximally efficacious and minimally toxic regimens can be prescribed.  The goal of the workshop is educational and it will foster the exchange of scientific information among regulatory, industry and academic investigators.  It is expected that workshop participants will gain a solid understanding of pharmacodynamic principles and how these approaches can be employed in the different stages of the drug development process.  Further, it is anticipated that there will be interchange on how these approaches may be employed to potentially foreshorten the development process.

    The workshop will be sponsored by the Committe for Advanced Scientific Education (CASE) at the Center for Drug Evaluation and Research (CDER) of the Food and Drug Administration (FDA) on the one hand and the International Society of Antiinfective Pharmacology (ISAP) on the other hand.