Evaluation of Exposure-Response Relationships Using Clinical Data: Basic Concepts and Applications

Abstract

An understanding of the relationships between drug exposure and efficacy and/or safety endpoints is useful for optimizing therapy for antimicrobial agents. Such knowledge can help explain why certain patients fail therapy while others are successfully treated and can shed light on whether certain safety endpoints are predictable rather than idiosyncratic. Such exposure-response relationships for efficacy and safety endpoints can together be used to identify both efficacious and safe dosing regimens and thereby balance the competing needs for high efficacy and low toxicity. In order to conduct analyses using clinical data, reliable estimates of drug exposure in individual patients, well-defined and reproducible efficacy and safety endpoints, and appropriate statistical approaches are needed. Herein, we describe the role of population PK methods to estimate drug exposure in patients and provide examples of exposure-response analyses for efficacy and safety for several antimicrobial agents. The examples described were chosen to illustrate different concepts. Applications of such data to improve patient care are also described.