The dose-response relationship in phase I clinical trials and beyond: use, meaning, and assessment.

Knowledge of the relationships among dose, drug concentration in blood, and clinical response is important for the safe and effective use of drugs in individual patients. Recently, pharmacokinetic-pharmacodynamic modeling has been taking an increasingly important place in clinical pharmacology because of its role in the determination of the optimal dosage of a new drug. Its primary objective is also to identify the characterization and prediction of the time course of drug effects under physiological and pathological conditions. Dose-response studies are useful in Phase I for assessing drug tolerance and safety, and invaluable in Phase II for characterizing drug efficacy. Apart from the confirmation of efficacy, the acquired information may help to investigate the shape and location of the dose-response curve, the choice of an appropriate therapeutic starting dose, the identification of optimal strategies for individual dose adjustments, and the determination of a maximal dose beyond which additional benefit is unlikely to be obtained. Recent development of pharmacodynamic models such as the mechanism-based indirect effect model may permit the identification of the physiological component of drug action that is affected by disease, other medications, gender, and other variables. Assessment of dose response should be an integral component of drug development, with studies designed to assess dose response an inherent part of establishing the safety and efficacy of the drug. Drug development can be enhanced with a good understanding of dose-response characteristics and ultimately the benefit/risk ratio of a drug.