Skipping a Pillar Does Not Make for Strong Foundations: Pharmacokinetic-pharmacodynamic Reasoning Behind the Shape of Dose-Response Relationships in Oncology.

Dose-response analysis is often applied to the quantification of drug-effect especially for slowly responding disease end points where a comparison is made across dose levels after a particular period of treatment. It has long been recognized that exposure - response is more appropriate than dose-response. However, trials necessarily are designed as dose-response experiments. Second, a wide range of functional forms are used to express relationships between dose and response. These considerations are also important for clinical development because pharmacokinetic (PK; and variability) plus pharmacokinetic-pharmacodynamic modeling may allow one to anticipate the shape of the dose-response curve and so the trial design. Here, we describe how the location and steepness of the dose response is determined by the PKs of the compound being tested and its exposure-response relationship in terms of potency (location), efficacy (maximum effect) and Hill coefficient (steepness). Thus, the location (50% effective dose [ED50 ]) is dependent not only on the potency (half-maximal effective concentration) but also the compound's PKs. Similarly, the steepness of the dose response is shown to be a function of the half-life of the drug. It is also shown that the shape of relationship varies dependent on the assumed time course of the disease. This is important in the context of drug-discovery where the in vivo potencies of compounds are compared as well as when considering an analysis of summary data (for example, model-based meta-analysis) for clinical decision making.