Introduction
organ dysfunction
DISEASE
The clinical development journey of novel pharmaceuticals is a complex multistage process, which continues to evolve as our understanding of disease biology deepens, new therapeutic entities and classes of drugs are designed, and regulatory mechanisms adapt to the changing therapeutic landscape. Traditionally, oncology clinical development began with dose-escalation studies that aimed to identify the maximum tolerated dose in small cohorts of patients (One of the objectives of clinical pharmacology is to characterize pharmacokinetics by understanding the absorption, distribution, metabolism, and excretion pathways of the drug in the body. Another major objective is to determine how drug concentrations are altered by intrinsic and extrinsic factors. Intrinsic factors are inherent to a person and include age, sex, race, genomics, and organ function, whereas extrinsic factors are external influences that may affect drug exposure, such as concomitant medications or the type of food ingested around the time of drug administration. Finally, the main goal of clinical pharmacology is to justify the dose based on the relationship between exposure and biological response, which can be assessed in terms of efficacy, safety, or pharmacodynamic biomarkers.Clinical pharmacology findings generated in early studies can inform late-stage study designs. For example, insight into potential interactions with food and concomitant medications can guide decisions on drug administration schedules and prohibited or permitted concomitant medications (In this article, we describe the clinical pharmacology characterization of giredestrant, a highly potent nonsteroidal oral selective estrogen receptor (ER) antagonist and degrader (This first-in-human phase Ia/Ib dose-escalation/-expansion study was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant. In particular, the pharmacokinetics were evaluated by characterizing the absorption, distribution, metabolism, and excretion of giredestrant, and generated signal-seeking data on the impact of certain intrinsic factors (including race and organ dysfunction) and extrinsic factors (including the effect of food and DDIs) on giredestrant exposure. The primary results from this study have been reported elsewhere (