PURPOSE: We describe the clinical pharmacology characterization of giredestrant in a first-in-human study. EXPERIMENTAL DESIGN: This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg once daily. Dose-escalation and -expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg. RESULTS: Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration-time curve from 0 to 24 hours at steady state was 4,320 ng·hour/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug-drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients. CONCLUSIONS: This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development. SIGNIFICANCE: This work illustrates how comprehensive clinical pharmacology characterization can be integrated into first-in-human studies in oncology. It also demonstrates the value of understanding clinical pharmacology attributes to inform eligibility, concomitant medications, and combination dosing and to directly influence late-stage trial design and accelerate development.