multipleascendingdose

Multiple ascending dose (MAD) studies are a type of early-phase clinical trial in which an investigational drug is administered to participants at increasing dose levels across successive cohorts, with each cohort receiving multiple doses over a defined period. The goal is to characterize safety, tolerability, pharmacokinetics, and pharmacodynamics under repeated dosing and to understand dose-proportionality and potential accumulation.

Design and methodology commonly involve small cohorts (for example 6–12 participants per cohort). Within a cohort, participants receive the same dose for a defined period, and a safety review occurs before advancing to a higher dose in a new cohort. Escalation continues until predefined stopping criteria are met, such as the appearance of dose-limiting toxicities, unfavorable pharmacokinetic profiles, or intolerability. Sentinel dosing may be used at the first dose level to minimize risk. Pharmacokinetic sampling is performed to determine parameters such as Cmax, trough concentrations, AUC, half-life, and accumulation. Pharmacodynamic endpoints or biomarker measurements may be included to relate exposure to effect.

MAD studies are standard in Phase I to support selection of a recommended Phase II dose or the maximum tolerated dose in oncology, while in non-oncology programs the aim is often to identify a safe and potentially efficacious dose. The approach provides critical information on safety and exposure for repeated dosing but requires careful ethical and regulatory oversight, as well as consideration of study duration, variability, and resource use. The term is commonly abbreviated MAD.