Applying Longitudinal Dose-Response Modeling to Early Phase Data from SAD and MAD Studies for Enhanced Decision-Making

Music City Center 

Early-phase clinical studies, including single ascending dose (SAD)
and multiple ascending dose (MAD) trials, provide essential data for
defining the dose-response relationship of investigational
compounds. Standard dose-response analyses often rely on
endpoint-based assessments, which may overlook temporal trends in
response that impact later-phase dosing decisions. To address these
complexities, we applied a longitudinal dose-response model using an
additive exponential framework to capture both the up- and down-trends
in response over time, providing a nuanced understanding of drug
activity and safety throughout early development.


The additive exponential model accommodates fluctuations in response
by modeling the increase and subsequent attenuation of drug effects
following each dose. Specifically, this approach combines exponential
functions to capture the rapid initial response and the slower decay
observed at later time points. This structure is particularly
well-suited to represent the pharmacodynamic profiles observed in SAD
and MAD studies, where the magnitude and duration of response can vary
significantly between single and repeated dosing regimens. By treating
dose and time as continuous covariates and incorporating a
random-effects component, the model allows for the simultaneous
estimation of dose-response trajectories across various dose levels
and time points, accounting for inter-individual variability and
ensuring applicability across diverse patient profiles.


The additive model, while simple to implement, provides an accurate
characterization of the temporal patterns in response that has a
reasonable mechanistic interpretation, which is especially valuable for
compounds with complex pharmacokinetic and pharmacodynamic
profiles. The results enable refined predictions of efficacy and
safety profiles, facilitating improved go/no-go decision-making, dose
selection for Phase II trials, and adaptive design strategies.

Dose-response modeling, longitudinal analysis, additive exponential model

SAD studies, MAD studies, early-phase clinical trials

Bayesian hierarchical model, pharmacokinetics,
pharmacodynamics