What is Exposure-Response Modeling?
Exposure-response analysis refers to developing empirical models to characterize the relationship between drug exposure vs. drug response. Drug response can refer to biomarker changes, safety events, and clinical responses. Data from all individuals in a population are used simultaneously.
When to use Population PK and Exposure-Response Modeling
PopPK is used to characterize pharmacokinetic parameters and the variability in a population. By characterizing the relationship between dose, exposure, and response, the effect of new doses and regimens that have not been studied clinically can be predicted and used to choose the most appropriate doses for further study.
Determining sources of variability in PK, PD, and response can also be achieved through population modeling with covariate analysis. Patient characteristics (or covariates) like body weight, age, gender, ethnicity, kidney and liver function status, or disease state can affect exposure and response. Choosing a dose that maximizes response for all patients, or implementing dose adjustments in particular populations, is critical to the success of new drugs. Understanding how these characteristics impact PK, PD and response is also important when bridging between different patient populations.
Additionally, comprehensive covariate analysis conducted as part of a population modeling effort may even preclude the need to conduct dedicated clinical pharmacology studies. These analyses inform not only internal decision-making but also decisions by regulatory agencies, who have come to expect population modeling support to support decisions from early drug development through submission and beyond.
Example questions addressed by popPK and ER models:
- Justification of dose selection for phase 2 and phase 3 studies
- Justification of switch to flat dosing from weight-based dosing without additional clinical studies
- Justification of dose in pediatric population
- Justification of dose in new indication
- Decision on dose adjustments for special populations
Pediatric Study Support
Population modeling is critical for clinical trials design with pediatric patients from the selection of an appropriate dose in these patients to addressing data limitations due to challenges in collecting sufficient samples from pediatric patients to characterize PK and PD. Tiered fixed and fixed dosing regimens can be explored, and optimal sampling methods can be applied to determine sparse sampling schemes that ensure appropriate information is obtained to characterize PKPD in children and adolescents. Exposure-response models developed in adults can then be used to link exposures in pediatrics to outcomes, with adjustments made for differences in disease pathophysiology in children compared to adults. Regulatory agencies expect such analyses to support pediatric drug development, and internal decision-making can be improved by the use of such approaches.