Implementation of an MIDD strategy for ruxolitinib dosing in pediatric GvHD populations, and varying opinions of regulators
Karen Sinclair, Justine Badée, Annie St-Pierre
Novartis Pharma AG
Introduction: Ruxolitinib is approved globally for the treatment of myelofibrosis (MF) and Polycythemia Vera (PV) in adults, and acute/chronic Graft vs. Host Disease (a/cGvHD) in adults and adolescents. Due to the extensive amount of ruxolitinib data, a Model Informed Drug Development (MIDD) strategy was agreed with EMA’s PDCO and other Health Authorities for further pediatric development, for patients aged 2-<12y with GvHD. PBPK modeling was used to recommend starting doses, to be tested in two pediatric studies in a/cGvHD patients aged 2-<12y, and to extrapolate to patients <2y who were not recruited to the studies. PopPK and E-R models were to be used to analyse the data from the two pediatric studies to confirm the doses in patients aged 2-<12y. After discussing the evolution of this MIDD strategy over time, this presentation will look at the differences in interpretation of the modeling results by regulators, leading to the adoption of different dosing regimens in different regions. Methods: Dose recommendation for patients aged 2-<12y: An exposure-matching concept based on the principle of similarity in disease and PK between adults and pediatrics, was applied to recommend doses with the intention of reaching a target exposure level (based on median AUC0-12) observed in adult GvHD patients. Targeting the AUC associated with the approved and efficacious dose in adults and adolescents, would imply an efficacious response in pediatric patients. To identify the doses in a/cGvHD patients aged 2-<6y and 6-<12y, PBPK models were developed based on GvHD adult and adolescent data. Dose confirmation for patients aged 2-<12y: PopPK models were developed in a/cGvHD adult and adolescent patients to describe specific properties of ruxolitinib in GvHD. The data collected in the pediatric studies in patients aged 2-<12y were then combined with adult and adolescent data to characterize the drug properties across the entire GvHD population (a/c, adults/adolescents/children). Exposure-response models for efficacy and safety events were developed in adults and adolescents, and combined with data from children <12y, to compare consistency of exposure/response/safety between children and adults. Extrapolation to patients <2y: Upon completion of the pediatric studies (2-<12y), PBPK models were updated and used to recommend doses for patients <2y with a target exposure level based on the median AUC value observed in pediatrics. Results: A lower median AUC was observed in some subgroups of pediatric patients compared to the target AUC level in adults, but various parameters were generally within a 95% target exposure range obtained from adults. Exposure-response models developed for pediatric patients together with adult/adolescent data, showed consistency of the efficacy and safety rates, as well as the exposure effect across age groups. The PBPK model updated with data from the pediatric studies and information relating to covariate effects from the PopPK model delivered dose recommendations for patients <2y. However, there was some uncertainty due to the high PK variability and limited sample size in pediatrics, prohibiting the qualification of the model. To provide reassurance of the doses, an additional PopPK model with an ontogeny function implemented was developed, as proposed by the CHMP. These dose recommendations overlapped with those recommended by PBPK, for most of the patient age groups, increasing confidence in the methods used for the final dose proposals in patients <2y, and even the older pediatric age groups. The original MIDD strategy was consistent across regions, however the adoption of the doses proposed by modeling varied across interactions with regulators. In some regions, modeling was supportive evidence to justify the doses tested in the pediatric studies and allow extrapolation to younger patients based on those tested doses only. In EU, modeling provided the basis to adjust the dose even in the tested age groups, as well as propose alternative doses to the younger age group. The difference in opinion on the strength of evidence from MIDD across regions highlights the need for continued alignment in modeling approaches and techniques and the purpose for which they are used (dose recommendation/confirmation/adjustments).
Video link:
https://www.youtube.com/watch?v=IEzMp69JLGE
