Authors :
Presenting Author: James Youakim, MD – Acadia Pharmaceuticals, Inc.
First Author: Mona Darwish, MD, PhD – Acadia Pharmaceuticals Inc.
Julie Passarell, MA – Cognigen Corporation; Heather Barcomb, MA – Cognigen Corporation (a Simulations Plus company); James Youakim, MD – Acadia Pharmaceuticals; Kathie Bishop, PhD – Acadia Pharmaceuticals
Rationale: Rett syndrome (RTT) is a debilitating neurodevelopmental disorder associated with a range of symptoms, including seizures. Trofinetide (DAYBUE
™) is the first drug to be approved for the treatment of RTT in patients two years of age and older. Seizure is common in RTT and is managed using antiepileptic drugs (AEDs), which are known to interact with a wide range of medications. Pharmacokinetic (PK) and exposure-response (E-R) modeling were used to assess potential drug-drug interactions (DDI) with AEDs, and to correlate trofinetide exposure and seizure incidence. Methods: Safety data from three studies in females with RTT were pooled. Individual trofinetide exposure measures including area under the concentration-time curve for the dosing interval of 0 to 12 hours (AUC
0-12) and maximum drug concentration (C
max) were estimated from a population pharmacokinetic model and Bayesian approach. Potential DDIs were investigated by comparing the AUC in study participants with and without co-administered AED. For E-R models, logistic regression models were used to predict the probability of seizures for each predicted drug exposure. Model development involved: 1) Exploratory data analysis; 2) Base structural model development incorporating drug exposure; 3) Evaluation of covariate effects; 4) Model refinement; and 5) Model evaluation.
Results: The safety dataset included 323 participants (trofinetide n=185 and placebo n=138). Comparing exposure parameters (AUC) in participants receiving trofinetide showed a complete overlap in exposures between participants with and without AED indicating a lack of effect of AED on trofinetide (
Figure 1). Exploratory E-R analyses demonstrated that the occurrence of seizures was consistently low across trofinetide exposure measures, and the range of trofinetide exposures overlapped across the seizure severity categories of mild, moderate, and severe (
Figure 2) indicating no E-R relationship between trofinetide exposures and seizures. E-R assessments using linear and exponential logistic regression models, showed none of the exposure measures were statistically significant predictors (α = 0.05) of the probability of seizures confirming the lack of correlation.
: There is no potential DDI between trofinetide, the first approved treatment for Rett syndrome, and AEDs, which are commonly used to manage seizures in RTT. Furthermore, trofinetide treatment does not increase the incidence of seizures in RTT. These findings confirm that trofinetide can be coadministered with AEDs without any safety concerns.
Funding: Acadia Pharmaceuticals, Inc