Introduction: Oral trofinetide administered using a body weight-banded dosing regimen was approved in the US for the treatment of Rett syndrome (RTT) in patients aged ≥ 2 years. This approval was principally based on efficacy and safety findings of the phase 3 LAVENDER study in girls and women aged 5-20 years with RTT and extended to younger children aged 2-4 years with supporting data from the DAFFODIL study. Weight-banded dosing regimens were selected based on early clinical population pharmacokinetic (popPK) modeling and different scenario simulations. We report the development and application of an updated popPK model to confirm that steady-state trofinetide exposures achieved in individual patients in the LAVENDER study were within target exposure range.
Methods: A previously developed popPK model using data from nine clinical studies was updated based on 13 clinical studies of trofinetide in healthy volunteers and pediatric and adult patients, including the LAVENDER study. PopPK model and empiric individual Bayesian pharmacokinetic parameter estimates were used to generate trofinetide exposures. Covariate data from the pharmacokinetic dataset from LAVENDER study subjects (n = 92) were used to estimate individual steady-state trofinetide exposure (area under concentration-time curve over 0-12 h [AUC0-12]). Steady-state exposures in individual patients in the LAVENDER study were used to confirm that the dosing regimens resulted in exposures within the target range.
Results: Among 5- to 20-year-olds receiving the LAVENDER BID dosing regimen [trofinetide 6 g (12‒20 kg), 8 g (> 20‒35 kg), 10 g (> 35‒50 kg), and 12 g (> 50 kg)], simulated AUC0-12 values overlapped with the target exposure range; median AUC0-12 values were within target exposure range for all weight bands.
Conclusions: PopPK model-based simulations confirm that weight-banded trofinetide dosing used in LAVENDER in girls and women aged 5-20 years with RTT achieved target exposure. Graphical abstract available for this article.
Keywords: LAVENDER study; Population pharmacokinetic modeling; Rett syndrome; Trofinetide; Weight-banded dosing regimen.
Trofinetide is the first approved treatment for Rett syndrome, a rare genetic condition that affects brain development. Researchers first used computer modeling called population pharmacokinetics to show that the dose of trofinetide needs to increase as body weight increases in order to get the same level of trofinetide that is predicted to be effective in the blood of people with Rett syndrome. This dosing method was used in the LAVENDER study in girls and women aged 5–20 years with Rett syndrome, in which four different doses of trofinetide were matched to specific bands or groups of body weight as follows: twice daily doses of 6 g to people weighing between 12 and 20 kg, 8 g for people weighing from 20 kg up to 35 kg, 10 g for people weighing from 35 kg up to 50 kg, or 12 g for people weighing over 50 kg. To confirm that the weight-banded dosing used in LAVENDER resulted in blood levels that fell within the range known to be effective, researchers used an updated model to predict blood levels over time for each of the four weight-banded dosing groups. Researchers showed that the computer simulated blood levels over time for each of the weight-banded dosing groups all fell within the range known to be effective, thus confirming that the weight-banded dosing used in LAVENDER was appropriate, and ensured that people in the study were exposed to the target level of trofinetide.
© 2024. The Author(s).