Population Pharmacokinetic Modeling to Support Trofinetide Dosing for the Treatment of Rett Syndrome

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.

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 [AUC_0–12]). 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.

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 AUC_0-12 values overlapped with the target exposure range; median AUC_0–12 values were within target exposure range for all weight bands.

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.

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