Population Pharmacokinetics of Trofinetide in a Pediatric Population Aged 2–4 Years with Rett Syndrome

Weight-banded trofinetide dosing improved physician- and caregiver-rated efficacy measures and had acceptable tolerability in patients aged 2‒4 years (DAFFODIL study) and 5‒20 years (LAVENDER study) with Rett syndrome (RTT). Selection of weight-banded dosing regimens for these studies was based on population pharmacokinetic (popPK) modeling and exposure simulations. This study applied an updated popPK model to confirm steady-state trofinetide exposures achieved in DAFFODIL patients were within target range.

A popPK model was developed using data from 14 clinical studies of trofinetide in healthy volunteers and pediatric and adult patients, including the LAVENDER and DAFFODIL studies. Individual exposure measures (area under concentration–time curve over 0–12 h [AUC_0–12] were generated via integration of the predicted concentration–time profile for each DAFFODIL study participant based on the popPK model and individual empiric Bayesian pharmacokinetic parameter estimates. Distributions of steady-state AUC_0–12 values for each body-weight group were compared against target exposure (AUC_0–12 = 800‒1200 µg·h/mL).

Distribution and box plots of simulated steady-state AUC_0–12 values achieved with the weight-banded DAFFODIL dosing regimen used in younger individuals aged 2–4 years with RTT (twice daily trofinetide 5 g [≥ 9 to < 12 kg] or 6 g [≥ 12 to < 20 kg]) indicated good overlap with the target exposure range. Median steady-state AUC_0–12 values for both body-weight bands fell within the target exposure range.

PopPK model-based simulations confirm that the weight-banded dosing regimen used in DAFFODIL is adequate to achieve target trofinetide exposure in 2- to 4-year-olds with RTT.