Introduction: 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.
Methods: 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 [AUC0-12] 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 AUC0-12 values for each body-weight group were compared against target exposure (AUC0-12 = 800‒1200 µg·h/mL).
Results: Distribution and box plots of simulated steady-state AUC0-12 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 AUC0-12 values for both body-weight bands fell within the target exposure range.
Conclusions: 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.
Keywords: DAFFODIL 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. To make sure people with Rett syndrome get the same level of trofinetide in their blood, the dose increases as body weight increases, which is called weight-based dosing. The DAFFODIL study looked at how well girls aged 2–4 years with Rett syndrome responded to trofinetide after receiving twice-daily doses of 5 g for girls weighing from 9 up to 12 kg or 6 g for girls weighing from 12 up to 20 kg. In order to check whether the weight-based dosing used in DAFFODIL resulted in blood levels that were known to achieve the best response with trofinetide, researchers used computer modeling called population pharmacokinetics to predict trofinetide blood levels in DAFFODIL. The population pharmacokinetic modeling showed that the amount of trofinetide in the blood over a 12-h time period following a single dose of 5 g (for body weights ≥ 9 to < 12 kg) or 6 g (for body weights ≥ 12 to < 20 kg) achieved the same blood level of trofinetide that is known to be effective in Rett syndrome. These results confirm that the weight-based dosing that was used in the DAFFODIL study was suitable to achieve the best possible outcome with trofinetide in girls aged 2–4 years with Rett syndrome.
© 2024. The Author(s).