Back to Search
Start Over
Exposure-Response Efficacy Modeling to Support Trofinetide Dosing in Individuals with Rett Syndrome.
- Source :
-
Advances in therapy [Adv Ther] 2024 Apr; Vol. 41 (4), pp. 1462-1480. Date of Electronic Publication: 2024 Feb 16. - Publication Year :
- 2024
-
Abstract
- Introduction: Trofinetide was recently approved for the treatment of Rett syndrome (RTT) on the basis of the efficacy and safety findings of the phase 3 LAVENDER study, which used a body weight-based dosing regimen. Exposure-response (E-R) efficacy modeling was used to characterize relationships between trofinetide exposure measures (maximum drug concentration and area under the concentration-time curve for the dosing interval of 0-12 h [AUC <subscript>0-12</subscript> ]) and efficacy endpoints in RTT clinical studies to support the trofinetide dosing regimen.<br />Methods: Efficacy endpoints were modeled using trofinetide exposure measures predicted from the population pharmacokinetic model and Bayesian estimates. The analysis population for each E-R model comprised individuals receiving placebo or trofinetide who had available trofinetide exposure measures. Efficacy endpoints were scores from the Rett Syndrome Behaviour Questionnaire (RSBQ), the Clinical Global Impression-Improvement, the Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite, and the Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC).<br />Results: Higher trofinetide exposure was associated with improvements in RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Assuming target trofinetide AUC <subscript>0-12</subscript> values of 800-1200 μg·h/mL, the reductions in RSBQ total scores at week 12 were approximately five- to seven-fold greater with trofinetide (range 3.55-4.94) versus placebo (0.76). Significant E-R relationships were also found for the CSBS-DP-IT Social Composite and RTT-COMC scores.<br />Conclusion: E-R efficacy modeling demonstrated significant relationships between trofinetide exposure and RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Trofinetide is efficacious within the target exposure range, supporting the approved dosing regimen for trofinetide.<br />Trial Registration: NCT01703533, NCT02715115, NCT04181723.<br /> (© 2024. The Author(s).)
Details
- Language :
- English
- ISSN :
- 1865-8652
- Volume :
- 41
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Advances in therapy
- Publication Type :
- Academic Journal
- Accession number :
- 38363467
- Full Text :
- https://doi.org/10.1007/s12325-024-02796-y