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Introduction <p>Trofinetide is an approved treatment in the USA and Canada for Rett syndrome in patients aged ≥ 2&#xa0;years. Trofinetide is currently supplied as a ready-to-use oral solution (TOS). A new trofinetide powder for oral solution (TPOS) offers potential advantages: smaller configuration of unit-dose packs; excludes preservatives, synthetic red dye, and maltitol; can be dissolved in a range of volumes in cold/room temperature water or water-based beverages; does not require refrigeration. To ensure that the formulation change does not impact trofinetide pharmacokinetics, a bioequivalence study assessed trofinetide pharmacokinetics after single 12,000-mg oral trofinetide doses administered as TOS and TPOS and the impact of a reduced constitution volume on trofinetide bioavailability.</p> Methods <p>In this randomized, open-label, three-period, three-treatment design study, 38&#xa0;healthy adults each received one 12,000-mg trofinetide dose of TOS (60&#xa0;mL [200&#xa0;mg/mL]; treatment&#xa0;A), TPOS constituted in 60&#xa0;mL of water (200&#xa0;mg/mL; treatment&#xa0;B), and TPOS constituted in 25&#xa0;mL of water (480&#xa0;mg/mL; treatment&#xa0;C) in sequence ABC or BAC. Bioequivalence for each treatment comparison was confirmed if the 90% confidence interval (CI) of the geometric mean ratio (GMR) for the maximum observed drug concentration (<i>C</i><sub>max</sub>), area under the concentration–time curve from time&#xa0;0 to time <i>t</i> (AUC<sub>0–<i>t</i></sub>), and AUC from time&#xa0;0 to infinity (AUC<sub>0–∞</sub>) fell within 80–125%.</p> Results <p>The criteria for bioequivalence were met for AUC<sub>0–<i>t</i></sub> (GMR 99.62%; CI 96.52–102.83), AUC<sub>0–∞</sub> (GMR 99.50%; CI 96.44–102.66), and <i>C</i><sub>max</sub> (GMR 99.52%; CI 94.99–104.27) between treatment&#xa0;B and treatment&#xa0;A. All other treatment comparisons (C vs A and B vs C) also met the bioequivalence criteria. The most frequent treatment-emergent adverse event was diarrhea (<i>n</i> = 6 [15.8%]). No serious or unexpected adverse events occurred during the study.</p> Conclusion <p>The bioequivalence demonstrated in this study supports the clinical interchangeability of TPOS and TOS and shows that TPOS can be constituted using adjustable volumes of water without affecting bioavailability. There were no unexpected adverse events reported with trofinetide when administered as TPOS and TOS.</p> Graphical Abstract <p></p>

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A Phase 1, Randomized, Open-Label Study to Assess the Bioequivalence of Trofinetide as a Ready-to-Use Oral Solution and Constituted Powder for Oral Solution in Healthy Adults

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  • 发表日期：

    2026年2月12日

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  • Mona Darwish,
  • Amy Yamamoto,
  • Yvonne Adegbenle,
  • Ravi Tejwani,
  • Yonghua Chen,
  • Rene Nunez-Disla,
  • James M. Youakim,
  • Sanjeev Pathak

摘要

Introduction

Trofinetide is an approved treatment in the USA and Canada for Rett syndrome in patients aged ≥ 2 years. Trofinetide is currently supplied as a ready-to-use oral solution (TOS). A new trofinetide powder for oral solution (TPOS) offers potential advantages: smaller configuration of unit-dose packs; excludes preservatives, synthetic red dye, and maltitol; can be dissolved in a range of volumes in cold/room temperature water or water-based beverages; does not require refrigeration. To ensure that the formulation change does not impact trofinetide pharmacokinetics, a bioequivalence study assessed trofinetide pharmacokinetics after single 12,000-mg oral trofinetide doses administered as TOS and TPOS and the impact of a reduced constitution volume on trofinetide bioavailability.

Methods

In this randomized, open-label, three-period, three-treatment design study, 38 healthy adults each received one 12,000-mg trofinetide dose of TOS (60 mL [200 mg/mL]; treatment A), TPOS constituted in 60 mL of water (200 mg/mL; treatment B), and TPOS constituted in 25 mL of water (480 mg/mL; treatment C) in sequence ABC or BAC. Bioequivalence for each treatment comparison was confirmed if the 90% confidence interval (CI) of the geometric mean ratio (GMR) for the maximum observed drug concentration (Cmax), area under the concentration–time curve from time 0 to time t (AUC0–t), and AUC from time 0 to infinity (AUC0–∞) fell within 80–125%.

Results

The criteria for bioequivalence were met for AUC0–t (GMR 99.62%; CI 96.52–102.83), AUC0–∞ (GMR 99.50%; CI 96.44–102.66), and Cmax (GMR 99.52%; CI 94.99–104.27) between treatment B and treatment A. All other treatment comparisons (C vs A and B vs C) also met the bioequivalence criteria. The most frequent treatment-emergent adverse event was diarrhea (n = 6 [15.8%]). No serious or unexpected adverse events occurred during the study.

Conclusion

The bioequivalence demonstrated in this study supports the clinical interchangeability of TPOS and TOS and shows that TPOS can be constituted using adjustable volumes of water without affecting bioavailability. There were no unexpected adverse events reported with trofinetide when administered as TPOS and TOS.

Graphical Abstract