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  11. Physiologically-based Pharmacokinetic Modeling Of Trofinetide In Moderate Renal Impairment For Phase 1 Clinical Study Dose Selection With Model Validation

Physiologically-Based Pharmacokinetic Modeling of Trofinetide in Moderate Renal Impairment for Phase 1 Clinical Study Dose Selection with Model Validation

Mona Darwish1, Thomas C Marbury2, Rene Nunez3

  • 1Acadia Pharmaceuticals Inc, 12830 El Camino Real, Suite 400, San Diego, CA, 92130, USA. mdarwish@acadia-pharm.com.

European Journal of Drug Metabolism and Pharmacokinetics
|November 8, 2024

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View abstract on PubMed

Summary
This summary is machine-generated.

Trofinetide, a treatment for Rett syndrome, requires dose adjustment in moderate renal impairment. A 50% dose reduction was validated through pharmacokinetic modeling and a Phase 1 study, showing no new safety concerns.

Area of Science:

  • Pharmacology
  • Clinical Pharmacology
  • Renal Impairment

Background:

  • Rett syndrome (RTT) treatment trofinetide is renally excreted.
  • Assessing trofinetide exposure in renal impairment is crucial for safe dosing.
  • Pharmacokinetic modeling aids dose finding in special populations.

Purpose of the Study:

  • Evaluate trofinetide pharmacokinetics, safety, and tolerability in moderate renal impairment.
  • Validate a physiologically-based pharmacokinetic (PBPK) model's predictions for dose adjustment.
  • Compare trofinetide exposure in healthy individuals versus those with moderate renal impairment.

Main Methods:

  • A PBPK model predicted dose adjustments for renal impairment stages.
  • A Phase 1, open-label study assessed trofinetide exposure in healthy (n=10) and moderate renal impairment (n=10) participants.

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  • Observed exposures (AUCinf, Cmax) were compared to PBPK model predictions.

    • Main Results:

    • Dose-normalized Cmax was comparable between groups; AUCinf was ~2-fold higher in moderate renal impairment.
    • Observed exposures closely aligned with PBPK model predictions.
    • Adverse events were comparable, with no new safety concerns identified.

    Conclusions:

    • PBPK modeling accurately predicted a 50% trofinetide dose reduction for moderate renal impairment.
    • Phase 1 study results validated the predicted dose reduction.
    • Trofinetide demonstrated a favorable safety profile in individuals with moderate renal impairment.