ArticleEuropean journal of drug metabolism and pharmacokinetics2025
Physiologically-Based Pharmacokinetic Modeling of Trofinetide in Moderate Renal Impairment for Phase 1 Clinical Study Dose Selection with Model Validation.
Article in European journal of drug metabolism and pharmacokinetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- 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.Advances in therapy · 2026Trial
- Real-World Demographics, Clinical Characteristics, and Predictors of Persistence Among Males with Rett Syndrome Treated with Trofinetide.Advances in therapy · 2026Article
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Authors and funding
8 authors.
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Abstract
BACKGROUND AND
objectivesTrofinetide, the first approved treatment for Rett syndrome (RTT), is primarily excreted unchanged in the urine; therefore, it is important to assess the extent to which the exposure is affected in patients with renal impairment. Pharmacokinetic modeling overcomes the challenge of dose finding in phase 1 studies that include special populations where there is the potential for increased exposure to study drug. The objectives of this phase 1 study were to evaluate trofinetide pharmacokinetics, safety, and tolerability in a population with moderate renal impairment and normal renal function. The observed pharmacokinetic profiles were used to validate the dosing adjustments in moderate renal impairment that were previously predicted using a physiologically-based pharmacokinetic (PBPK) model.
methodsThe PBPK model was first used to predict dose adjustments that are necessary to achieve similar exposure in the four stages of renal impairment (mild, moderate, severe, end stage renal disease) as in healthy controls. The predicted dose adjustment from 12 to 6 g for the moderate renal impairment category was then applied to the phase 1 clinical study. Subsequent validation of the PBPK model was achieved by comparing the model-predicted and clinically observed exposures in subjects with moderate renal impairment. In a phase 1, open-label study, trofinetide exposure was assessed in healthy (n = 10) and moderate renal impairment (n = 10) participants receiving single oral doses of 12 g or 6 g, respectively. Observed exposures [area under the blood concentration-time curve from time 0 to infinity (AUC
resultsDose-normalized geometric mean ratios for C
conclusionPBPK modeling of trofinetide in a virtual population with moderate renal impairment predicted a 50% dose reduction compared to individuals with normal renal function. Comparison of observed pharmacokinetic results from a phase 1 study in subjects with moderate renal impairment and matched healthy participants to the model-predicted exposures validated this dose reduction. No new safety concerns for trofinetide emerged.
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