132: Limited Potential for Interactions Between Trofinetide, a New Treatment for Rett Syndrome, & Drugs Metabolized By CYP3A4

Statement of Purpose: Trofinetide, the first drug to be approved for the treatment of Rett syndrome, showed potential for CYP3A4 mediated drug-drug interaction (DDI) in vitro. Although the measured concentration producing 50% inhibition of CYP3A4 (IC50) was high ( >15 mM), relatively high intestinal concentrations are expected following oral dosing, thus there is potential for DDI in vivo. Using a physiologically based pharmacokinetic (PBPK) model, we studied the effect of trofinetide at the therapeutic dose on the pharmacokinetics of coadministered midazolam, a sensitive index substrate for CYP3A4.

Description of Methods & Materials: Deterministic and stochastic simulations were performed using the PBPK model to assess oral (15 mg) or intravenous (2 mg) midazolam exposure parameters (maximum drug concentration [C_max] and area under the concentration-time curve from time 0 to infinity [AUC_inf]) with and without coadministration of single and multiple oral trofinetide doses (12 g).

Data & Results: Deterministic and stochastic simulations indicated that trofinetide does not impact CYP3A4 enzyme activity in the liver, as C_max and AUC_inf were unchanged for intravenous midazolam following trofinetide coadministration (Table). For oral midazolam, simulations with trofinetide coadministration predicted small increases in the C_max (17—20%) and AUC_inf (25—33%) due to higher concentrations of trofinetide in the intestinal wall immediately after oral administration (Table & Figure).

Interpretation, Conclusion or Significance: The PBPK model suggests that at the therapeutic dose, trofinetide does not impact CYP3A4 metabolism in the liver but may be a weak inhibitor of CYP3A4 metabolism in the gut.

Disclosures: MD, JMY, HB, KMB are employees of Acadia Pharmaceutical Inc; ID, VL, JSO are employees of Simulations Plus Inc.