Abstracts

Rationale: Trofinetide is a novel synthetic analog of the tripeptide glycine–proline–glutamate (GPE), a product of the naturally occurring cleavage of insulin-like growth factor 1. It is thought to stimulate synaptic maturation and normalize aberrant neuronal and glial functioning characteristic of Rett syndrome (RTT) pathophysiology. Trofinetide showed improvements across clinician and caregiver efficacy measures in phase 2 RTT trials (4–6 weeks duration) in pediatric and adult subjects. Almost 9 of 10 individuals with RTT have seizures during their lifetime; the majority require antiseizure medication at some point. Many anticonvulsants are metabolized by Cytochrome P450 (CYP) 3A4. In vitro studies suggest that trofinetide has low potential to inhibit CYP3A4 in the liver at targeted plasma concentrations but could potentially inhibit CYP3A4 at higher trofinetide concentrations that may be present in the gut after oral dosing. Using a physiologically based pharmacokinetic (PBPK) model, we studied the effect of trofinetide on the PK of coadministered midazolam, a sensitive index substrate for CYP3A4. Simulations of oral versus IV midazolam administration allowed the differentiation of local (gut) from systemic (liver) metabolism.

Methods: Using the validated PBPK model, deterministic and stochastic simulations were performed to assess midazolam exposure parameters (C_max and AUC_inf) for oral (15 mg) or IV (2 mg) midazolam with and without coadministration of oral trofinetide at the anticipated therapeutic dose (12 g).

Results: Deterministic and stochastic simulations indicated that trofinetide does not impact CYP3A4 enzyme activity in the liver. Exposure parameters (C_max and AUC_inf) were unchanged for IV midazolam following trofinetide coadministration (Table). For oral midazolam, simulations with trofinetide coadministration predicted small increases in the C_max and AUC_inf, by 24% and 37%, respectively (Table & Figure). This is due to higher concentrations of trofinetide in the intestinal wall immediately after oral administration, prior to absorption, causing a time-dependent local inhibition of CYP3A4 in the gut.

Conclusions: The PBPK model suggests that trofinetide levels in plasma do not impact CYP3A4 metabolism in the liver. However, after oral administration of an anticipated therapeutic dose, trofinetide may be a weak inhibitor of CYP3A4 metabolism locally in the gut, because of the relatively high concentrations of trofinetide present in the intestinal wall immediately after dosing. Accordingly, although the level of inhibition is weak, staggering the administration time of anticonvulsants metabolized by CYP3A4 for 2-3 hours after trofinetide administration may be a strategy to minimize the potential for an increase in systemic anticonvulsant.

Funding: Please list any funding that was received in support of this abstract.: Acadia Pharmaceuticals.