178: In Silico Physiologically Based Pharmacokinetic Model of the Effect of Hepatic Impairment on Trofinetide Exposures

Statement of Purpose: Trofinetide is the first approved treatment for Rett syndrome (RTT). It is not expected that hepatic impairment would affect the pharmacokinetic (PK) profile of trofinetide due to predominant renal excretion; however, there is a need to confirm hepatic impairment has no effect on trofinetide PK. This study used a physiologically based pharmacokinetic (PBPK) model to estimate trofinetide exposures in virtual healthy subjects and virtual patients with varying stages of hepatic impairment.

Description of Methods & Materials: Deterministic and stochastic simulations were performed using a validated PBPK model to estimate trofinetide exposure (maximum observed concentration [C_max] and area under the concentration–time curve from time zero to infinity [AUC_inf]) at the anticipated therapeutic dose of 12 g in virtual patients with mild, moderate and severe hepatic impairment (per Child-Pugh classification) compared with virtual healthy subjects. In the stochastic simulation, bioequivalence was confirmed if the 90% confidence interval fell within the limits of 0.80 and 1.25.

Data & Results: Based on stochastic simulations, predicted plasma exposures were similar for virtual healthy subjects and patients with mild, moderate, and severe hepatic impairment but exposures in whole blood increased slightly with increasing hepatic impairment severity (Figure). Bioequivalence was demonstrated between subjects with hepatic impairment and healthy subjects with regards to plasma exposures, but upper CI bounds for C_max in whole blood were just outside bioequivalence limit for the populations with moderate and severe hepatic impairment (Table).

Interpretation, Conclusion or Significance: Hepatic impairment is not anticipated to have any clinically relevant effect on trofinetide exposure.

Disclosures: MD, JMY, HB are employees of Acadia Pharmaceuticals Inc; ID, VL are employees and hold stock in Simulations Plus; ONO is a former employee of Simulations Plus.