A Phase 1, Open-Label Study to Evaluate the Effects of Food and Evening Dosing on the Pharmacokinetics of Oral Trofinetide in Healthy Adult Subjects

• Published in: Clinical drug investigation Vol. 42; no. 6; pp. 513 - 524
• Main Authors: Darwish, Mona, Youakim, James M., Harlick, Jim, DeKarske, Daryl, Stankovic, Serge
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2022; Springer Nature B.V
• Subjects: Bioavailability; Bioequivalence; Birth control; Caffeine; Drug dosages; Electrocardiography; Females; Internal Medicine; Laboratories; Medicine; Medicine & Public Health; Metabolism; Neurodevelopmental disorders; Original; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Urine; Vital signs; United States > US
• ISSN: 1173-2563; 1179-1918; 1179-1918
• DOI: 10.1007/s40261-022-01156-4

Background and Objective Trofinetide, a synthetic analog of tripeptide glycine-proline-glutamate, is an investigational agent for the treatment of Rett syndrome, a neurodevelopmental disorder with affected individuals requiring lifelong support. Food can affect the pharmacokinetic profile of a drug, and this phase 1 study assessed the potential effect of food on the pharmacokinetics of trofinetide. The study also evaluated the potential effect of evening dosing on trofinetide bioavailability and characterized the pharmacokinetic profile of trofinetide in urine. Methods A 60 mL oral solution of trofinetide (12 g) was administered in three dosing periods: morning fasted (A; reference), morning fed (B), and evening fasted (C). Healthy adult subjects (18−45 years) were randomized to sequence ABC ( n = 19) or BAC ( n = 22). Blood and urine samples were collected at scheduled timepoints for trofinetide pharmacokinetic analysis. Bioequivalence was confirmed if 90% confidence intervals for geometric mean ratio between B/A or C/A fell within 80–125% equivalence limits for area under the concentration-time curve (AUC) and maximum concentration ( C max ) in whole blood. Results Bioequivalence criteria were met for all conditions (i.e., morning fed vs. morning fasted and evening fasted vs. morning fasted) except C max in the fed versus fasted condition, which was just below the bioequivalence limit (75.49%), suggesting a negligible food effect and lack of diurnal variation on bioavailability. Trofinetide was primarily excreted unchanged in urine. Trofinetide was well tolerated, and there were no significant changes in vital signs or laboratory parameters. Conclusion This study supports dosing of trofinetide without regard to food.