Population pharmacokinetics of Trofinetide in paediatric Rett syndrome patients

S. P. Oosterholt¹, N. E. Jones², L. Glass², O. Della Pasqua¹. ¹Clinical Pharmacology & Therapeutics, University College London, London, United Kingdom, ²Neuren Pharmaceuticals, Ltd, Port Melbourne, Australia.

Introduction: Trofinetide is a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1). It is being developed as a treatment to reduce neurodevelopmental symptoms in Rett syndrome, a rare genetic disease. Given the difficulties associated with frequent blood sampling for the characterisation of pharmacokinetics in these severely impaired patients, a meta-analytical approach is proposed using additional data from healthy subjects. We aim at describing the impact of clinical and demographic covariate factors on pharmacokinetic properties of trofinetide.

Methods: Rich pharmacokinetic data from three different phase I trials in healthy subjects were analysed in conjunction with sparsely sampled data from a phase II study in paediatric female patients with Rett syndrome, dosed with 50, 100 or 200 mg/kg, yielding a pool of 82 subjects (median age: 9, range 5-15, median body weight: 22.8 kg, range: 15.1 - 62.1 kg). The analysis was performed using a non-linear mixed effects approach. Secondary pharmacokinetic parameters (AUC and C_max) were used as measures of systemic exposure and correlated to selected clinical scales as measures of drug efficacy.

Results: The pharmacokinetics of trofinetide was best described by a two-compartment model with first order absorption and elimination. There was no accumulation, metabolic inhibition, or induction observed during treatment. Median secondary parameters for the 50, 100 and 200 mg/kg BID dosing arms were respectively: 17.7, 52.6 and 82.2 μg/mL for C_max, and 139.4, 338.6 and 505.1 μg/mL·h for AUC. Despite the limited sample size, an exploratory analysis of the data suggests a correlation between drug exposure and changes in Clinical Global Impression of Improvement scale, Clinician Rated Domain Specific Concerns, and the Rett Syndrome Behaviour Questionnaire.

Conclusion: The analysis shows show how population pharmacokinetic modelling can be used to understand sources of variability in efficacy measures in rare diseases. Moreover, our results show how a model-based approach can be used to estimate secondary parameters, where the number of patients and blood samples available for analysis is limited.