Sean Oosterholt (1), Nancy Jones (2), Joe Horrigan (2), Larry Glass (2), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics, UCL School of Life and Medical Sciences, London, UK, (2) Neuren Pharmaceuticals Limited
Objectives: NNZ-2566 is a synthetic analog of a naturally occurring neurotrophic peptide derived from insulin-like growth factor-1 (IGF-1). It has been developed as a treatment to reduce cognitive and neurodevelopmental symptoms in Rett syndrome, a rare genetic disease. Given the limited number and difficulties associated with frequent blood sampling in these severely impaired patients, a meta-analytical approach is proposed to characterise the pharmacokinetics of NNZ-2566 and most importantly evaluate the impact of clinical and demographic covariate factors on pharmacokinetic parameters and consequently on systemic exposure.
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 adolescent and adult female patients with Rett syndrome, yielding a pool of 97 subjects (age: 23 ±4.6, body weight: 60.9 ±17.1). The analysis was performed using a non-linear mixed effects approach using NONMEM 7.2.0. Model building was based on changes in the objective function (OFV) and goodness of fit plots (GOF). Covariate selection was based on a stepwise forward inclusion backward deletion procedure. Secondary pharmacokinetic parameters including AUC, Cmax and Ctau were used as measures of systemic exposure. Model evaluation was performed using goodness-of-fit and predefined predictive performance criteria. Using final parameter estimates and allometric scaling, NNZ-2566 levels were subsequently simulated to explore the dose rationale in the paediatric patients aged between 5-15 years.
Results: The pharmacokinetics of NNZ-256 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. Body weight was found to be a significant covariate on clearance and volume of distribution. In addition, bioavailability after afternoon doses were systematically lower than after morning dosing suggesting that intake of food may have an effect on the absorption of NNZ-2566.
Conclusion: The analysis shows show how population pharmacokinetic modelling can be used to understand sources of variability in rare diseases, where the number of patients and blood samples available for analysis is limited. Moreover, our results show how clinical trial simulations can be used as basis for optimising the dose selection and design of prospective studies in rare diseases.
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Reference: PAGE 24 (2015) Abstr 3597 [www.page-meeting.org/?abstract=3597]
Poster: Drug/Disease modeling - CNS