Alessandro Di Deo (1), Sean Oosterholt (1), Joseph Horrigan (2), Alison McMorn (2), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics Group, University College London, UK, (2) AMO Pharma Ltd, Wonersh, Surrey, UK
Introduction: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in Type 1 myotonic dystrophy (DM-1), a rare neuromuscular disorder [1-6]. Tideglusib inhibits GSK3β activity in preclinical models of DM-1 and promotes cellular maturation, normalising aberrant molecular and behavioural phenotypes [7]. In addition to the uncertainties regarding the translation of preclinical findings, the dose rationale in humans is fraught with the paucity of PK and PD data available for subsequent evaluation in Phase II and III studies. These limitations are amplified when considering the dose selection for the paediatric population, as assumptions have to be made about the comparability of disease and underlying PKPD relationships in adults and children. Implementation of an integrated modelling approach based on Bayesian principles can be successfully used to mitigate these limitations, enabling the evaluation of the effect of covariate factors on pharmacokinetics, and more specifically on systemic exposure to an investigational product [8-11].
Objectives: To characterise the population pharmacokinetics and assess the effect of intrinsic (e.g., age, weight) and extrinsic (i.e., food) effects on the overall exposure and safety profile of tideglusib in adolescents and adult patients affected by congenital and juvenile-onset DM-1 using Bayesian priors.
Methods: Data from Phase I studies in healthy adult and elderly subjects were initially used for the purpose of this investigation. Taking into account the safety profile, food effect and bioavailability of different formulations, 1832 plasma samples from 54 healthy subjects were used to describe the population pharmacokinetics of tideglusib. Model parameter distributions were subsequently used as priors for the evaluation of the disposition of tideglusib in adolescent and adult DM-1 patients (N=16), for whom only very sparse pharmacokinetic data was available. Data analysis was performed using a nonlinear mixed effects approach. Prior distributions were implemented using the $PRIOR NWPRI subroutines in NONMEM. Fixed effect parameters (THETAs) were assumed to be normally distributed while OMEGA2 and SIGMA2 were assumed to be distributed as an Inverse-Wishart distribution [12-13]. Secondary pharmacokinetic parameters (AUC, Cmax and Tmax) were derived to assess the clinical implications of significant covariates on the overall exposure and safety profile of tideglusib, taking into account baseline demographic characteristics and food intake after drug administration. Clinical trial simulations were then performed to support the dose rationale for subsequent paediatric studies.
Results: Tideglusib pharmacokinetics was described by a two-compartment model with first-order elimination. Despite linear pharmacokinetics, as demonstrated by clearance estimates across the different dose levels, the pharmacokinetic profiles of tideglusib were found to be dose-dependent, with exposure varying due to the limited solubility of the compound. There were no significant differences between healthy subjects and DM-1 patients. Body weight was a significant covariate on clearances and volumes of distribution. Mean elimination half-life and AUC(0-12) were 2.6 h and 1214.8 ng/mL·h and 1.8 h and 3054.2 ng/mL·h for the 400 mg and the 1000 mg dosing regimen, respectively. In addition, neither varying time of food intake after 1 h post-dose nor type of meal appeared to affect the overall exposure to tideglusib. A dose titration protocol was recommended using the dosage form with the most favourable pharmaceutic profile.
Conclusions: Evaluation of pharmacokinetics in paediatric rare diseases remains challenging due to the small number of patients and sparse blood sampling available in clinical trials. These limitations are further compounded by the variability caused by extrinsic factors such as formulation and food effect. The use of prior parameter distributions showed that in addition to the effect of body weight on disposition parameters, the increase in systemic exposure to tideglusib is less than proportional due to dose-dependent bioavailability. Despite the relatively high intra and interindividual variability in drug concentrations, our analysis supported the dose rationale for a subsequent Phase II study in paediatric patients based on target exposure range observed in adult subjects following a 1000 mg dose of tideglusib (i.e., median AUC (90%CI)= 3145.7 (1571.4 – 5109.4) ng/mL·h).
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Reference: PAGE 30 (2022) Abstr 10201 [www.page-meeting.org/?abstract=10201]
Poster: Drug/Disease Modelling - CNS