Della Pasqua, Oscar

Di Deo, Alessandro

Horrigan, Joseph P

McMorn, Alison

Oosterholt, Sean

English

UCL Discovery

Exploratory analysis of the correlations between tideglusib exposure and coreefficacy measures showed that changes from baseline were significantly correlatedwith tideglusib AUC. Briefly, despite large heterogeneity in the population, clinicallyand statistically significant improvement was observed in Repetitive Behaviours(mainly Ritualistic Behavior and Restricted interests Behavior).Initially, concentration data from Phase I studies in healthy adult and elderlysubjects (n=54) were used to investigate the population PK of tideglusib andexplore the role of relevant factors affecting systemic exposure. Model parameterdistributions were subsequently used as priors for the evaluation of sparse PK datain adolescents affected by ASD (n=38). Data analysis was performed using anonlinear mixed effects approach. Finally, linear regression techniques were usedto assess the statistical significance of the correlation between model-predictedestimates of exposure (e.g., AUC, Cmax, cumulative AUC, Css) and core measuresof efficacy (e.g., Repetitive Behaviour Scale - Revised, Vineland Adaptive BehaviorScales – II and Aberrant Behaviour Checklist), as determined by linear interpolationof the area under the effect curve (AUEC) during treatment and the change inscores at predefined visit days relative to baseline.1. Kaidanovich-Beilin O et al. GSK-3: Functional Insights from Cell Biology and Animal Models. Front Mol Neurosci. 2011; 4:40.2. Mannion A et al. Comorbidity in autism spectrum disorder: A literature review. Research in Autism Spectrum Disorders. 2013;7(12):1595-1616.3. Mannion A et al. An investigation of comorbid psychological disorders, sleep problems, gastrointestinal symptoms and epilepsyin children and adolescents with autism spectrum disorder: A two year follow-up. Res Aut Spect Dis. 2016; 22:20-33.4. Simonoff E et al. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associatedfactors in a population-derived sample. J Am Acad Child Adolesc Psychiatry. 2008; 47(8):921-929.5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5-TR). 2013; 21.Alessandro Di DeoPhD student, School of Pharmacy, University College London (UCL), London, UK.E-mail: a.deo@ucl.ac.ukPopulation pharmacokinetics and pharmacokinetic-pharmacodynamiccorrelations of tideglusib for the treatment of adolescents with autismspectrum disorders (ASD)Alessandro Di Deo1, Sean Oosterholt1,  Joseph Horrigan2, Alison McMorn2, Oscar Della Pasqua1(1) Clinical Pharmacology & Therapeutics Group, University College London, UK, (2) AMO Pharma Ltd, Godalming, Surrey, UKINTRODUCTIONTideglusib exposure in adolescent patients (12-17 years old) suffering from ASDwas adequately described by a 2-compartment PK model. Dose (strength) wasfound to have a statistically significant effect on residual variability in thispopulation, with different parameter estimates for doses higher than 400 mg. IIVwas identified for all PK parameters (i.e., CL, V1, V2,Q and KA).PharmacokineticsTideglusib is a glycogen synthase kinase 3ß (GSK-3ß) inhibitor. Dysregulation ofsignalling pathways involving GSK-3 is associated with several neurological andpsychiatric disorders [1]. Recently, tideglusib has been proposed as a potentialtherapeutic agent for the treatment of ASDs. ASDs are complex, pervasive, andmultifactorial neurodevelopmental conditions [2-4]. Observation of aberrantbehaviour forms the basis of diagnosis, with criteria focused on impairment insocial communication and interaction, and restricted, repetitive patterns ofbehaviour, interests, or activities [5]. In addition to the uncertainties in thetranslation of preclinical data, the dose rationale in humans is fraught with thepaucity of pharmacokinetic (PK) and pharmacodynamic (PD) data available forsubsequent evaluation of efficacy in Phase II-III studies. Implementation of anintegrated modelling approach based on Bayesian principles can be successfullyused to mitigate these limitations. The objective of this investigation was tocharacterise the PK of tideglusib in adolescents with ASD following treatment overa period of 12 weeks and explore the correlation between exposure and coremeasures of efficacy.METHODOLOGYCoreMeasuresSubscalesEfficacy AssessmentSocial FunctionVineland Adaptive Behavior Scales - IIRepetitive Behavior Scale -revisedSocial EngagementAberrant Behavior ChecklistRepetitive BehavioursIrritabilityLethargySocial withdrawalStereotypicBehaviourHyperactivity   NoncomplianceInappropriate speechStereotypedSelf-injuriousCompulsiveRitualisticSamenessRestricted interestsEfficacy Endpoints• Implementation of an integrated modelling approach based on Bayesianprinciples can be successfully used to mitigate the paucity of PK and PD data inrare diseases, enabling the evaluation of the effect of covariate factors onpharmacokinetics, and more specifically on systemic exposure.• Evidence of a correlation between drug exposure and changes in core measuresof efficacy in adolescents with ASD represent an initial step in the evaluation ofthe efficacy of tideglusib,• The observed clinical improvement in subscales (domains) can be assigned tothe beneficial effects of tideglusib. These results also suggest that there may beselectivity of action. Endpoints that describe impairing behaviours associatedwith ASD should be prioritised in future clinical trials.CommunicationDaily living skillsSocializationMotor skillsCONCLUSIONFigure 2. Upper panels show the predicted concentration vs. time profiles in adolescent. Solid circles areobserved concentrations stratified by visit. Red and blue dashed lines indicate the individual and populationpredicted concentrations, respectively.Lower panels depict the visual predictive checks for the final PK model. Solid line represents the median profile,whilst the shaded area indicates the 90%-confidence interval of simulated values. Dots are the observed data.PKPD CORRELATIONReferencesFigure 1. Schematic diagram of the core measures of efficacy and corresponding subscales available for thePKPD analysis. Figure 3. Correlation between AUC and change from baseline in RBS Revised (Ritualistic Behavior - TotalSubscale Score). Individual observations are represented by dots; each individuals is shown with a differentcolour. Results are presented for different treatment intervals in separate panels.Figure 4. Correlation between AUC and change from baseline in RBS Revised (Restricted Behavior - TotalSubscale Score). Individual observations are represented by dots; each individuals is shown with a differentcolour. Results are presented for different treatment intervals in separate panels.Time elapsed since last dose (h)Dose normalized concentration

Population pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of tideglusib for the treatment of adolescents with autism spectrum disorders

https://discovery.ucl.ac.uk/10168547/1/ADD%20Pharmacology%20Poster%202022.v1.pdf

Population pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of tideglusib for the treatment of adolescents with autism spectrum disorders

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