Xiaofeng Wang, PhD1; Mathangi Gopalakrishnan, PhD2; Benjamin Rich, PhD2,3; Frank Larsen, PhD4; Joga Gobburu, PhD2; Arash Raoufinia, PharmD1
1. Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA 2. Pumas-AI Inc., Centreville, VA, USA 3. InnoMx Inc., Outremont, QC, Canada 4. H. Lundbeck A/S, Valby, Copenhagen, Denmark
Introduction:
The FDA recently released a general advice letter to sponsors, permitting the effectiveness of second-generation antipsychotics for the treatment of schizophrenia in adults to be extrapolated to paediatric patients aged ≥13 years.1 This conclusion was based on a demonstration of similarity in disease characteristics and symptomatic changes between adult and adolescent schizophrenia, and on an analysis of antipsychotic exposure–response across multiple antipsychotics that modulate dopaminergic signalling.1-3 The FDA decision will facilitate accelerated paediatric drug development in this vulnerable population.
Because aripiprazole and brexpiprazole are second-generation antipsychotics that reduce dopaminergic signalling through D2 receptor partial agonism and modulate serotonergic and/or noradrenergic signalling in the brain,4,5 it is hypothesized that the similarity in exposure–response (where exposure is capture by steady-state average plasma concentration) between adults and adolescents that has been observed across multiple antipsychotic drugs, including aripiprazole, could also apply to brexpiprazole. Extrapolation of efficacy from adults to adolescents for brexpiprazole is also considered feasible.
Objectives:
These analyses aimed to quantitatively assess the exposure–response similarity of aripiprazole between adults and adolescents in the treatment of schizophrenia, to extend the aripiprazole exposure–response modelling to brexpiprazole using adult data, and to predict schizophrenia symptom response to brexpiprazole in adolescents.
Methods:
The disease–drug modelling analyses used individual patient-level data from aripiprazole and brexpiprazole clinical studies. The aripiprazole analyses included data from 1,007 adults with schizophrenia from three studies (31-97-201; 31-97-202; CN138-001) and 294 adolescents with schizophrenia from one study (NCT00102063).6-9 The brexpiprazole analyses included data from 1,235 adults with schizophrenia from two studies (NCT01393613; NCT01396421).10,11
Exposure–response (disease–drug) models of aripiprazole for schizophrenia symptoms assessed by PANSS Total score in adults and adolescents, were developed and qualified separately. The exposure–response for aripiprazole between adults and adolescents was assessed for similarity.
A disease–drug model was developed to characterize the placebo response, as well as the exposure–response for brexpiprazole on PANSS Total score in adults with schizophrenia. The final disease–drug model in adults was used to predict brexpiprazole response in adolescents based on pharmacokinetic data in adolescents and an adolescent dropout model.
Results:
Consistent with the FDA approach, the aripiprazole analysis demonstrated similarity in placebo response and exposure–response between adults and adolescents with schizophrenia by demonstrating that the predicted PANSS response in adolescents based on the adult model was similar to the observed adolescent PANSS response.
The brexpiprazole analysis demonstrated that the aripiprazole exposure–PANSS model was able to adequately characterize PANSS response in adults receiving brexpiprazole. Simulations of PANSS score response in adolescents receiving brexpiprazole, based on the adult brexpiprazole exposure–PANSS model and adolescent pharmacokinetics, predicted that brexpiprazole is efficacious in adolescents.
Conclusions:
The current analysis extrapolates from a disease–drug model for brexpiprazole in adults to predict the response in adolescents. Extrapolation validity is provided by the current aripiprazole analysis, and the analysis by Kalaria et al.,2,3 which gives a quantitative justification of similarity in placebo response and exposure–response between adults and adolescents in the treatment of schizophrenia.
References:
[1]. Kalaria SN, Farchione TR, Uppoor R, Mehta M, Wang Y, Zhu H. Extrapolation of efficacy and dose selection in pediatrics: a case example of atypical antipsychotics in adolescents with schizophrenia and bipolar I disorder. J Clin Pharmacol 2021; 61 (Suppl 1): S117–S124.
[2]. Kalaria SN, Zhu H, Farchione TR, Mathis MV, Gopalakrishnan M, Uppoor R, Mehta M, Younis I. A quantitative justification of similarity in placebo response between adults and adolescents with acute exacerbation of schizophrenia in clinical trials. Clin Pharmacol Ther 2019; 106 (5): 1046–1055.
[3]. Kalaria SN, Farchione TR, Mathis MV, Gopalakrishnan M, Younis I, Uppoor R, Mehta M, Wang Y, Zhu H. Assessment of similarity in antipsychotic exposure–response relationships in clinical trials between adults and adolescents with acute exacerbation of schizophrenia. J Clin Pharmacol 2020; 60 (7): 848–859.
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[10]. Kane JM, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, Nyilas M, Carson WH, Sanchez R, Eriksson H. A multicenter, randomized, double-blind, controlled Phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res 2015; 164 (1–3): 127–135.
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Reference: PAGE 30 (2022) Abstr 10092 [www.page-meeting.org/?abstract=10092]
Poster: Drug/Disease Modelling - CNS