Assessment of Similarity in Antipsychotic Exposure‐Response Relationships in Clinical Trials Between Adults and Adolescents With Acute Exacerbation of Schizophrenia

Abstract

Despite agreement that early‐onset schizophrenia is continuous with the adult‐onset form, quantitative relationships between antipsychotic exposure and clinical response are relatively unexplored in adolescents, compared to adults. Clinical efficacy data from second‐generation antipsychotic development programs (N = 5951 adults and N = 1035 adolescents ranging from 12 to 17 years old) were collected from available new drug applications submitted to the US Food and Drug Administration from 1993 to 2017. The developed disease–drug trial models adequately predicted the longitudinal trend in total positive and negative syndrome scale scores in both adults and adolescents using a Weibull placebo response, time‐delayed drug effect, and a Weibull structural dropout model. Maximum drug effect was similar between the two populations and was estimated to be between a range of 5% to 11% in adults and 5% to 7% in adolescents. Half maximal effective concentration parameter estimates also indicated similar exposure‐response relationships in adults and adolescents across all 4 antipsychotics. Simulated adolescent data using final model parameter estimates from the adult model were in agreement with adolescent observations. This analysis confirms similarity in exposure‐response for efficacy and could expedite the development of second‐generation antipsychotics for adolescents.

Extrapolation of Efficacy and Dose Selection in Pediatrics: A Case Example of Atypical Antipsychotics in Adolescents With Schizophrenia and Bipolar I Disorder

“…Both databases included positive, negative (studies that demonstrate no difference in effect on the primary end point between treatment and placebo arms), and failed trials (studies that demonstrated no difference in effect on the primary end point between active control and placebo arms). Trial, demographic, and clinical characteristics for each patient population enrolled have been described previously 14–17 …”

“…Protocols across different drugs and between adult and pediatric patients differed with regard to the number of samples collected and the sampling times. To derive exposures at steady state at each clinical assessment, adult and pediatric pharmacokinetic models were used to simulate various exposure metrics (ie, average concentration, trough concentration, maximum concentration, and area under the curve) 15 . Figures 2 and 3 provide visual comparisons of the exposure‐response relationship in patients with schizophrenia and bipolar I disorder, respectively.…”

“…Red and blue box plots represent the distribution of steady‐state exposures in adults and adolescents, respectively. (A‐D) Drugs previously published by Kalaria et al 15 …”

Population Pharmacokinetic Analysis of Brexpiprazole to Support its Indication and Dose Selection in Adolescents With Schizophrenia

“…In order to accelerate and optimize pediatric drug development, regulatory agencies may allow efficacy to be extrapolated from adults to pediatrics according to the evidence‐based assumptions that disease characteristics and response to therapy are similar in adult and pediatric populations 7‐9 . In schizophrenia, these assumptions have been demonstrated using clinical efficacy data from atypical antipsychotic development programs 2,10,11 . Consequently, in 2020, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the efficacy of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to pediatric patients aged 13 years or older, provided that the drug has the respective approved indication in adults, and shares a similar mechanism of action to current FDA‐approved antipsychotics (dopamine D 2 receptor antagonism or partial agonism, serotonin 5‐HT 1A receptor partial agonism, and/or serotonin 5‐HT 2A receptor antagonism) 2 .…”

“…[7][8][9] In schizophrenia, these assumptions have been demonstrated using clinical efficacy data from atypical antipsychotic devel-opment programs. 2,10,11 Consequently, in 2020, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the efficacy of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to pediatric patients aged 13 years or older, provided that the drug has the respective approved indication in adults, and shares a similar mechanism of action to current FDA-approved antipsychotics (dopamine D 2 receptor antagonism or partial agonism, serotonin 5-HT 1A receptor partial agonism, and/or serotonin 5-HT 2A receptor antagonism). 2 In addition, a pharmacokinetic (PK) analysis to justify dose selection and a safety study in adolescent patients are required.…”