Model-based approaches to increase efficiency of drug development in schizophrenia: a can't miss opportunity

Abstract

Background: Schizophrenia is a severe mental disorder characterized by definite specificities and complexities (heterogeneity of the disease symptoms, large between-subject variability in disease progression and response to therapeutic agents, placebo response, dropout, questionable preclinical models, importance of market differentiation, etc.) that make drug development in this field particularly difficult when compared to the other therapeutic areas. However, drug receptor binding (especially to D₂, 5-HT₂ and H₁ receptors) can provide a useful quantitative framework that can be related to the downstream clinical (amelioration of disease-related scores) and unwanted (neurological effects and metabolic disregulation) effects. Objective: This paper reviews the pharmacokinetic, pharmacodynamic and disease progression approaches applied to the development of new drugs for the treatment of schizophrenia. Conclusions: Only model-based methodologies, able to integrate the diverse characteristics of a compound, can provide a rational approach to increase efficiency in drug development in this area, through the development of pharmacokinetic–pharmacodynamics models able to integrate quantitative descriptions of pharmacokinetics, desired and unwanted effects. These holistic approaches can be used in clinical trial simulations for reliably predicting the outcome of future trials. Meta-analyses of the competitor environment are also essential to position the new drug into a crowded competitive landscape.

Keywords::

• dropout
• efficacy
• model-based drug-development
• PK–PD
• safety
• schizophrenia
• variability

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