Balancing Efficacy and Safety in the Clinical Development of an Atypical Antipsychotic, Paliperidone Extended-Release

The clinical outcomes of three pivotal clinical trials with paliperidone ER, an atypical antipsychotic were prospectively predicted with a model using a limited amount of paliperidone ER pharmacokinetic data, human in vivo D2-receptor occupancy data and the generally accepted D2-receptor derived therapeutic window hypothesis. The latter was further substantiated using historical risperidone safety data. Model predictions guided the selection of the dose range for clinical trials, particularly with regards to the extremes of the dose range studied.