Bridging Formulations of Quetiapine for Children with Schizophrenia or Bipolar Disorder
Quetiapine is an atypical antipsychotic for treating schizophrenia, bipolar depression, bipolar mania that helps to restore the balance of certain natural substances (neurotransmitters) in the brain. Changing the formulation of quetiapine, originally approved as an immediate release (IR) formulation, given twice per day, to a daily extended release (XR) delivery was undertaken to improve patient adherence. The Simcyp Advanced, Dissolution, Absorption and Metabolism (ADAM) module was used to compare exposure between the two formulations. The modeling showed differences in regional distribution, with most of drug in the IR formulation being absorbed in the duodenum and jejunim, while the XR formulation was releasing further down the intestine and being absorbed in the colon.
Physiologically-based pharmacokinetic PBPK models using the Simcyp Simulator employing in vitro absorption, distribution, metabolism, and excretion (ADME) and physicochemical data, clinical pharmacokinetic (PK) data of quetiapine IR/XR in adults and clinical PK data of quetiapine IR in children were developed. These models predicted the effects of CYP3A4 inhibition and induction on the PK of quetiapine, the PK profile of quetiapine IR in children and adults, and the PK profile of quetiapine XR in adults. Most important, the PBPK model predicted that children and adolescents are likely to achieve a similar exposure following administration of either the XR formulation once daily or the IR formulation twice daily at similar total daily doses.
This was a high impact use of pediatric PBPK modelling given that a clinical study was avoided and approval was given for the pediatric labeling of quetiapine XR.
Early onset schizophrenia and bipolar disorder can occur in children as young as 12 years. As with many mental illnesses, adherence to drug regimen is a challenge, especially for teenagers.