The sponsor needed to understand the impact of different dosing scenarios for this new injectable antipsychotic drug, including missing doses, since schizophrenia patients often struggle with medication adherence. This was accomplished by building a model using the Simcyp whole body physiologically-based pharmacokinetic (PBPK) Simulator for the evaluation of oral metabolism, combined with the Simulator’s MechDermA model for evaluation of the new intramuscular injection route of administration. PBPK modeling was able to show the drug uptake in the combination therapy (oral and injectable) for final drug labeling.

That same PBPK model was leveraged to evaluate the impact of concomitant administration of strong CYP3A4 inhibitors and inducers and strong CYP2D6 inhibitors on the drug’s pharmacokinetics. Because patients that are CYP2D6 poor metabolizers have a reduced ability to eliminate CYP2D6 substrates, the sponsor also wanted to know if these patients would require dose adjustments. The effects of CYP3A and CYP2D6 modulators on different CYP2D6 phenotype groups (efficient, intermediate, and poor metabolizers) were provided via Simcyp PBPK modeling and simulation as in the label.

Schizophrenia is a chronic brain disorder, affecting approximately 1% of adults in the United States. It is associated with positive and negative symptoms including delusions, hallucinations, trouble concentrating, lack of motivation, flat affect, and impairments in cognitive and excutive function. Individuals with schizophrenia have trouble maintaining employment, but with effective treatment they can sometimes improve over time.

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