Translational Modeling in Schizophrenia: Predicting Human Dopamine D2 Receptor Occupancy

Area of Science:

• Pharmacology
• Pharmacokinetics
• Neuroscience

Background:

• Physiology-based pharmacokinetic-pharmacodynamic (PBPKPD) models are crucial for predicting drug effects.
• Previous models were developed in rats to understand dopamine D2 receptor occupancy (D2RO).
• Translating these models from rats to humans presents significant challenges.

Purpose of the Study:

• To evaluate a hybrid PBPKPD model's ability to predict human D2RO.
• To assess the model's accuracy for antipsychotic drugs in the human striatum.

Main Methods:

• A hybrid PBPKPD model, initially developed in rats, was adapted for human predictions.
• Rat physiological and pharmacokinetic parameters were replaced with human data.
• Blood-brain barrier transport and receptor binding were scaled from rat to human.

Main Results:

• The adapted model accurately predicted human D2RO for five out of six antipsychotics.
• In vitro data integration improved D2RO predictions for most compounds.
• Haloperidol's D2RO was under-predicted by the model.

Conclusions:

• The hybrid PBPKPD model structure, incorporating in vitro and human data, provides a valid basis for predicting human D2RO.
• This approach supports the prediction of antipsychotic drug effects in humans.
• Further refinement may be needed for specific compounds like haloperidol.