Precision dosing of clozapine: A physiologically based pharmacokinetic/pharmacodynamic model integrating genetic polymorphisms and clinical outcomes - PubMed
2 days ago
- #PBPK/PD model
- #clozapine
- #genetic polymorphism
- Precision dosing of clozapine is needed due to pharmacokinetic variability caused by genetic polymorphisms, drug interactions, and environmental factors.
- A PBPK/PD model was developed to simulate clozapine plasma and brain concentrations, receptor occupancies, efficacy, and safety risks.
- The model incorporated genetic profiles (CYP1A2, CYP2D6, ABCB1), drug interactions (fluvoxamine, carbamazepine), smoking effects, and ethnic-specific adjustments.
- Simulations showed high predictive accuracy, with CYP1A2 polymorphisms being a major driver of clozapine concentration variability.
- Genotype-guided dosing improved clinical response and reduced adverse events, with fluvoxamine posing high-risk interactions in poor metabolizers.
- Smoking reduced clozapine concentrations, requiring dose adjustments, and ethnic-specific dosing addressed population variability.
- Sensitivity analyses identified glutathione status as a key determinant in agranulocytosis risk, highlighting the role of GSTT1 and GSTM1 polymorphisms.
- The PBPK/PD model supports genotype-guided dosing and therapeutic drug monitoring to optimize clozapine efficacy and safety.