Haloperidol dopamine receptor occupancy and antagonism correspond to delirium agitation scores and EPS risk: A PBPK-PD modeling analysis.

• Tác giả: Paul M Burkat
• Ngôn ngữ: eng
• Thông tin xuất bản: United States : Journal of psychopharmacology (Oxford, England) , 2025
• Bộ sưu tập: NCBI
• ID: 216968

Tóm tắt

 BACKGROUND: Delirium is a severe neuropsychiatric disorder associated with increased morbidity and mortality. Numerous precipitating factors and etiologies merge into the pathophysiology of this condition which can be marked by agitation and psychosis. Judicious use of antipsychotic medications such as intravenous haloperidol reduces these symptoms and distress in critically ill individuals. AIMS: This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model for the antipsychotic medication haloperidol
  estimate plasma and unbound interstitial brain concentrations for repetitive haloperidol administrations used in hyperactive delirium treatment
  determine dopamine receptor occupancy and antagonism under these conditions
  and correlate these results with Richmond Agitation-Sedation Scale (RASS) scores and the risk of developing extrapyramidal symptoms (EPSs). METHODS: The PBPK model for single and repetitive administrations of peroral and intravenous haloperidol was developed with PK-Sim software. The pharmacodynamic (PD) model for RASS scores with haloperidol unbound interstitial brain concentration passed as the regressor was developed with the MonolixSuite 2021R platform. RESULTS: Peak haloperidol plasma and unbound interstitial brain concentrations following a single 2 mg intravenous dose are 32 ± 5 nM and 2.4 ± 0.4 nM. With repetitive administrations, dopamine receptor occupancy is 70%-83% and D2 CONCLUSIONS: Haloperidol dopamine receptor occupancy time course and D2