Pharmacokinetics of Haloperidol in Critically Ill Patients: Is There an Association with Inflammation?

Abstract

Haloperidol is considered the first-line treatment for delirium in critically ill patients. However, clinical evidence of efficacy is lacking and no pharmacokinetic studies have been performed in intensive care unit (ICU) patients. The aim of this study was to establish a pharmacokinetic model to describe the PK in this population to improve insight into dosing. One hundred and thirty-nine samples from 22 patients were collected in a single-center study in adults with ICU delirium who were treated with low-dose intravenous haloperidol (3–6 mg per day). We conducted a population pharmacokinetic analysis using Nonlinear Mixed Effects Modelling (NONMEM). A one-compartment model best described the data. The mean population estimates were 51.7 L/h (IIV 42.1%) for clearance and 1490 L for the volume of distribution. The calculated half-life was around 22 h (12.3–29.73 h) for an average patient. A negative correlation between C-Reactive Protein (CRP) and haloperidol clearance was observed, where clearance decreased significantly with increasing CRP up to a CRP concentration of 100 mg/L. This is the first step towards haloperidol precision dosing in ICU patients and our results indicate a possible role of inflammation.

Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy

“…The impact of C-reactive protein (CRP) on exposure to haloperidol following the administration of low haloperidol doses in critically ill adults was described in contribution (16). By constructing its parametric Bayesian model and by performing Monte Carlo simulations, the authors showed that the clearance of haloperidol is negatively correlated with increasing CRP up to approximately 50 mg/L, pointing to the utility of individualized dosing at the intensive care unit to overcome delirium.…”