Population pharmacokinetics of intramuscular droperidol in acutely agitated patients

Abstract

BACKGROUNDIntramuscular droperidol is used increasingly for sedation of aggressive and violent patients. This study aimed to characterise the pharmacokinetics of intramuscular droperidol in these patients to determine how rapidly it is absorbed and the expected duration of measurable drug concentrations. METHODSWe undertook a population pharmacokinetic analysis of a subgroup of patients from a clinical trial comparing droperidol and midazolam: 17 receiving 5 mg and 24 receiving 10 mg droperidol. Droperidol was measured using high-performance liquid chromatography. Pharmacokinetic modelling was performed under a nonlinear mixed effects modelling framework (NONMEM v7.2). The model was used to simulate concentration time profiles of three typical doses, 5 mg, 10 mg and 10 mg + 10 mg repeated at 15 min. RESULTSA two-compartment first-order input with first-order output model fitted the data best. The absorption rate constant was poorly characterised by the data and an estimate of the first order rate constant of absorption when fixed to 10 h -1 provided a stable model and lowest objective function. This represents extremely rapid absorption with a half-life of 5 min. The final model had a clearance of 41.9 l h -1 and volume of distribution of the central compartment of, 73.6 l. Median and interquartile range of initial (alpha) half-life was 0.32 h (0.26-0.37 h) and second (beta) half-life was 3.0 h (2.5-3.6 h). Simulations indicate that 10 mg alone provides an 80% probability of being above the lower limit of quantification (5 μg l -1 ) for 7 h, 2 h longer than for 5 mg. Giving two 10 mg doses increased this duration to 10 h. CONCLUSIONSIntramuscular droperidol is rapidly absorbed with high therapeutic concentrations after 5 and 10 mg doses, and supports clinical data in which droperidol sedates rapidly for up to 6 h. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Intramuscular droperidol is a safe and effective for sedation of aggressive patients • The pharmacokinetics of intramuscular droperidol is poorly characterised. WHAT THIS STUDY ADDS• Droperidol is rapidly absorbed when given by the intramuscular route.• Intramuscular droperidol with doses of 5 mg and 10 mg provides good exposure • Drug concentrations remain above the lower limit of detection for at least 7 h.

A Study of Cardiac Outcomes After Droperidol Administration in an Inpatient Psychiatric Cohort

“…Furthermore, pharmacokinetic models show that droperidol is eliminated within hours of administration. 2 Only 19 of 263 (7.2%) of our ECG recordings were captured on the same day as droperidol administration. Electrocardiograms taken beyond this time are less informative about droperidol-induced QT prolongation but do confirm the absence of major cardiac arrhythmias.…”

“…1 When administered as an intramuscular injection, droperidol has a rapid onset of action within minutes and can provide effective management of agitation in behaviorally disturbed patients for up to 6 hours. 2 Given these properties, droperidol is indicated in some high-risk psychiatric emergencies for patients experiencing paranoid delusions, agitated psychosis, mania, or drug-induced hyperarousal, among other indications. Despite droperidol's clinical utility, cardiac adverse effects began to be noticed in the 1990s.…”

“…Droperidol is a centrally acting butyrophenone and dopamine-2 receptor antagonist, first approved by the US Food and Drug Administration (FDA) in 1970 as a sedative and antiemetic agent 1 . When administered as an intramuscular injection, droperidol has a rapid onset of action within minutes and can provide effective management of agitation in behaviorally disturbed patients for up to 6 hours 2 . Given these properties, droperidol is indicated in some high-risk psychiatric emergencies for patients experiencing paranoid delusions, agitated psychosis, mania, or drug-induced hyperarousal, among other indications.…”

Utilization of Data Below the Analytical Limit of Quantitation in Pharmacokinetic Analysis and Modeling: Promoting Interdisciplinary Debate

“…Method numbering system according to Beal, 2001 [12] where appropriate. Keep BLQ observations in the model and estimate the likelihood of those values being between 0 and LLOQ M4 [12,35,116,180,186,187] All BLQ data are substituted with LLOQ/2 M5 [12,24,[30][31][32][33]35,55,62,133,153, BLQ data are substituted with LLOQ/2, however subsequent, consecutive BLQ observations from the same subject are discarded M6 [1,12,34,35,59,63,117,[225][226][227][228][229][230][231][232][233][234][235][236][237][238][239][240][241][242][243] All BLQ data are substituted with 0 M7 [12,31,33,207,244] All BLQ data are substituted with LLOQ …”

Randomized Double‐blind Trial of Intramuscular Droperidol, Ziprasidone, and Lorazepam for Acute Undifferentiated Agitation in the Emergency Department

“…First‐line IM medications to treat agitation in the ED are typically antipsychotics or benzodiazepines, 6 although there is no consensus on a single preferred agent. Droperidol exhibits properties suggesting it may be the ideal agent for undifferentiated agitated patients, including rapid absorption via the IM route, typically within 5 minutes, 11 and a half‐life of 2.3 hours 12 , which may allow for timely reassessment of patients in the ED. Multiple randomized clinical trials (RCTs) suggest droperidol is a safe, rapid, effective treatment when compared to benzodiazepines and other antipsychotics, 13,14 although the majority of these studies examine the IV route only 15–20 .…”