Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal.

AIMS: To describe the pharmacokinetics and pharmacodynamics (PKPD) of escitalopram in overdose and its effect on QT prolongation, including the effectiveness of single dose activated charcoal (SDAC). METHODS: The data set included 78 escitalopram overdose events (median dose, 140mg [10-560mg]). SDAC was administered 1.0 to 2.6 h after 12 overdoses (15%). A fully Bayesian analysis was undertaken in WinBUGS 1.4.3, first for a population pharmacokinetic (PK) analysis followed by a PKPD analysis. The developed PKPD model was used to predict the probability of having an abnormal QT as a surrogate for torsade de pointes. RESULTS: A one compartment model with first order input and first-order elimination described the PK data, including uncertainty in dose and a baseline concentration for patients taking escitalopram therapeutically. SDAC reduced the fraction absorbed by 31% and reduced the individual predicted area under the curve adjusted for dose (AUC(i) /dose). The absolute QT interval was related to the observed heart rate with an estimated individual heart rate correction factor (α= 0.35). The heart rate corrected QT interval (QT(c) ) was linearly dependent on predicted escitalopram concentration [slope = 87ms/(mgl(-1) )], using a hypothetical effect-compartment (half-life of effect-delay, 1.0h). Administration of SDAC significantly reduced QT prolongation and was shown to reduce the risk of having an abnormal QT by approximately 35% for escitalopram doses above 200mg. CONCLUSIONS: There was a dose-related lengthening of the QT interval that lagged the increase in drug concentration. SDAC resulted in a moderate reduction in fraction of escitalopram absorbed and reduced the risk of the QT interval being abnormal.

Inter-rater reliability of manual QT measurement and prediction of abnormal QT,HR pairs.

OBJECTIVES: To assess interobserver agreement when trained healthcare staff measure the QT interval using a standardized approach across a range of QT lengths. METHODS: A sample of 110 electrocardiograms (ECGs) was taken from general and psychotropic overdose admissions to the emergency department including drugs known to cause QT prolongation and Torsades de Pointes. Four of the authors measured the QT interval in all ECGs using a previously developed approach. Each rater was blinded to the ECG admission details and the measurements of the other raters. The primary outcome was the inter-rater agreement for the median QT and interobserver classification as to whether the QT interval was abnormal or not, based on the QT nomogram. RESULTS: There was good agreement between raters (intraclass correlation coefficient, 0.61; 95% CI = 0.53 to 0.69). When classifying the QT as abnormal there was good agreement between the raters with a Fleiss' kappa of 0.61. There was perfect agreement between all four raters on 86 of 110 ECGs (78.2%), agreement between three raters on 18 of 110 (16.3%), and a split between the four on 6 of 110 (5.5%). Disagreement between the automated QT measurement and the majority of the raters was slightly more than within raters. CONCLUSIONS: The study demonstrates that there is good agreement between trained observers when manually measuring the QT interval using a standardized approach. This provides an inexpensive method for the measurement of QT in clinical studies of drug overdose and a potentially useful approach in the clinical assessment of patients with possible QT prolongation.

Clinical and ECG effects of escitalopram overdose.

STUDY OBJECTIVE: We investigate the clinical effects of escitalopram overdose and determine the risk of QT prolongation and serotonin toxicity. METHODS: A review of escitalopram overdoses to a clinical toxicology unit was undertaken. Patient demographics, details of the ingestion, clinical effects, including evidence of serotonin toxicity, complications (arrhythmias and seizures), ICU admission, and length of stay were obtained. QT and QRS intervals were manually measured on ECGs by using a standardized approach. In a subgroup of 34 prospectively recruited patients, escitalopram was detected in blood from 33 patients. Medians and interquartile ranges (IQR) were reported, and QT versus pulse rate was plotted on a QT nomogram to investigate QT prolongation. RESULTS: Median ingested dose in the 79 presentations was 140 mg (IQR 75 to 260 mg; range 20 to 560 mg), and escitalopram was the only drug ingested or all coingested drugs were nontoxic in 46 cases. Median length of stay for patients receiving clinically important coingestants was 19 hours (IQR 9 to 33 hours) compared with that of patients receiving escitalopram alone (median 12 hours; IQR 7 to 19 hours). Serotonin toxicity occurred in 7 of the 46 escitalopram-alone ingestions (15%) but in only 1 of the 33 patients coingesting other medications. Common features were inducible clonus and hyperreflexia. Central nervous system depression and ICU admission were rare in escitalopram-alone overdoses compared with those in cases with sedative coingestants. Bradycardia (pulse rate <60 beats/min) occurred in 11 cases (14%) and an abnormal QT-HR pair in 11 (14%), which was associated with normal or slow pulse rates. There were no deaths, seizures, or arrhythmias. CONCLUSION: Major manifestations of escitalopram overdose were serotonin toxicity, QT prolongation, and bradycardia. The study suggests a potential for cardiac arrhythmias in escitalopram overdose.