Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses

Abstract

Aims: To develop a pharmacokinetic-pharmacodynamic model describing the time-course of QT interval prolongation after citalopram overdose and to evaluate the effect of charcoal on the relative risk of developing abnormal QT and heart-rate combinations.

Methods: Plasma concentrations and electrocardiograph (ECG) data from 52 patients after 62 citalopram overdose events were analysed in WinBUGS using a Bayesian approach. The reported doses ranged from 20 to 1700 mg and on 17 of the events a single dose of activated charcoal was administered. The developed pharmacokinetic-pharmacodynamic model was used for predicting the probability of having abnormal combinations of QT-RR, which was assumed to be related to an increased risk for torsade de pointes (TdP).

Results: The absolute QT interval was related to the observed heart rate with an estimated individual heart-rate correction factor [alpha = 0.36, between-subject coefficient of variation (CV) = 29%]. The heart-rate corrected QT interval was linearly dependent on the predicted citalopram concentration (slope = 40 ms l mg(-1), between-subject CV = 70%) in a hypothetical effect-compartment (half-life of effect-delay = 1.4 h). The heart-rate corrected QT was predicted to be higher in women than in men and to increase with age. Administration of activated charcoal resulted in a pronounced reduction of the QT prolongation and was shown to reduce the risk of having abnormal combinations of QT-RR by approximately 60% for citalopram doses above 600 mg.

Conclusion: Citalopram caused a delayed lengthening of the QT interval. Administration of activated charcoal was shown to reduce the risk that the QT interval exceeds a previously defined threshold and therefore is expected to reduce the risk of TdP.

Figure 1

Observed QT intervals vs. time (top) and vs. RR intervals (bottom). Measurements from the same overdose event are connected with dotted lines. The solid line in the bottom graph are approximately the 97.5th percentile of normal QT–RR combinations illustrated by Fossa et al., Figure 1 [4]. The observed QT–RR combinations above the lines would therefore be associated with an increased risk of torsade de pointes

Figure 2

Distribution of age for men (Gender = 0) and women (Gender = 1) (left panel) and for the occurrence of taking coingestant drugs with no (rating = 0), intermediate (rating = 1) and high (rating = 2) risk for QT prolongation (right panel). The ‘box’ represents the interquartile range with the median. The whiskers are extended to points that are less than 1.5 times the interquartile range below (above) the first (third) quartile. Values outside this range are indicated separately (–•–)

Figure 3

Estimated relationship between the baseline heart rate corrected QT (QTci₀) and age for men (dotted line) and women (solid line)

Figure 4

Observed QT intervals vs. individual predicted QT intervals with the line of identity (——)

Figure 5

Ninety-five percent prior intervals (Prior) and 95% credible intervals for the final model (Final model), when using reduced prior precision on the PK parameters (Prior Prec PK↓), and when using reduced prior precision on QTci₀ (Prior Prec QTci₀↓), i.e. when the 95% prior interval for QTci₀ was increased and ranged between 392 and 457 ms. Men (♂) and women (♀) were allowed to have different distributions of QTci₀. Note that because of the vague prior distributions used, the distributions of t_eq and Slope are on log-scale

Figure 6

Simulated plasma concentrations () and QT intervals () vs. time for a patient with typical PK and PD parameters after an overdose citalopram, without taking charcoal (top panel). The bottom panel shows the predicted effect on QT interval prolongation without () and with () administration of activated charcoal. In both panels the dose was 1200 mg and the RR interval was 760 ms

Figure 7

Simulated probability over time for having a QT ≥ 447 ms for a given RR interval of 760 ms. Ten different dose levels are shown, ranging from 100 mg to 1800 mg. The top panel shows the probability without charcoal administration and the lower panel the probability if charcoal is administered. In the simulations all patients were assumed to be 30-year-old women who were also taking citalopram therapeutically

Figure 8

Relative decreases in cumulative hazard for having an abnormal QT interval (≥ 447 ms) at an RR interval of 760 ms associated with administration of charcoal for different dose levels of citalopram when the average effect of charcoal estimated in the PK modelling was used (solid line) and for the ‘worst-case’ scenario where the previously estimated charcoal effect is only present on clearance at 4–16 h after the overdose (dashed line)