A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers

Abstract

Prolongation of the QT interval on an ECG is a surrogate marker for predicting the proarrhythmic potential of a drug under development. The aim of this study was to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine immediate release (IR) and escitalopram, in healthy individuals. This was a randomized, open-label, 4×4 Williams crossover study, with four single-dose treatments [placebo, 400 mg moxifloxacin (positive control), 20 mg escitalopram, and 100 mg quetiapine IR], conducted in 40 healthy volunteers. Serial blood samples for pharmacokinetics and ECG were collected. Individually, RR-corrected QTc intervals (QTcI) and placebo-adjusted changes from baseline values of QTcI (ΔΔQTcI) were evaluated. Lower-bound values of the one-sided 95% confidence interval for ΔΔQTcI of moxifloxacin with more than 5 ms confirmed the sensitivity of the assay. The maximum upper bound 95% confidence interval for the ΔΔQTcI of quetiapine IR and escitalopram was 13.7 and 10.5 ms, with mean estimates of 10.2 and 6.9 ms, respectively. Peak effects of moxifloxacin and quetiapine IR on ΔΔQTcI were observed at approximately time to maximum concentration (Tmax), whereas that of escitalopram was observed 3 h after Tmax. The concentration-ΔΔQTcI relationships of quetiapine IR and escitalopram were relatively flat, as compared with that of moxifloxacin. The results demonstrated the validity of trial methodology and that quetiapine IR and escitalopram caused QT prolongation in healthy individuals. In addition, hysteresis of escitalopram-induced QTc prolongation. These results indicate that higher doses of these drugs could lead to greater QT prolongation in a dose-response manner.

Escitalopram population pharmacokinetics in people living with human immunodeficiency virus and in the psychiatric population: Drug–drug interactions and probability of target attainment

“…The risk of QT prolongation and torsade de pointes following escitalopram administration and the reported dose–response relationship with QT prolongation has raised concerns, with escitalopram dosage limitations from the European medicines agency and the UK medicines and healthcare products regulatory agency, but not from the Food and Drug Administration . Taking into account the large between‐subject variability in escitalopram exposure, the modest influence of CYP2C19 inhibitors is not expected to put patients at increased risk of QT prolongation.…”

“…The risk of QT prolongation and torsade de pointes following escitalopram administration and the reported dose-response relationship with QT prolongation has raised concerns, [55][56][57] with escitalopram dosage limitations from the European medicines agency and the UK medicines and healthcare products regulatory agency, but not from the Food and Drug Administration. [58][59][60] Taking into account the large A recently published study demonstrated that clinicians tend to overestimate the impact of the inhibitory effect of ritonavir/cobicistat, resulting in the use of too low doses of psychotropic drugs in PLWH due to fear of DDIs.…”

Q-T prolongation secondary to methadone use for severe and resistant restless legs syndrome

“…The exact pathophysiology is not clear. Methadone metabolites [3], interaction with other medications that cause Q-T prolongation (e.g., antibiotics and atypical antipsychotics) [4,5], hepatic dysfunction and electrolytes abnormalities [6] are potential mechanisms. Although our patient's medications include Quetiapine which is an atypical antipsychotic that is known to cause Q-T prolongation, he was on this medication for many years and his baseline Q-T was 459 milliseconds.…”

„Lithium in der Behandlung der Altersdepression. Was spricht dafür, was dagegen?“

“…Bei Patienten mit Altersdepression wären solche direkten Vergleichsstudien, insbesondere auch in Hinblick auf die Erhaltungstherapie, wünschenswert. Bezüglich der Verträglichkeit sollte das Nebenwirkungsprofil der Antipsychotika beachtet werden, welches häufig den Einsatz einschränkt: neben den oben genannten Nebenwirkungen unter Aripiprazol zeigt sich bei älteren Menschen insbesondere unter Quetipain häufig eine Sedierung, Schwindel, QTc-Zeit-Verlängerungen und auch orthostatische Dysregulationen [37] -Nebenwirkungen, die unter Lithium seltener auftreten.…”