Small doses of droperidol do not present relevant torsadogenic actions: a double-blind,ondansetron-controlled study

AIM

Drugs used for postoperative nausea and vomiting prophylaxis are believed to provoke torsadogenic changes in cardiac repolarization. The aim of this study was to assess the effect of small doses of droperidol on the parameters of cardiac repolarization, including the QT_c interval and transmural dispersion of repolarization.

METHODS

A total of 75 patients were randomly allocated to receive 0.625 or 1.25 mg droperidol or 8 mg ondansetron. The QT_c interval was calculated using Bazett''s formula and the Framingham correction. The transmural dispersion of repolarization was determined as T_peak–T_end time.

RESULTS

Transient QT prolongation, corrected with both formulae, followed 1.25 mg of droperidol 10 min after administration. No change in the QT_c value was observed in the other groups. When corrected with Bazett''s formula, QT_c was prolonged above 480 ms in two patients receiving 1.25 mg droperidol (at the 10^th and 20^th minute of the study) and in one receiving ondansetron. No patients developed a QT_cB prolongation over 500 ms. No increase above 480 ms was observed relative to the Framingham correction method. There were no significant differences in the T_peak–T_end time either between or within the groups.

CONCLUSION

In men without cardiovascular disorders small doses (1.25 mg) of droperidol prophylaxis induced transient QT_c prolongation without changes in transmural dispersion of repolarization. The apparently low risk of the drug applies only in low risk male patients with a low pro-QT_c score.     

Use of selective serotonin re-uptake inhibitors and the heart rate corrected QT interval in a real-life setting: the population-based Rotterdam Study

Aims

Selective serotonin re-uptake inhibitors (SSRIs), specifically citalopram and escitalopram, are thought to cause QT_c prolongation, although studies have shown contradictory results. Nevertheless, a maximum citalopram dosage of 20 mg in high risk patients (e.g. >60 years of age) is recommended. We aimed to investigate the association between use of (individual) SSRIs and QT_c in a population-based study in older adults.

Methods

This study, which was part of the prospective Rotterdam Study (period 1991–2012), included participants with up to five electrocardiograms (ECGs). We used linear mixed models to compare QT_cF (QT corrected according to Fridericia) measured during use of individual SSRIs with QT_cF measured during non-use of any antidepressant. For citalopram, analyses were additionally restricted to a maximum dosage of 20 mg in participants aged 60 years and older.

Results

We included 12 589 participants with a total of 26 620 ECGs of which 436 ECGs were made during SSRI use. The mean QT_cF was similar during use of any drugs from the SSRI class and during non-use. After stratifying to individual SSRIs, ECGs recorded during use of citalopram had the longest QT_c compared with ECGs recorded during non-use (+12.8 ms, 90% CI 7.5, 18.2). This result remained similar in the analysis comprising participants aged 60 years and older with a maximum prescribed daily dosage of 20 mg citalopram.

Conclusions

Although no SSRI class effect was observed, use of citalopram was associated with a longer QT_cF, even after considering the recommended restrictions. Other SSRIs may not give a clinically relevant QT_cF prolongation.     

Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria

Aims

The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment.

Methods

Exposure–response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100–800 mg and 160–1440 mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing.

Results

A significant relation between plasma concentrations and placebo-corrected change from baseline QT_cF (ΔΔQT_cF) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng ml⁻¹ (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QT_cF effect of 14 ms (90% CI 10, 18 ms) and 18 ms (90% CI 14, 22 ms) was predicted at expected plasma concentrations of a single dose 800 mg OZ439 combined with PQP 960 mg (188 ng ml⁻¹) and 1440 mg (281 ng ml⁻¹), respectively, administered in the fasted state.

Conclusions

Piperaquine prolongs the QT_c interval in a concentration-dependent way. A single dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3 day PQP-artemisinin combinations and can therefore be predicted to cause less QT_c prolongation.     

Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation

Aims

Given the similarities in QT_c response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QT_c interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin.

Methods

Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration.

Results

A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QT_c prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans.

Conclusions

Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QT_c prolongation in humans. Furthermore, the risk of QT_c prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule.     

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol

Aim

To study the differences in QT_c interval on ECG in response to a single oral dose of rac-sotalol in men and women.

Methods

Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration–QTc analyses were performed using a linear mixed effects model.

Results

Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QT_cI) most effectively removed the heart rate dependency of the QT_c interval. Mean QT_cI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QT_cI in both genders. The largest mean change in QT_cI (ΔQT_cI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean C_max 1.8 μg ml⁻¹ (range 1.1–2.8) vs. 1.4 μg ml⁻¹ (range 0.9–1.9), P = 0.0009). The slope of the concentration–ΔQT_cI relationship was steeper in women (30 ms per μg ml⁻¹ vs. 23 ms per μg ml⁻¹ in men; P = 0.0135).

Conclusions

The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.     

Assessment of QTc-prolonging potential of BX471 in healthy volunteers. A 'thorough QTc study' following ICH E14 using various QT correction methods

AIMS

Within the framework of the clinical development of BX471, this study was intended to provide experience in conducting ‘thorough QT_c studies’ according to ICH E14. A broad range of QT correction methods and analysis strategies was employed.

METHODS

A double-blind, placebo- and positive-controlled, single-centre, three-way cross-over study was conducted in 74 healthy volunteers. Electrocardiograms were read by blinded experts. QT correction methods included Bazett''s (QT_cB), Fridericia''s (QT_cF) and several regression-based corrections.

RESULTS

There was a significant QT_cF prolongation of 10.26 ms by the positive control compared with placebo [95% confidence interval (7.83, 12.70)]. BX471 at therapeutic doses did not cause substantial QT_c prolongation [QT_cF estimate 2.93 ms, 95% confidence interval (1.00, 4.86); QT_cB estimate 3.30 ms, 95% confidence interval (0.85, 5.74)]. Regression-based QT correction methods yielded similar results to Fridericia''s correction [e.g. using a linear regression across the study population, QT_c estimate 2.39 ms, 95% confidence interval (0.55, 4.23)]. Differences between the various regression-based correction methods were small. Results were not affected by whether the QT corrections were performed per ECG or per beat.

CONCLUSIONS

BX471 does not cause meaningful QT_c prolongation. Three QT correction methods may be sufficient in future studies: Bazett''s (required by regulatory authorities), Fridericia''s (as the most reliable fixed formula) and a regression-based correction (individually or population-based), each performed per ECG (i.e. applied to the means of several beats of one ECG recording).     

Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study

AIMS

To assess steady-state effects of therapeutic and supra-therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control.

METHODS

A double-blind, double-dummy, placebo- and active-controlled study was conducted in 120 healthy male and female volunteers ({"type":"clinical-trial","attrs":{"text":"NCT00903747","term_id":"NCT00903747"}}NCT00903747). Volunteers were randomized to receive prucalopride 2–10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve-lead 24 h Holter ECGs recorded at various time-points were evaluated blind and centrally.

RESULTS

Estimated mean difference in study specific corrected QT interval (QT_cSS) time-matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl −0.33, 6.38 ms]). Upper limits of the two-sided 90% CI for QT_cSS were all <10 ms. There were no outlying QT_cSS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT_cSS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time-points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min^–1), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment.

CONCLUSION

Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.     

Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers

Aim

The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QT_c in 131 healthy CYP2D6 poor metabolizer males were compared.

Methods

Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days −2 and −1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QT_cM) on day 7 was the primary endpoint.

Results

QT_cM differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one-sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one-sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QT_c was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QT_cM for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration−QT_c change observed was consistent with the literature.

Conclusion

Atomoxetine was not associated with a clinically significant change in QT_c. However, a statistically significant increase in QT_c was associated with increasing plasma concentrations.     

Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects

Aims

Exenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QT_c) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QT_c.

Methods

Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction.

Results

Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml⁻¹, 399 ± 11.9 pg ml⁻¹ and 627 ± 21.2 pg ml⁻¹). QT_cP, a population-based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QT_cP (ΔΔQT_cP) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml⁻¹ (ΔΔQT_cP^avg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQT_cP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin.

Conclusions

These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QT_c and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.     

A repeat-dose thorough QT study of inhaled fluticasone furoate/vilanterol combination in healthy subjects

AIMS

This study was designed as a thorough QT (TQT) study to evaluate the effects of fluticasone furoate(FF)/vilanterol (VI) in healthy subjects. Supportive data from a TQT study conducted with FF are also presented.

METHODS

This was a randomized, placebo-and positive-controlled, double-dummy, double-blind, four-way crossover study, in which healthy subjects (n = 85) were randomized to 7 days of once-daily treatment of FF/VI (200/25 or 800/100 μg) or placebo or single-dose oral moxifloxacin (single-blind, 400 mg). In the supportive TQT study, subjects (n = 40) were randomized to single-dose inhaled FF(4000 μg), oral moxifloxacin (400 mg) or placebo.

RESULTS

There was a lack of effect of FF/VI (200/25 μg) on QTcF (Fridericia''s correction); all time-matched mean differences from baseline relative to placebo (0–24 h) were <5 ms, with upper 90% confidence intervals (CI) of <10 ms. At 800/100 μg, FF/VI had no significant clinicaleffect on QTcF except at 30 min postdose when the 90% CI was >10 ms [mean (90% CI), 9.6 ms (7.2, 12.0)]. No effect on QTci (individually corrected) was observed at either strength of FF/VI, with mean time-matched treatment differences <5 ms at all time points [upper 90% CIs <10 ms (0–24 h)]. Assay sensitivity was confirmed; moxifloxacin prolonged QTcF and QTci, with time-matched mean differences from baseline relative toplacebo of >10 ms (1–8 h postdose).

CONCLUSIONS

Repeat once-daily dosing of FF/VI (200/25 μg), which is the highest therapeutic strength used in phase III studies, is not associated with QTc prolongation in healthy subjects. Supratherapeutic strength FF/VI (800/100 μg) demonstrated a small transient effect on QTcF but not on QTci.     

The effect of tafamidis on the QTc interval in healthy subjects

Aims

The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day⁻¹). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect of tafamidis on the QT_c interval in healthy subjects.

Methods

This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra-therapeutic C_max of ∽20 µg ml⁻¹) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of  ≥ 14 days. Serial triplicate 12-lead electrocardiograms were performed. QT_c intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs).

Results

A total of 42 subjects completed the study. The upper limit of the two-sided 90% confidence intervals (CIs) for the difference in baseline-adjusted QT_cF between tafamidis 400 mg and placebo was <10 ms (non-inferiority criterion) for all time points. The lower limit of the two-sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre-specified moxifloxacin t_max of 3 h post-dose, confirming assay sensitivity. C_max and AUC(0,24 h) for tafamidis were 20.36 µg ml⁻¹ and 305.4 µg ml⁻¹ h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs.

Conclusions

This thorough QT_c study suggests that a supra-therapeutic single 400 mg oral dose of tafamidis does not prolong the QT_c interval and is well-tolerated in healthy volunteers.     

Evaluation of a QT nomogram for risk assessment after antidepressant overdose

AIMS

A QT-heart rate nomogram has recently been proposed as a means of identifying patients at risk of torsades de pointes after antidepressant overdose, based on published cases of drug-induced torsades de pointes. The present study sought to examine the performance of the nomogram in patients who ingest an antidepressant overdose but do not develop arrhythmia.

METHODS

A retrospective case control study of patients presenting to hospital after overdose of citalopram, mirtazapine and venlafaxine was carried out. The primary outcome variable was QT higher than the nomogram, and was compared with occurrence of QT_c (QT corrected by Bazett''s formula) greater than ≥440 ms and QT_c≥500 ms, with comparison between drugs. Data are expressed as proportions in each group with 95% confidence intervals.

RESULTS

There were 858 electrocardiograms from 541 patients. QT was higher than the nomogram in 2.4% (1.4, 4.1%), whereas QT_c was ≥440 ms in 23.1% (95% CI 19.8, 26.8%), and QT_c was ≥500 ms in 1.1% (0.5, 2.5%). Citalopram overdose was more likely to be associated with QT higher than the nomogram compared with the other agents (difference 7.0%, 95% CI 2.9, 11.9%, P = 0.001) and more likely to be associated with QT_c≥440 ms (difference = 11.0%, 95% CI 2.6, 19.0%, P = 0.013).

CONCLUSIONS

The QT nomogram was associated with a lower false positive rate than widely accepted QT_c criteria, and allowed detection of different effects of individual drugs. The nomogram offers potential advantages over QT_c criteria and merits further investigation in a clinical setting.     

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, 140 mg [10–560 mg]). 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 = 87 ms/(mg l^–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 200 mg.

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.     

Eltrombopag does not affect cardiac repolarization: results from a definitive QTc study in healthy subjects

AIM

To evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QT_c.

METHODS

This was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences.

RESULTS

Eighty-seven subjects entered the study and 48 completed. There was no prolongation of QT_c (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QT_cF between drug and placebo (ddQT_cF) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag C_max and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days'' dosing. Proportions of subjects with adverse events were similar across treatments (52–66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug.

CONCLUSIONS

No clinically significant QT_c prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.     

No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a ‘thorough QT/QTc study’ performed according to ICH guidelines

AIMS

To evaluate the effects of therapeutic and supratherapeutic doses of rupatadine on cardiac repolarization in line with a ‘thorough QT/QTc study’ protocol performed according to International Conference on Harmonization guidelines.

METHODS

This was a randomized (gender-balanced), parallel-group study involving 160 healthy volunteers. Rupatadine, 10 and 100 mg day⁻¹, and placebo were administered single-blind for 5 days, whilst moxifloxacin 400 mg day⁻¹ was given on days 1 and 5 in open-label fashion. ECGs were recorded over a 23-h period by continuous Holter monitoring at baseline and on treatment days 1 and 5. Three 10-s ECG samples were downloaded at regular intervals and were analysed independently. The primary analysis of QTc was based on individually corrected QT (QTcI). Treatment effects on QTcI were assessed using the largest time-matched mean difference between the drug and placebo (baseline-subtracted) for the QTcI interval. A negative ‘thorough QT/QTc study’ is one where the main variable is around ≤5 ms, with a one-sided 95% confidence interval that excludes an effect >10 ms.

RESULTS

The validity of the trial was confirmed by the fact that the moxifloxacin-positive control group produced the expected change in QTcI duration (around 5 ms). The ECG data for rupatadine at both 10 and 100 mg showed no signal effects on the ECG, after neither single nor repeated administration. Furthermore, no pharmacokinetic/pharmacodynamic relationship, gender effects or clinically relevant changes in ECG waveform outliers were observed. No deaths or serious or unexpected adverse events were reported.

CONCLUSIONS

This ‘thorough QT/QTc study’ confirmed previous experience with rupatadine and demonstrated that it had no proarrhythmic potential and raised no concerns regarding its cardiac safety.     

Insulin at normal physiological levels does not prolong QTc interval in thorough QT studies performed in healthy volunteers

Aims

Food is known to shorten the QT_c (QT_cI and QT_cF) interval and has been proposed as a non-pharmacological method of confirming assay sensitivity in thorough QT (TQT) studies and early phase studies in medicines research. Intake of food leads to a rise in insulin levels together with the release of C-peptide in equimolar amounts. However, it has been reported that euglycaemic hyperinsulinemia can prolong the QT_c interval, whilst C-peptide has been reported to shorten the QT_c interval. Currently there is limited information on the effects of insulin and C-peptide on the electrocardiogram (ECG). This study was performed to assess the effect of insulin, glucose and C-peptide on the QT_c interval under the rigorous conditions of a TQT study.

Methods

Thirty-two healthy male and female, Caucasian and Japanese subjects were randomized to receive six treatments: (1) placebo, (2) insulin euglycaemic clamp, (3) carbohydrate rich ‘continental’ breakfast, (4) calorie reduced ‘American’ FDA breakfast, (5) moxifloxacin without food, and (6) moxifloxacin with food. Measurements of ECG intervals were performed automatically with subsequent adjudication in accordance with the ICH E14 guideline and relevant amendments.

Results

No effect was observed on QT_cF during the insulin euglycaemic clamp period (maximal shortening of QT_cF by 2.6 ms, not significant). Following ingestion of a carbohydrate rich ‘continental’ breakfast or a calorie reduced ‘American’ FDA standard breakfast, a rapid increase in insulin and C-peptide concentrations were observed. Insulin concentrations showed a peak response after the ‘continental’ breakfast observed at the first measurement time point (0.25 h) followed by a rapid decline. Insulin concentrations observed with the ‘American’ breakfast were approximately half of those seen with the ‘continental’ breakfast and showed a similar pattern. C-peptide concentrations showed a peak response at the first measurement time point (0.25 h) with a steady return to baseline at the 6 h time point. The response to the ‘continental’ breakfast was approximately double that of the ‘American’ FDA breakfast. A rapid onset of the effect on QT_cF was observed with the ‘continental’ breakfast with shortening by >5 ms in the time interval from 1 to 4 h. After the ‘American’ FDA breakfast, a similar but smaller effect was seen.

Conclusions

The findings of this study demonstrate that there was no change in QT_c during the euglycaemic clamp. Given that insulin was raised to physiological concentrations comparable with those seen after a meal, whilst the release of C-peptide was suppressed, insulin appears to have no effect on the QT_c interval in either direction. The results suggest a relationship exists between the shortening of QT_c and C-peptide concentrations and indicate that glucose may have a QT_c prolonging effect, which will require further research.     

Patterns of toxicity and factors influencing severity in acute adult trimipramine poisoning

AIMS

To analyze the clinical features of trimipramine poisoning, identify a minimal toxic dose, and the dose bearing a 50% risk of developing a moderate, severe or fatal outcome.

METHODS

All acute adult trimipramine monointoxications reported by physicians to the Swiss Toxicological Information Centre between January 1992 and December 2009 were identified.

RESULTS

Two hundred and thirty cases (26 confirmed and 204 probable) were analyzed, the mean age was 35.7 years and 74% were females. One hundred and thirty-seven patients showed mild, 54 moderate and 21 severe symptoms. Three cases were fatal due to refractory cardiovascular collapse. Ninety-three per cent of the events were attempted or completed suicides. The most common symptoms were central nervous system depression (79.2%), tachycardia (19.1%) and QT_c prolongation (13.9%). The severity of poisoning depended significantly on the ingested dose (P < 0.001). The minimal dose for moderate symptoms was 250 mg (median dose 1.2 g) and 850 mg for severe symptoms (median dose 2.7 g). The dose for a 50% risk of developing a moderate, severe or fatal outcome was 5.11 g. In 38 patients early gastrointestinal decontamination was performed. Overall, these patients ingested higher trimipramine doses than the late- or not-decontaminated patients (P= 0.113). The median doses were also higher in the decontaminated group within each severity category except in the fatal cases.

CONCLUSIONS

We demonstrated that moderate trimipramine poisoning can already occur after ingestion of doses in the high therapeutic range. Poisoned patients have to be monitored for central nervous system depression, dysrhythmias and QT_c prolongation. Early decontamination might be beneficial.     

Electrocardiogram changes and arrhythmias in venlafaxine overdose

AIMS

To investigate serial electrocardiogram (ECG) parameters, haemodynamic changes and arrhythmias following venlafaxine overdose.

METHODS

The study included 369 venlafaxine overdoses in 273 patients presenting to a toxicology unit where an ECG was available. Demographic information, details of ingestion, haemodynamic effects [heart rate and blood pressure (BP)] and complications (arrhythmias and conduction defects) were obtained. ECG parameters (QT, QRS) were measured manually and analysed by visual inspection, including plotting QT–HR pairs on a QT nomogram.

RESULTS

The median ingested dose was 1500 mg [interquartile range (IQR) 600–3000 mg; range 75–13 500 mg). Tachycardia occurred in 54% and mild hypertension (systolic BP >140 mmHg) in 40%. Severe hypertension (systolic BP >180 mmHg) and hypotension (systolic BP <90 mmHg) occurred in 3% and 5%, respectively. No arrhythmias occurred based on continuous telemetry, and conduction defects were found in only seven of 369 admissions; five of these conduction defects were pre-existing abnormalities. In 22 admissions [6%, 95% confidence interval (CI) 4–10] there was an abnormal QT–HR pair, with larger doses being more likely to be associated with an abnormal QT. The median maximum QRS width was 85 ms (IQR 80–90 ms; range 70–145 ms) and the QRS was greater than 120 ms in only 24 admissions (7%, 95% CI 4–10).

CONCLUSIONS

Venlafaxine overdose causes only minor abnormalities in the QT and QRS intervals, unlikely to be associated with major arrhythmias, except possibly with large doses.     

Thorough QT study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects

Aims

The aims of this study were three-fold and were to (i) investigate the effect of food (fasted and fed state) on the degree of QT prolongation caused by moxifloxacin under the rigorous conditions of a TQT study, (ii) differentiate the effects on QT_c that arise from changes in PK from those arising as a result of electrophysiological changes attributable to raised levels of C-peptide [11] offsetting in part the I_Kr blocking properties of moxifloxacin and (iii) characterize the QT_cF profile of oral moxifloxacin (400 mg) in healthy Japanese volunteers compared with Caucasian subjects.

Methods

The study population consisted of 32 healthy non-smoking, Caucasian (n = 13) and Japanese (n = 19), male and female subjects, aged between 20–45 years with a body mass index of between 18 to 25 kg m⁻². Female volunteers were required to use an effective contraceptive method or be abstinent. Subjects with ECGs which were deemed unsuitable for evaluation in a TQT study were excluded. ECGs were recorded in triplicate with subsequent blinded manual adjudication of the automated interval measurements. Electrocardiograms in the placebo arm were recorded twice in fasted and fed condition.

Results

The results demonstrated a substantial change in the typical moxifloxacin effect on the ECG. The effect on ΔΔQT_c in the fed state led to a significant delay and a modest reduction compared with the fasted state correcting both conditions with the corresponding placebo data. The largest QT_cF change from baseline in the fed state was observed at 4 h with a peak value of 11.6 ms (two-sided 90% CI 9.1, 14.1). In comparison, the largest QT_cF change observed in the fasted state was 14.4 ms (90% CI 11.9, 16.8) and occurred at 2.5 h post-dose. The PK of moxifloxacin were altered by food and this change was consistent with the observed QT_cF change. In the fed state plasma concentrations of moxifloxacin were considerably and consistently lower in comparison with the fasted state, and this applied to both ethnicities. The concentration–effect analysis revealed that there was no change in slope and confirmed that the difference in this analysis was caused by a change in the PK profile of moxifloxacin. Comparisons of the moxifloxacin effect in the fed state compared with fasted placebo also revealed a pharmacodynamic effect whereby a meal appears to antagonize the effects of moxifloxacin on the lengths of the QT_c interval.

Conclusions

Our findings demonstrate that the food effect by itself leads to a shortening of the QT_c interval offsetting in part the effects of a 400 mg single dose of oral moxifloxacin. The typical moxifloxacin PK profile is also altered by food prior to dosing reducing the C_max and delays the peak effects on QT_c up to several hours thereby reducing the overall magnitude of the effect and delaying the peak QT_c prolongation. The contribution of the two effects was clearly discernible. Given that moxifloxacin is sometimes given with food in TQT studies, consideration should be given to adequate baseline corrections and appropriate sampling time points. In this study the PK–PD relationship was similar for Japanese and Caucasian subjects in the fed and fasted conditions, thereby providing further evidence that the sensitivity to the QT_c prolonging effects of fluoroquinolones was likely to be independent of ethnicity. The small differences observed between the two subpopulations were not statistically significant. However, future studies should give consideration to formal ethnic comparisons as a secondary outcome parameter as very little is known about the relationship between ethnicity and drug effects on cardiac repolarization.