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.     

Orally administered moxifloxacin prolongs QTc in healthy Chinese volunteers: a randomized,single-blind,crossover study

Aim:

To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers.

Methods:

This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin.

Results:

The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects.

Conclusion:

Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers.     

Not-in-trial simulation I: Bridging cardiovascular risk from clinical trials to real-life conditions

Aims

The assessment of heart rate-corrected QT (QTc) interval prolongation relies on the evidence of drug effects in healthy subjects. This study demonstrates the relevance of pharmacokinetic–pharmacodynamic (PKPD) relationships to characterize drug-induced QTc interval prolongation and explore the discrepancies between clinical trials and real-life conditions.

Methods

d,l-Sotalol data from healthy subjects and from the Rotterdam Study cohort were used to assess treatment response in a phase I setting and in a real-life conditions, respectively. Using modelling and simulation, drug effects at therapeutic doses were predicted in both populations.

Results

Inclusion criteria were shown to restrict the representativeness of the trial population in comparison to real-life conditions. A significant part of the typical patient population was excluded from trials due to weight and baseline QTc interval criteria. Relative risk was significantly different between sotalol users with and without heart failure, hypertension, diabetes and myocardial infarction (P < 0.01). Although drug effects do cause an increase in the relative risk of QTc interval prolongation, the presence of diabetes represented an increase from 4.0 [95% confidence interval (CI) 2.7–5.8] to 6.5 (95% CI 1.6–27.1), whilst for myocardial infarction it increased from 3.4 (95% CI 2.3–5.13) to 15.5 (95% CI 4.9–49.3).

Conclusions

Our findings show that drug effects on QTc interval do not explain the observed QTc values in the population. The prevalence of high QTc values in the real-life population can be assigned to co-morbidities and concomitant medications. These findings substantiate the need to account for these factors when evaluating the cardiovascular risk of medicinal products.     

Atenolol offers better protection than clonidine against cardiac injury in kainic acid-induced status epilepticus

Background and Purpose

Status epilepticus is increasingly associated with cardiac injury in both clinical and animal studies. The current study examined ECG activity for up to 48 h following kainic acid (KA) seizure induction and compared the potential of atenolol and clonidine to attenuate this cardiac pathology.

Experimental Approach

Sprague-Dawley rats (male, 300–350 g) were implanted with ECG and electrocorticogram electrodes to allow simultaneous telemetric recordings of cardiac and cortical responses during and after KA-induced seizures. Animals were randomized into saline controls, and saline vehicle-, clonidine- or atenolol-pretreated KA groups.

Key Results

KA administration in the saline-pretreated group produced an immediate bradycardic response (maximal decrease of 28 ± 6%), coinciding with low-level seizure activity. As high-level seizure behaviours and EEG spiking increased, tachycardia also developed, with a maximum heart rate increase of 38 ± 7% coinciding with QTc prolongation and T wave elevation. Both clonidine and atenolol pretreatment attenuated seizure activity and reduced KA-induced changes in heart rate, QTc interval and T wave amplitude observed during both bradycardic and tachycardic phases in saline-pretreated KA animals. Clonidine, however, failed to reduce the power of EEG frequencies. Atenolol and to a lesser extent clonidine attenuated the cardiac hypercontraction band necrosis, inflammatory infiltration, and oedema at 48 h after KA, relative to the saline-KA group.

Conclusions and Implications

Severe seizure activity in this model was clearly associated with altered ECG activity and cardiac pathology. We suggest that modulation of sympathetic activity by atenolol provides a promising cardioprotective approach in status epilepticus.     

Levofloxacin can be used effectively as a positive control in thorough QT/QTc studies in healthy volunteers

AIMS

To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies.

METHODS

Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design. Digital 12-lead ECGs were recorded in triplicate. Measurement of QT interval was performed automatically with subsequent manual onscreen over-reading using electronic callipers. Blood samples were taken for determination of levofloxacin and moxifloxacin concentrations.

RESULTS

Mean QTcI (QT interval corrected for heart rate using a correction factor that is applicable to each individual) was prolonged in subjects receiving moxifloxacin 400 mg compared with placebo. The largest time-matched difference in QTcI for moxifloxacin compared with placebo was observed to be 13.19 ms (95% confidence interval 11.21, 15.17) at 3.5 h post dose. Prolonged mean QTcI was also observed in subjects receiving levofloxacin 1000 mg and 1500 mg compared with placebo. The largest time-matched difference in QTcI compared with placebo was observed at 3.5 h post dose for both 1000 mg and 1500 mg of levofloxacin [mean (95%) 4.42 ms (2.44, 6.39) in 1000 mg and 7.44 ms (5.47, 9.42) in 1500 mg]. A small increase in heart rate was observed with levofloxacin during the course of the study. However, moxifloxacin showed a greater increase compared with levofloxacin.

CONCLUSIONS

Both levofloxacin and moxifloxacin can fulfil the criteria for a positive comparator. The ICH E14 guidelines recommend a threshold of around 5 ms for a positive QT/QTc study. The largest time-matched difference in QTc for levofloxacin suggests the potential for use in more rigorous QT/QTc studies. This study has demonstrated the utility of levofloxacin on the assay in measuring mean QTc changes around 5 ms.     

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.     

QTc interval prolongation by fexofenadine in healthy human volunteers and its correlation with plasma levels of fexofenadine: A demonstration of anticlockwise hysteresis

Aim:

The study was designed to establish relationship between the plasma concentration and QTc interval prolonging effect of fexofenadine and demonstrate the phenomenon of anticlockwise hysteresis.

Materials and Methods:

Six subjects were given fexofenadine 60 mg tablet orally under stable conditions, and their drug concentrations were measured at regular intervals. At predetermined time, their ECGs were recorded. Data were analyzed and plotted graphically.

Design and Setting:

Randomized parallel design, single group study conducted at clinical research organization of Ahmadabad.

Results:

In all subjects time taken for maximum plasma concentration of fexofenadine (T_max) was around 3 h and the value of average maximum plasma concentration was 460.63 ng/mL, the effect of fexofenadine on the heart (measured as QTc interval prolongation) was maximum (E_max) after 6 h and average QTc interval was 469.75 ms. Thus, the time to maximum concentration of fexofenadine did not match with the maximum effect on the heart as measured by QTc interval.

Conclusion:

The relationship between the drug concentration and drug effect on the heart are at two different time scales. It can be understood by two-compartment model of pharmacokinetics, and this retardation or lagging of an effect behind the concentration is known as hysteresis. The increase of QTc was not beyond 500 ms and not sustained, demonstrating overall cardiac safety of fexofenadine.     

Effect of experimental hyperlipidaemia on the electrocardiographic effects of repeated doses of halofantrine in rats

BACKGROUND AND PURPOSE

Halofantrine can cause a prolongation of the cardiac QT interval, leading to serious ventricular arrhythmias. Hyperlipidaemia elevates plasma concentration of halofantrine and may influence its tissue uptake. The present study examined the effect of experimental hyperlipidaemia on QT interval prolongation induced by halofantrine in rats.

EXPERIMENTAL APPROACH

Normolipidaemic and hyperlipidaemic rats (induced with poloxamer 407) were given 4 doses of halofantrine (i.v., 4–40 mg·kg⁻¹·d⁻¹) or vehicle every 12 h. Under brief anaesthesia, ECGs were recorded before administration of the vehicle or drug and 12 h after the first and last doses. Blood samples were taken at the same time after the first and last dose of halofantrine. Hearts were also collected 12 h after the last dose. Plasma and heart samples were assayed for drug and desbutylhalofantrine using a stereospecific method.

KEY RESULTS

In the vehicle group, hyperlipidaemia by itself did not affect the ECG. Compared to baseline, QT intervals were significantly higher in both normolipidaemic and hyperlipidaemic rats after halofantrine. In hyperlipidaemic rats, plasma but not heart concentrations of the halofantrine enantiomers were significantly higher compared to those in normolipidaemic rats. Despite the lack of difference in the concentrations of halofantrine in heart, QT intervals were significantly higher in hyperlipidaemic compared to those in normolipidaemic rats.

CONCLUSIONS AND IMPLICATIONS

The unbound fraction of halofantrine appeared to be the controlling factor for drug uptake by the heart. Our data suggested a greater vulnerability to halofantrine-induced QT interval prolongation in the hyperlipidaemic state.     

Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects

AIM

To characterize the effects of lamotrigine on QT interval in healthy subjects.

METHODS

Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic–pharmacodynamic (PK–PD) modelling.

RESULTS

Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo −7.48 ms, 90% CI −10.49, −4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK–PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied.

CONCLUSIONS

Therapeutic doses of lamotrigine (50–200 mg b.d.) were not associated with QT prolongation in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Drugs that inhibit the human cardiac delayed rectifier potassium current may lead to prolongation of the cardiac QT interval and are associated with a fatal, polymorphic, ventricular tachycardia known as torsades de pointes.
• Lamotrigine is indicated in the treatment of epilepsy and the prevention of mood episodes in patients with bipolar disorder.
• Lamotrigine inhibits the human cardiac delayed rectifier potassium current in vitro, and it has been hypothesized that QT prolongation may contribute to the risk of sudden unexpected death in epilepsy patients.

WHAT THIS STUDY ADDS

• This is the first reported thorough QT/QTc study with lamotrigine conducted to International Conference on Harmonization guidelines.
• The mean QTc interval was not prolonged by lamotrigine in healthy subjects, as assessed by the standard heart rate correction methods (Fridericia''s and Bazett''s).
• The in vitro inhibition of the delayed rectifier potassium current does not translate into an effect on QT in man.

     

Optimizing Smart Pump Technology by Increasing Critical Safety Alerts and Reducing Clinically Insignificant Alerts

Background:

Alerts generated by intravenous (IV) infusion pump safety software prevent life-threatening situations that might otherwise go unnoticed. However, when alerts are often clinically insignificant, health care workers may become desensitized and discount their importance, resulting in potentially dangerous situations. Little research has been devoted to visual alert desensitization.

Method:

This paper describes how the Carolinas HealthCare System decreased the number of nonclinically relevant infusion pump alerts by analyzing alert data that were formatted into scatter plots. This in turn enabled the identification of the medications associated with the most meaningful alerts and those associated with the least meaningful alerts.

Conclusion:

By revising drug library limits for specific medications, it was possible to decrease the number of less clinically meaningful alerts, reduce alert fatigue, and thereby increase the effectiveness of the smart infusion pumps. This added another layer of safety to patient care.     

Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials

Background and Purpose

Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential.

Experimental Approach

We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC₅₀ value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions.

Key Results

Introducing a 50% hERG-channel current block results in 8% prolongation of the APD₉₀ and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD₉₀ is not affected.

Conclusions and Implications

Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.     

Pharmacy Students' Ability to Identify Potential Drug-Drug Interactions

Objective

To evaluate the ability of third- and fourth-year pharmacy students to identify clinically significant drug-drug interactions (DDIs)

Methods

A questionnaire designed to measure DDI knowledge was disseminated to fourth-year pharmacy students in a school of pharmacy. A second questionnaire was distributed to third-year pharmacy students in 2 schools of pharmacy (schools A and B) and re-administered to students in 1 of the schools 1 year later.

Results

Class of 2005 fourth-year pharmacy students correctly categorized an average of 52% ± 13% DDI pairs on the first questionnaire. Third-year pharmacy students at schools A and B correctly categorized an average of 61% ± 18% and 66% ± 15% of DDI pairs, respectively. The average percentage of correct responses for fourth-year students from the class of 2007 was 65% (± 17%).

Conclusion

Pharmacy students'' ability to identify important DDIs is far from optimal, even after completing experiential requirements.     

Opioid maintenance patients with QTc prolongation: Congenital long QT syndrome mutation may be a contributing risk factor

Objectives

This study investigates opioid maintenance treatment (OMT) patients found to have corrected QT (QTc) interval above 500 ms, with particular focus on past medical history, genetic testing and cardiac investigations.

Methods

Detailed medical and cardiac history was obtained, with particular focus upon risk factors. Cardiac investigations, including genetic testing for the five most common long QT syndrome (LQTS) mutations, exercise electrocardiography (ECG) and 24-h ECG recordings, were performed.

Results

Of 200 OMT patients assessed with ECG, seven methadone maintained patients identified with QTc interval above 500 ms participated in this study. Two were identified as heterozygous LQTS mutation carriers. Both had experienced cardiac symptoms prior to and during OMT. No other risk factors for QTc prolongation were detected among the seven patients. Six of the seven patients underwent further cardiac investigations. QTc intervals fluctuated widely over 24 h and during exercise for all patients. Only one of the LQTS mutation carriers switched to buprenorphine and started on a beta-blocker. Despite strong medical advice and information, none of the other patients wanted to switch to buprenorphine or take other cardiac protective measures.

Conclusion

Findings indicate the importance of recording a thorough past medical history, focusing specifically on previous cardiac symptoms, and on other known risk factors for QTc prolongation, prior to initiating patients on methadone.     

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).     

Pharmacokinetics of Coadministered Guanfacine Extended Release and Lisdexamfetamine Dimesylate

Background

In clinical practice, α₂-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv^®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug–drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse^®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated.

Objective

The primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination.

Study Design

This was an open-label, randomized, three-period crossover, DDI study.

Setting

The study was conducted in a single clinical research center.

Participants

Forty-two healthy adults were randomized in this study.

Interventions

Subjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination.

Main Outcome Measures

Blood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90 % confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration–time curve extrapolated to infinity (AUC_0–∞) and maximum plasma concentration (C_max) falling within the bioequivalence reference interval (0.80–1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs).

Results

Forty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC_0–∞ and C_max of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90 % CI of the geometric mean ratio of AUC_∞ for the two treatments was within the bioequivalence criteria, but for C_max the upper bound of the 90 % CI exceeded the standard range for bioequivalence by 7 %. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9 % of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3 %) and headache (7.5, 4.9, and 7.3 %) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX.

Conclusions

In healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.     

Comparison of the effects of levofloxacin on QT/QTc interval assessed in both healthy Japanese and Caucasian subjects (pages

AIMS

There is no consensus as to what extent the results of thorough QT interval/corrected QT interval (QT/QTc) studies need to be bridged.

METHODS

The results of two studies using levofloxacin in Japanese and Caucasian subjects were compared in a post hoc analysis to investigate the similarity of dose–effect responses.

RESULTS

Concentration–response analysis based on the change of QT interval corrected using Fridericia''s formula (QTcF) from time-matched placebo was planned and performed in the combined data sets. At the geometric maximum mean concentration for the two doses in the Caucasian study, a predicted effect on QTcF comparable to the effects observed was found. For the Japanese study, the predicted effect was lower, but the difference was not statistically significant.

CONCLUSIONS

No statistically significant differences in QTc-prolonging effect between Japanese and Caucasian subjects were observed following levofloxacin dosing. However, a trend suggests that Caucasian subjects may be more sensitive. Age and sex did not have an impact.     

The role of the Na+/Ca2+ exchanger,INa and ICaL in the genesis of dofetilide-induced torsades de pointes in isolated,AV-blocked rabbit hearts

Background and purpose:

The Na⁺/Ca²⁺ exchanger (NCX) may contribute to triggered activity and transmural dispersion of repolarization, which are substrates of torsades de pointes (TdP) type arrhythmias. This study examined the effects of selective inhibition of the NCX by SEA0400 on the occurrence of dofetilide-induced TdP.

Experimental approach:

Effects of SEA0400 (1 µmol·L⁻¹) on dofetilide-induced TdP was studied in isolated, Langendorff-perfused, atrioventricular (AV)-blocked rabbit hearts. To verify the relevance of the model, lidocaine (30 µmol·L⁻¹) and verapamil (750 nmol·L⁻¹) were also tested against dofetilide-induced TdP.

Key results:

Acute AV block caused a chaotic idioventricular rhythm and strikingly increased beat-to-beat variability of the RR and QT intervals. SEA0400 exaggerated the dofetilide-induced increase in the heart rate-corrected QT interval (QTc) and did not reduce the incidence of dofetilide-induced TdP [100% in the SEA0400 + dofetilide group vs. 75% in the dofetilide (100 nmol·L⁻¹) control]. In the second set of experiments, verapamil further increased the dofetilide-induced QTc prolongation and neither verapamil nor lidocaine reduced the dofetilide-induced increase in the beat-to-beat variability of the QT interval. However, lidocaine decreased and verapamil prevented the development of dofetilide-induced TdP as compared with the dofetilide control (TdP incidence: 13%, 0% and 88% respectively).

Conclusions and implications:

Na⁺/Ca²⁺ exchanger does not contribute to dofetilide-induced TdP, whereas Na⁺ and Ca²⁺ channel activity is involved in TdP genesis in isolated, AV-blocked rabbit hearts. Neither QTc prolongation nor an increase in the beat-to-beat variability of the QT interval is a sufficient prerequisite of TdP genesis in rabbit hearts.     

Using Smart Pumps to Understand and Evaluate Clinician Practice Patterns to Ensure Patient Safety

Background:

Safety software installed on intravenous (IV) infusion pumps has been shown to positively impact the quality of patient care through avoidance of medication errors. The data derived from the use of smart pumps are often overlooked, although these data provide helpful insight into the delivery of quality patient care.

Objective:

The objectives of this report are to describe the value of implementing IV infusion safety software and analyzing the data and reports generated by this system.

Case study:

Based on experience at the Carolinas HealthCare System (CHS), executive score cards provide an aggregate view of compliance rate, number of alerts, overrides, and edits. The report of serious errors averted (ie, critical catches) supplies the location, date, and time of the critical catch, thereby enabling management to pinpoint the end-user for educational purposes. By examining the number of critical catches, a return on investment may be calculated. Assuming 3,328 of these events each year, an estimated cost avoidance would be $29,120,000 per year for CHS. Other reports allow benchmarking between institutions.

Conclusion:

A review of the data about medication safety across CHS has helped garner support for a medication safety officer position with the goal of ultimately creating a safer environment for the patient.