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.     

Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study

AIMS

To assess the steady-state pharmacokinetic and QT_c effects of domperidone and ketoconazole, given alone and together.

METHODS

A randomized, placebo-controlled, double-blind, crossover study was carried out. Healthy subjects (14 men, 10 women; age 18–39 years; mean weight 73.5 kg, range 53.8–98.8 kg; 23 Europid, 1 Afro-Caribbean) received orally, for 7 days each, placebo, domperidone 10 mg, four doses daily, at 4 h intervals, ketoconazole 200 mg 12-hourly and domperidone and ketoconazole together. The washout period was 15 days. Pharmacokinetics and serial 12-lead ECGs were assessed on day 7, and serial ECGs on day −1 and at follow-up. Two subjects withdrew before the third treatment period, so data were available for 22–24 subjects.

RESULTS

Ketoconazole tripled domperidone concentrations at steady-state. Domperidone, ketoconazole and their combination significantly increased QT_cF in men. Overall adjusted mean differences from placebo were 4.20 (95% CI 0.77, 7.63), 9.24 (95% CI 5.85, 12.63) and 15.90 (95% CI 12.47, 19.33) ms, respectively. In women, QT_cF was not significantly different from placebo on either domperidone or ketoconazole alone, or in combination. However, QT_c was positively correlated with plasma drug concentrations, in both men and women. ΔQT_cF increased by about 2 ms per 10 ng ml^–1 rise in domperidone concentration, and per 1 µg ml^–1 rise in ketoconazole concentration.

CONCLUSIONS

Ketoconazole tripled the plasma concentrations of domperidone. Domperidone and ketoconazole increased QT_cF in men, whether given together or separately. The effect of domperidone alone was below the level of clinical importance. The negative result in women is unexplained.     

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).     

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.     

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.     

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.     

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.     

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.     

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.     

High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings

Aims

To investigate the QT interval after high dose droperidol using continuous 12-lead Holter recordings.

Methods

This was a prospective study of patients given droperidol with a continuous Holter recording. Patients were recruited from the DORM II study which included patients with aggression presenting to the emergency department. Patients initially received 10 mg droperidol as part of a standardized sedation protocol. An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist''s discretion. Continuous 12-lead Holter recordings were obtained for 2–24 h utilizing high resolution digital recordings with automated QT interval measurement. Electrocardiograms were extracted hourly from Holter recordings. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine if it was abnormal. QT_cF (Fridericia''s HR correction) was calculated and >500 ms was defined as abnormal.

Results

Forty-six patients had Holter recordings after 10–40 mg droperidol and 316 QT–HR pairs were included. There were 32 abnormal QT measurements in four patients, three given 10 mg and one 20 mg. In three of the four patients QT_cF >500 ms but only in one taking methadone was the timing of QT_cF >500 ms consistent with droperidol dosing. Of the three other patients, one took amphetamines, one still had QT prolongation 24 h after droperidol and one took a lamotrigine overdose. No patient given >30 mg had a prolonged QT. There were no arrhythmias.

Conclusion

QT prolongation was observed with high dose droperidol. However, there was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs.     

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.     

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.     

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.     

Effect of Prucalopride on the Pharmacokinetics of Oral Contraceptives in Healthy Women

Background

Prucalopride is a selective, high-affinity, 5-hydroxytryptamine 4 (5-HT₄) receptor agonist, which is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Women of childbearing potential, many of whom will be using oral contraceptives, comprise a large proportion of patients seeking medical therapy for constipation.

Objective

The aim of this study was to evaluate the effect of prucalopride on the absorption and steady-state pharmacokinetics of oral contraceptives in healthy women.

Methods

Sixteen women (aged 18–45 years) were enrolled in this open-label, two-way crossover trial (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01036893","term_id":"NCT01036893"}}NCT01036893) and given two 5-day treatments with a once-daily oral contraceptive (ethinylestradiol 0.035 mg + norethisterone 1 mg), alone and in combination with prucalopride 2 mg once daily. Treatments were separated by a 7 ± 2-day washout period. On days 1 and 5, blood samples were obtained pre-dose and at regular intervals post-dose up to 24 and 48 hours, respectively, to determine ethinylestradiol and norethisterone plasma concentrations. Prucalopride plasma concentrations were determined pre-dose and 3 hours post-dose on days 1 and 5, and 24 hours post-dose on day 6. Safety was assessed.

Results

Thirteen participants completed the study. One participant was thought to be non-compliant on days 3 and/or 4, and was excluded from the day 5 analysis. On days 1 and 5, maximum plasma concentrations of both oral contraceptive constituents were attained in ~1 hour and were unaffected by prucalopride administration. On day 5, steady-state prucalopride and oral contraceptive concentrations had been achieved. Prucalopride did not affect the pharmacokinetics of the oral contraceptives: point estimates for the maximum plasma concentration and area under the plasma concentration–time curve values and their associated 90 % confidence intervals were contained within predefined equivalence limits (80–125 %). Prucalopride was well tolerated, with a safety profile consistent with those observed in previous studies.

Conclusion

Co-administration of prucalopride with an oral contraceptive did not result in any clinically meaningful pharmacokinetic interactions and was well tolerated.     

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.     

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.     

Selective desensitization of the 5-HT4 receptor-mediated response in pig atrium but not in stomach

Background and purpose:

The time dependency of the effect of 5-HT₄ receptor agonists depends on many specific regulatory mechanisms, which vary between tissues. This has important implications with regard to the effects of endogenous 5-HT, as well as to the clinical use of 5-HT₄ receptor agonists, and might contribute to tissue selectivity of agonists.

Experimental approach:

The progression and desensitization of 5-HT₄ receptor-mediated responses were evaluated in an organ bath set-up using two, clinically relevant, porcine in vitro models: gastric cholinergic neurotransmission and atrial contractility.

Key results:

Exposure of gastric tissue to 5-HT or to the selective 5-HT₄ receptor agonists prucalopride and M0003 results in a sustained non-transient effect during exposure; after washout, the response to a subsequent challenge with 5-HT shows no clear desensitization. Incubation of left atrial tissue with 5-HT resulted in a transient response, leading after washout to a marked desensitization of the subsequent response to 5-HT. The selective 5-HT₄ receptor agonists prucalopride and M0003 induce only very weak atrial responses whereas they are very effective in desensitizing the atrial response to 5-HT. The observations also suggest that the properties of prucalopride and M0003 to bind to and/or activate the 5-HT₄ receptor differ from those of 5-HT. This difference might have contributed to the observed desensitization.

Conclusions and implications:

The high potency of prucalopride and M0003 in desensitizing the response to 5-HT together with their low efficacy in the atrium emphasizes the cardiac safety of this class of 5-HT₄ receptor agonists.     

Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

AIM

To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y₁₂ receptor antagonist, in healthy volunteers.

METHODS

This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50–600 mg once daily or 50–300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day⁻¹, or placebo for 14 days.

RESULTS

Ticagrelor was absorbed with median t_max 1.5–3 h, exhibiting predictable pharmacokinetics over the 50–600 mg dose range. Mean C_max and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses ≥300 mg once daily and ≥100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor ≥100 mg twice daily was greater and less variable (93–100%, range 65–100%) than with clopidogrel (77%, range 11–100%) at trough concentrations. No safety or tolerability issues were identified.

CONCLUSIONS

Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50–600 mg once daily and 50–300 mg twice daily with C_max and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses ≥100 mg twice daily and ≥300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day⁻¹ was well tolerated.     

Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone

AIM

The aim of this study was to find out whether the inhibition of cytochrome P450 2D6 (CYP2D6) with paroxetine or concomitant inhibition of CYP2D6 and CYP3A4 with paroxetine and itraconazole, altered the pharmacokinetics and pharmacological response of orally administered oxycodone.

METHODS

A randomized placebo-controlled cross-over study design with three phases was used. Eleven healthy subjects ingested 10 mg of oral immediate release oxycodone on the fourth day of pre-treatment with either placebo, paroxetine (20 mg once daily) or paroxetine (20 mg once daily) and itraconazole (200 mg once daily) for 5 days. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacological (analgesic and behavioural) effects were evaluated.

RESULTS

Paroxetine alone reduced the area under concentration–time curve (AUC(0,0–48 h)) of the CYP2D6 dependent metabolite oxymorphone by 44% (P < 0.05), but had no significant effects on the plasma concentrations of oxycodone or its pharmacological effects when compared with the placebo phase. When both oxidative pathways of the metabolism of oxycodone were inhibited with paroxetine and itraconazole, the mean AUC(0,∞) of oxycodone increased by 2.9-fold (P < 0.001), and its C_max by 1.8-fold (P < 0.001). Visual analogue scores for subjective drug effects, drowsiness and deterioration of performance were slightly increased (P < 0.05) after paroxetine + itraconazole pre-treatment when compared with placebo.

CONCLUSIONS

Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone if the function of the CYP3A4 pathway is normal. When both CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially.