Division of Cardiac and Vascular Sciences

Food is known to shorten the QTc (QTcI and QTcF) interval and has been proposed as a nonpharmacological 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 QTc interval, whilst C-peptide has been reported to shorten the QTc 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 QTc interval under the rigorous conditions of a TQT study.

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.

Rupatadine is a marketed antihistamine indicated for symptomatic treatment of allergic rhinitis and urticaria. In this study,  the pharmacokinetics (PK), safety and tolerability of single and multiple dosing of Rupatadine was assessed in healthy Japanese male and female subjects.
METHODS
This was a Phase 1, randomised, placebo-controlled study with oral single and multiple doses of Rupatadine administered to healthy Japanese subjects between 20 to 45 years of age. Twenty seven subjects were randomised (1:1:1:1 ratio) to receive one dose of rupatadine (10 mg, 20 mg or 40 mg) or matching placebo. On Day -1, all subjects received a single dose of placebo, followed by one single daily oral dose on Day 1 and once single daily doses on Days 2 to 5. The PK data was assessed by collecting plasma samples on Days -1 and 5 before pre-dose and at 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 12 h after study drug administration,  and on Days 2, 3 and 4 before pre-dose to determine the minimum and maximum concentration of rupatadine. Safety was assessed by vital signs, electrocardiograms, physical examination and laboratory safety measurements.
RESULTS
PK analysis following administration of single and multiple doses in Japanese subjects were found to increase in a dose dependent manner. The arithmetic mean Cmax and AUC values were also found to increase in a dose dependent manner. The dose proportionality analysis revealed that the 90% CI of slope for Cmax and AUC0-∞ on Day 1 and Cmax and AUC0-tau on Day 5 for Rupatadine and UR12790 were very close to the range 0.8 to 1.25 and did clearly include 1. Single and multiple oral doses of Rupatadine were well tolerated.  There were no serious adverse events in this study and no subject withdrew due to safety reasons or any other reasons.


CONCLUSIONS
Rupatadine was safe and well tolerated when administered to Japanese subjects. The PK data are not incompatible with dose proportionality and appear to be even more conclusive after repeated doses instead of single doses. Additionally, the PK values in Japanese show similarity to the historic values obtained in Caucasian studies.

BACKGROUND: iQT studies are not solely designed to assess QTc changes. The small sample size and their ability to show small QTc changes still raises concerns. To reduce the likelihood of false negatives, moxifloxacin been used to confirm assay sensitivity in an iQT study, thus showing a greater variability in the effect when compared with TQT studies. The effect of a standardised meal on QTc has been considered as an alternative method.
METHODS: A concentration effect analysis was applied to a 4-way crossover Phase I study in order to investigate the effect of escalating single doses of E-52862. Each period consisted of a placebo baseline ECG day and treatment day. Standardised meals were served and ECGs were recorded.
RESULTS: All slopes were negative for E-52862. The sensitivity was confirmed by a shortening of QTcF of 8.1 ms (90%CI 10.4, 5.9) 1 h and 7.2 ms (90%CI 9.4, 5.0) 3 h after food intake.
CONCLUSION: This study shows that E-52862 has no QTc prolonging effects. The food effects on QTc confirmed assay sensitivity and reproducibility of the method. Similarly to moxifloxacin, an iQT setting also increased variability in the effect indicating that the robustness of the 2 methods is comparable.

Background
E 52862 is a Sigma 1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration effect model retrospectively to a four way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects.
Methods
Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E 52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day 1 were time matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day).
Results
In this conventional mean change to time matched placebo analysis, the largest time matched difference to placebo QTcI was 1.44 ms (90% CI:  4.04, 6.93 ms) for 500 mg;  0.39 ms (90% CI:  3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI:  1.89, 4.53 ms) for 800 mg of E 52862, thereby showing the absence of any QTc prolonging effect at the doses tested.
In addition concentration effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis.
Conclusion
The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of  8.1 (90% CI:  10.4,  5.9) one hour and  7.2 (90% CI:  9.4,  5.0) three hours after a standardised meal.

Aims: Lomitapide is a licensed treatment for patients with homozygous familial hypercholesterolae-mia in the USA, the EU, Canada, and Mexico. This study was conducted to compare the pharmaco-kinetics (PK), pharmacodynamics, safety, and tolerability of lomitapide between Japanese and Cauca-sian subjects with elevated low-density lipoprotein cholesterol (LDL-C) after single and multiple doses. Methods: In this randomized, double-blind, placebo-controlled study, 36 Japanese and 36 Caucasian subjects with LDL-C levels ≥ 110 mg/dL were administered an escalating lomitapide dose range of 10 – 60 mg or placebo. Subjects were assessed for safety, tolerability, and lipid levels. Results: Exposure to lomitapide as measured by Cmax was linear and increased over the dose range of 10 – 60 mg for both single-and multiple-dose administration. The correlation between AUC0–t and Ctrough demonstrated the lack of differences in the PK of lomitapide among ethnic groups. Lomi-tapide dose-dependent reductions in lipid parameters were observed and showed no ethnic differences. The safety assessments showed that the main treatment-related side effects identified were increases in hepatic enzymes and that the majority of treatment-related treatment-emergent AEs were gastrointestinal disorders. Conclusions: Lomitapide was effective in reducing LDL-C levels in a dose-dependent manner. Similar PK, efficacy, and safety profiles were observed in Japanese and Caucasian subjects, which suggest no differences in lomitapide activity or metabolism between the two populations compared in this study.

AIM The D 2 /D 3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT). METHODS This was a randomized, double-blind, placebo and positive-controlled, four-way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period. RESULTS The therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra-therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post-dose. The PK-PD relationship revealed no differences between Caucasian and Japanese subjects (p-value > 0.5). CONCLUSIONS Amisulpride has a plasma concentration-dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose.

Introduction
Rupatadine is a marketed second generation antihistamine, with anti-PAF activity, indicated for symptomatic treatment of allergic rhinitis and urticaria.This study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of rupatadine
in healthy Japanese subjects after single and multiple oral doses.
Methods
In this randomised, double-blind, placebo-controlled study, 27 male and female healthy Japanese subjects were administered single and multiple escalating rupatadine dose of 10, 20 and 40 mg or placebo. Blood samples were collected at different time points for PK measurements
and subjects were assessed for safety and tolerability. The effect of rupatadine on cognitive functioning was evaluated by means of computerized cognitive tests: rapid visual information processing (RVP), reaction time (RT), spatial working memory (SWM) and visual analogue scales (VAS).
Results
Exposure to rupatadine as measured by Cmax and AUC was found to increase in a dose dependent manner over the dose range of 10–40 mg for both single and multiple dose administration. The safety  assessments showed that all treatment related side effects were
of mild intensity and there were no serious adverse events (SAEs) or withdrawals due to treatment–emergent adverse events (TEAEs) in this study. The therapeutic dose of rupatadine did not show any CNS impairment in any of the cognitive tests.