Jorg Taubel
Dr Jorg Taubel is medical practitioner and CEO of Richmond Pharmacology, a centre of excellence for experimental medicine studies, which he co-founded in 2001. A specialist in clinical pharmacology, Dr Taubel has extensive experience in cardiology, neurology, gastroenterology, and ethnic bridging studies. He was Principal Investigator in over 500 clinical trials in Phases 1 – 3. He is an MHRA recognised investigator for First in Human trials involving healthy and/or patient participants.
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Preceding studies have described the effects of food on the QT interval and their utility to confirm the validity of QT assessments by confirming that a study is sufficiently sensitive to detect a small QTc change around 5-10 milliseconds.
In this paper, an analysis of the food effect at baseline across periods in two different studies is presented to support the robustness of the method.
Aims. Investigate the effects of iv doses of APD421 on the QT interval in healthy subjects of Caucasian and Japanese ethnicity in order to support the clinical use of APD421 as an antiemetic.
Methods. This Randomised, Double-blind, Four-period Crossover Study consisted of Japanese (n=17) and Caucasian (n=23) healthy subjects, aged between 20-45 years. All subjects received iv doses of APD421 (5 mg and 40 mg) or placebo; moxifloxacin was used as a positive control. Study was conducted according to ICH E14 guideline.
Results. The overall findings from the ECG analysis demonstrate that for the proposed APD421 dose to be used in PONV treatment, ΔΔQTcF was increased by 5.0 ms (90% CI: 2.8, 7.1), excluding the 10 ms threshold of regulatory concern. PK-PD analysis predictions were in close agreement with the observed data. Based on a concentration response analysis, no relevant difference between ethnicities could be detected.
Discussion. This thorough QT/QTc study provided reasonable assurance that the proposed dose of APD421 can be safely used as an antiemetic agent. There is paucity of published data comparing ethnic groups within the same study and here we present the QTc analysis of Japanese versus Caucasian to confirm the absence of a difference between the ethnicities.
(1) Kranke P et al (2013) Brit J Anaesth 111 (6): 938–45
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.
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.
METHODS
In this study, 27 healthy Japanese subjects between 20 to 45 years of age were randomly assigned (1:1:1:1: ratio) to one of four dose groups of rupatadine (10 mg, 20 mg or 40 mg) or 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 oral doses on Days 2 to 5. Three ECG recordings were recorded on the following times on Days -1, 1 and 5: at pre-dose, and at 0.33, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose. Fridericia’s QT correction (QTcF) formula was used to estimate the QTc interval. The effect of rupatadine on QTcF was assessed using concentration-response modelling.
RESULTS
The concentration-response analysis did not show a significant dependence of the change of QTcF from baseline and the two-sided 90 % confidence interval for the predicted effects at the geometric mean Cmax of each of the three dose groups was completely below the threshold of regulatory concern of 10 ms. Study sensitivity was confirmed with food. On Day 1the maximum QTcF shortening was observed at the 6 hours post-dose with a value of 8.96 ms (two-sided 90% CI: -11.26, -6.65) and on Day 5 at the 8 hours post-dose with a value of 3.38 ms (two-sided 90% CI: -5.89, -0.86).
CONCLUSIONS
Rupatadine at doses up to 40 mg does not have any effect on the QT interval. Overall, it can be stated the drug can be considered safe since the upper bound of 2-sided 90% CI is well below 10 ms.
[1] Donado E et al. (2010) Br J Clin Pharmacol 69(4):410-410
2. The net effect of that is a QTc shortening that lasts for up to 7 hours
3. The effect is around -5 to -10 ms after a mixed meal of around 500 kcal
4. The design of a study needs to consider this effect and needs be planned carefully around it.
5. If this is done well, one may as well measure and calculate this effect and use it to show assay sensitivity.
Finally, we have investigated our all data for ethnic differences and have found none of any significance!