The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.
R Re ed du uc ct ti io on n i in n s sy ym mp pa at th he et ti ic c a ac ct ti iv vi it ty y a af ft te er r l lo on ng g--t te er rm m C CP PA AP P t tr re ea at tm me en nt t i in n s sl le ee ep p a ap pn no oe ea a: : c ca ar rd di io ov va as sc cu ul la ar r i im mp pl li ic ca at ti io on ns s It is concluded that obstructive sleep apnoea is associated with high sympathetic activity both during sleep and waking periods. Urinary metanephrine excretion seemed to reflect blood pressure, but neither daytime nor night-time catecholamine excretion was directly related to disease severity in patients with severe obstructive sleep apnoea. In spite of a marked reduction of catecholamine excretion at followup, BP and cardiac structure remained unchanged. Although increased sympathetic activity may act as a contributory trigger for cardiovascular disease in sleep apnoea, a reduction of activity after nasal CPAP is not associated with changes in blood pressure or cardiac structure.
The ICH E14 guidance on how to clinically assess a new drug's liability to prolong the QT interval was adopted in May 2005. A centre-piece of the guidance was the establishment of one single trial, the 'thorough QT/QTcstudy', intended to confidently identify drugs that may cause QT prolongation. Initially perceived as a great challenge, this study has rapidly become a standard component of all clinical development programs for new molecular entities. The study is normally conducted in healthy volunteers, includes both a positive and a negative (placebo) control and is stringently powered to exclude an effect on the QTc interval exceeding 10 ms. The E14 guidance was intentionally not very prescriptive and allowed sponsors and service providers to explore new methodologies. This has allowed for a rapid development of new methods during the first years after the guidance's implementation, such as computer-assisted algorithms for QT measurements. Regulators have worked in close collaboration with pharmaceutical industry to set standards for the design and conduct of the 'thorough QT/QTc study', which therefore has evolved as a key component of cardiac safety assessment of new drugs. This paper summarizes the requirements on the 'thorough QT/QTc study' with emphasis on the standard that has evolved based on interactions between regulators and sponsors and the experience from a large number of completed studies.
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