Sibenadet Hydrochloride

Molecular packing in two polymorphs of sibenadet hydrochloride (AR-C68397AA, Viozan™) is investigated using a combined experimental (1) H double-quantum (DQ) solid-state magic-angle spinning nuclear magnetic resonance and computational (gauge including projected augmented wave calculation of chemical shifts) approach. For Form I, NH-NH and NH-OH (1) H DQ peaks are observed corresponding to nearest distances of 2.62 and 2.87 Å, respectively, for the intermolecular hydrogen-bonding arrangement in the single-crystal X-ray diffraction structure. The same (1) H DQ peaks at the same (1) H chemical shifts are observed for Form II, for which there is no single-crystal diffraction structure, indicating the same intermolecular hydrogen-bonding arrangement of the benzothiazolone moieties as in Form I. (1) H DQ build-up (as a function of the DQ recoupling time) curves are presented for the resolved NH-NH and NH-OH DQ peaks for the two polymorphs. For Form I, the ratio of the maximum intensity for the NH-OH and NH-NH DQ peaks is in excellent agreement with the ratio of the summed squares of the H-H dipolar couplings, as determined using H-H distances from the crystal structure up to 4 Å. Small differences in the (1) H DQ build-up behaviour for the two polymorphs are attributed to differences in the longer-range NH-OH distances associated with different inter-layer arrangements.

• When this study was conducted it was already known that the ‘standard’ methods of correcting the QT interval for heart rate were not optimal and that bias could result in their use in certain circumstances, in particular when drugs or conditions also induced wide fluctuations in heart rate.• The use of subject specific correction methods had been advocated and whilst these had been shown to apparently correct QT interval over usual physiological heart rates, they had not been tested under conditions where drugs could potentially increase heart rate and ‘standard’ correction methods gave apparent increases in QT interval. Furthermore, subject specific correction methods had usually been generated over a normal physiological heart rate range and made the assumption that the relationship remained linear outside of this usual range.

• A subject specific correction factor for QT correction can be calculated from a wide range of heart rates using exercise testing and the relationships between QT and RR are unique for a given individual.• The generation of subject specific correction factors from ECGs collected under resting conditions is not a robust method.• That subject specific correction factors derived from exercise testing are not appropriate to apply to drugs (with no evidence to suggest effects on the QT interval) that induce increases in heart rate and that the relationship between the QT and RR interval during exercise is clearly different to the QT/RR relationship of a drug that increases heart rate.

We sought to investigate subject specific QT interval correction factors (SSCF) determined at rest and after exercise and to determine the validity of these factors after the administration of a probe drug known to increase heart rate without directly affecting cardiac repolarization.

Thirty‐two healthy volunteers underwent graded exercise, multiple recordings of electrocardiogram during rest over a day and a treatment phase administering inhaled placebo or sibenadet (a β2‐adrenoceptor/dopamine D2‐receptor agonist) at 250, 500 or one of 750 or 1000 µg. SSCF were determined from linear regression of plots of log RR interval vs. log QT after exercise (QTcX), rest (QTcR), and combined data (QTcC). The SSCFs along with Bazett & Fridericia corrections were applied to the ECGs after inhalation of sibenadet.

SSCFs obtained from the combination of the exercise and resting day (mean QTcC = 0.41) and exercise alone (mean QTcX = 0.40) were similar with a good fit to the data (mean r2 = 0.92 and 0.93, respectively) while data at rest resulted in a less pronounced slope (mean QTcR = 0.27) and poorer fit (mean r2 = 0.52). After the administration of sibenadet, none of the SSCFs, Bazett or Fridericia corrections adequately corrected QT for heart rate induced changes.

Neither a SSCF from exercise, Bazett’s or Fridericia’s correction factors, adequately corrected the QT interval after the administration of a sympathomimetic agonist drug to increase heart rate in healthy volunteers demonstrating the potential need for QT/RR correction factors to be tailored for each drug studied.