Since the discovery of the hERG channel in 1994, sponsors conduct in vitro studies to evaluate all new chemical entities (NCE) for their potential to inhibit the current mediated by the native cardiac IKr channel.
PRECLINICAL INVESTIGATIONS OF
THE ‘QT-LIABILITY’ OF A DRUG
Since
the discovery of the hERG channel in 1994, sponsors conduct in vitro studies (unicellular
prepa-rations as well as recombinant hERG channels expressed in heterologous
systems) to evaluate all new chemical entities (NCE) for their potential to
inhibit the current mediated by the native cardiac IKr channel.
Indeed, early use of hERG channel studies as a screening test is now routine.
As long as the results are interpreted carefully with regard to safety margins
and other properties of the drug, these studies are valu-able in identifying
drugs with a potential to prolong the QT interval and hence probably induce
torsade de pointes (Shah, 2005a). Drugs known to be torsado-genic in man have
always been shown to be positive in these assays. False positive hERG studies
are rela-tively frequent. Rarely, a false negative result may arise if the drug
concerned prolongs repolarization not by inhibiting hERG, but by interfering
with normal trafficking of this channel protein (e.g. arsenic triox-ide or
pentamidine) (Ficker et al., 2004;
Katchman et al., 2006; Kuryshev et al., 2005).
Unicellular
recordings of action potentials from ventricular tissues, myocytes or Purkinje
fibres are also used to evaluate the effect of drugs on action potential
duration and therefore the QT interval. Aris-ing from the qualitative and
quantitative distribution of various ion channels, M-cells seem to have a
better predictive value than do other tissues. From one set of in vitro investigations, it is possible
to obtain a broad range of clinically
useful information. The species used for these tissue experiments could be
guinea pig, rabbit or dog, depending on laboratory skills and database. The
relevance of the selected species and tissue to man is perhaps the most
important deter-minant of how useful the information obtained from these
studies will be with regard to the risk posed by the drug to humans.
In
addition to the above in vitro
investigations, studies are also performed in
vivo using dogs or other suitable species, and a number of proarrhythmic
models have been developed over the last few years.
Preclinical
investigations of drugs for their potential to delay ventricular repolarization
and prolong the QT interval are now very sophisticated, and have a remarkable
predictive value with regard to clinical risk of torsade de pointes (Fenichel et al., 2004; Joshi et al., 2004; Shryock et al.,
2004; Recanatini et al., 2005; Sanguinetti and Mitcheson, 2005).
More
recent focus of preclinical studies is to docu-ment the predictive value of
transmural dispersion in repolarization and TRIaD (triangulation, reverse use
dependency, instability and dispersion), rather than QT interval prolongation
alone. HERG blockade still remains the basic mechanism underlying these
rela-tively new markers (Antzelevitch, 2004; Shah and Hondeghem, 2005). Efforts
are also underway to eval-uate the predictive value of beat-to-beat variations
in the morphology and amplitude of T-waves, which may potentially serve as
indicators of delayed repo-larization and electrophysiological instability.
Of
the drugs listed earlier in the Introduction, stud-ies with hERG channels would
have successfully predicted the proarrhythmic activities of pimozide,
sertindole, astemizole, terfenadine, cisapride, halo-fantrine, thioridazine,
droperidol and levacetyl-methadol. Studies using hERG channels have also been
used to characterize the relative QT-prolonging potencies of various members of
a chemical or phar-macological class, such as quinolone antibacterial agents or
gastric prokinetic drugs.
Recent
in vitro studies have confirmed that
terodi-line blocks the IKr current – the molecular substrate for
prolongation of the QT interval. Whereas the therapeutic concentrations of
terodiline are in the range of 1 5 μM, its IC50 value for IKr
block was found to be 0 7 μM (Jones et al.,
1998). In guinea pig papillary muscles and ventricular myocytes, clinically
relevant concentrations of terodiline length-ened the action potential duration
by up to 12%, while higher concentrations shortened the duration in a
concentration-dependent manner. Further voltage-clamp studies in guinea pig
ventricular preparations indicate that terodiline at much higher
concentra-tions also inhibits two other membrane currents that govern
repolarization: (i) an L-type calcium current (IC50 value of 12 μM)
and (ii) a slowly activating, delayed rectifier potassium current (IKs)
with an IC50 value of 26 M (Shuba et al., 1999). Fossa et al.
(2002) tested cisapride and terodiline in conscious dogs at their clinically
relevant free drug concen-trations. Using a sophisticated beat-to-beat QT–RR
interval assessment, they were able to demonstrate the QT-prolonging effects of
both these drugs. The dose-response curve for both was bell-shaped. For
terodi-line, the greatest mean QT prolongation occurred at a free drug
concentration of 0 0329 M, with concen-trations higher than this being less
active in this regard. This is interesting in view of the stereos-elective
concentration-dependent pharmacodynamic properties of terodiline discussed
earlier. Fossa et al. (2002) were
also able to show that for drugs that affect repolarization through multiple
channels, the effect on the mean QT interval may be more difficult to detect,
but individual responses to the QT–RR interval rela-tionship increased the
sensitivity for more accurate clinical prediction.
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