Preclinical Investigations of the ‘QT-Liability’ of a Drug

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Chapter: Pharmacovigilance: Withdrawal of Terodiline: A Tale of Two Toxicities

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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