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創薬早期における薬剤誘発性 QT 延長リスクの in vivo 評価法に関する研究
| Title: | 創薬早期における薬剤誘発性 QT 延長リスクの in vivo 評価法に関する研究 |
| Other Titles: | Studies of in vivo drug-induced QT interval prolongation in early-stage drug development |
| Authors: | 田保, 充康1 Browse this author |
| Authors(alt): | Tabo, Mitsuyasu1 |
| Issue Date: | 25-Mar-2010 |
| Publisher: | Hokkaido University |
| Abstract: | The potential for non-cardiac drugs to induce QT interval prolongation accompanied by a rare but life-threatening lethal arrhythmia has generated intense interest and concern in the development of pharmaceuticals. Because inhibition of the hERG channel is considered the main cause for the QT interval prolongation, in vitro hERG inhibitory tests are generally conducted in early-stage drug development. However, hERG inhibitors do not necessarily cause QT prolongation and hERG tests are considered insufficient for actual QT risk assessment. In this study, in consideration of accurate QT risk evaluation in the early stages, I developed in vivo assays using anesthetized guinea pigs, anesthetized dogs and conscious common marmosets. 1. Since the period of ventricular repolarization (QT interval) adapts to changes in the heart rate (or RR interval), studies using anesthetized guinea pigs and dogs were conducted under a fixed heart rate using atrial pacing to accurately assess the effects of drugs on the QT inteval. In addition, studies using anesthetized dogs and conscious marmosets were preformed under highly sensitive conditions using the appropriate QT correction formula obtained from a relationship between QT and RR intervals. 2. The monophasic action potential (MAP) was measured in anesthetized guinea pigs under a fixed heart rate using atrial pacing. Eight positive reference drugs (E-4031, cisapride, astemizole, terfenadine, bepridil, haloperidol, quinidine, dl-sotalol) and four negative reference drugs (diltiazem, verapamil, chlorpheniramine, captopril) were intravenously administered at various dosages to assess the effects on the MAP duration (MAP90(pacing): action potential duration at 90% repolarization level). All positive reference drugs showed dose-dependent MAP90(pacing) prolongation, whereas the negative reference drugs did not. There was a clear correlation between each estimated 5% MAP90(pacing) prolonging dose (ED5: 5% effective dose) of the eight positive reference drugs and the clinical plasma concentration associated with QT prolongation previously reported (R2=0.7214). 3. The electrocardiogram (ECG) under atrial pacing conditions was measured in anesthetized dogs. A relationship between the QT and RR intervals under a nontreatment condition was clarified. The QT/RR relationship indicated that when the RR interval was prolonged, prolongation of the QT interval followed. In order to obtain a QT interval uninfluenced by changes in the heart rate, QT corrections were compared among the formulae of Bazett, Fridericia, Matsunaga, Van de Water and the study original. The study original formula (QTcX=QT/RR0.3879) eliminated the influence of RR interval most effectively and resulted in small CV values, indicating that the method showed the most appropriate correction of the QT interval against the RR interval. Two positive reference drugs (astemizole, dl-sotalol) and one negative reference drug (propranolol) were intravenously administered to assess the effects on the QTc interval corrected by the study original QT correction formula at sinus rhythm (QTcX) and QT interval under atrial pacing (QT(pacing)) and the plasma drug concentrations were measured. All of the positive reference drugs dose-dependently prolonged the QTcX interval and QT(pacing), whereas the negative reference drugs failed to do so. The plasma concentrations of the positive reference drugs associated with QT prolongation were mostly consistent with those associated with previously reported clinical QT prolongation. 4. Common marmosets were implanted with telemetry transmitters. ECG was measured under a conscious condition and a relationship between QT and RR intervals was clarified. The QT/RR relationship indicated that when RR interval was prolonged, prolongation of the QT interval followed, as with the abovementioned anesthetized dogs. In order to obtain a QT interval uninfluenced by changes in heart rate, the QT correcting formulae of Bazett, Fridericia and individual correction were compared. The individual QT correction method (QTci=RRrefβ×QT/RRβ, where β is the individual correction coefficient) most effectively eliminated the influence of RR interval and resulted in small CV values, indicating that the method showed the most appropriate correction of the QT interval against the RR interval. Two positive reference drugs (astemizole, dl-sotalol) and two negative reference drugs (propranolol, nifedipine) were orally administered to assess the effects on the QTc interval corrected by the individual QT correction formula and the plasma drug concentrations measured. All positive reference drugs showed QTc interval prolongation, whereas the negative reference drugs did not. The plasma concentrations of the positive reference drugs associated with QT prolongation were mostly consistent with those associated with previously reported clinical QT prolongation. 5. All of the assays using anesthetized guinea pigs, anesthetized dogs and conscious marmosets developed in this study showed high sensitivity and high specificity. In addition, the quality of sensitivity was appropriate because the results of the positive reference compounds showed a clear correlation with clinical outcomes. Therefore, these assays would be useful for the assessment of drug-induced QT interval prolongation. The anesthetized guinea pig assay can deal with many different test compounds and is superior in throughput. The anesthetized dog assay can accurately clarify the safety margin of test compounds because of the many blood-sampling points for the measurement of plasma drug concentration. The conscious marmoset assay can be conducted with the same drug administration route used in clinic and thus could be effectively utilized. The appropriate assay should be selected according to the characteristics and the number of test compounds. Incorporation of these assays into early-stage drug development would provide a potentially accurate and more integrated assessment of QT risk and thus a more timely introduction of new pharmaceuticals into the clinic stages with fewer safety issues. |
| Conffering University: | 北海道大学 |
| Degree Report Number: | 甲第9487号 |
| Degree Level: | 博士 |
| Degree Discipline: | 獣医学 |
| Type: | theses (doctoral) |
| URI: | http://hdl.handle.net/2115/42814 |
| Appears in Collections: | 学位論文 (Theses) > 博士 （獣医学）
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Submitter: 田保 充康
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