Does the Prulifloxacin ECG Study Prove Cardiac Safety of the Drug?

Abstract

The regulatory requirements of the International Conference on Harmonisation E14 Guidance are presently well known and the majority of new pharmaceuticals (with well-defined exceptions) are subjected to the investigations of drug-induced QT/corrected QT (QTc) interval changes. One such investigation is reported by Rosignoli et al. in this issue of the journal, describing an ECG study of prulifloxacin. Rosignoli et al. have to be congratulated on the clarity of their expression and on the transparency of their manuscript. Unfortunately, limitations of their approach, both in the design of the study and in the interpretation of the results, seem to deserve deeper discussion. Firstly, Rosignoli et al. somewhat misinterpret the regulatory purpose of the so-called thorough QT/QTc studies conducted in healthy subjects. The goal of these studies is not to characterize the likelihood of the investigated drugs to cause torsades de pointes tachycardia. Rather, these studies are merely aimed at distinguishing between those drugs that do affect ventricular repolarization and those that do not. Drugs that are found to affect ventricular repolarization require further investigations in susceptible patients, e.g. those with cardiac, renal or hepatic failure in addition to the target disease of the new pharmaceutical. Hence, the QT/QTc interval prolongation is not used as a surrogate of torsadogenic proarrhythmia. Rather, it is used as a surrogate of general repolarization involvement. The regulatory requirements for a meaningful conduct of the thorough QT/QTc studies have repeatedly been discussed, including the most recent publication summarizing some of the problems encountered in design and review of the studies. Referring to this recent review article, the most important problem with the prulifloxacin study is that it used only the therapeutic dose. The investigators report that higher doses are not homogeneously absorbed and that they therefore decided to investigate only the therapeutic dose. Unfortunately, investigation of a therapeutic dose proves little in terms of repolarization involvement of the drug and even less in terms of its cardiac safety. Rosignoli et al. do not provide any publicly available data on the variability of the absorption of the higher doses. However, even if the individual absorptions were fairly different, pharmacokinetic/pharmacodynamic (PK/PD) modelling would be helpful in estimating the QTc effects at supra-therapeutic exposures. While it is true that the PK/PDmodels are not necessarily effective in estimating the maximumECG effects in individual subjects over a limited range of individual maximum concentrations, general trends of plasma concentrations in populations of healthy individuals correlate well with the QTc changes. One can even speculate that if a drug is absorbed differently in different healthy subjects, the precision of the population-based PK/PD mixed-effect model would be increased because of the increased range of concentration values at individual measurement time-points. Thus, investigating only the therapeutic dose is a serious limitation of the prulifloxacin study that might have even led to false negative results in terms of the effects of the drug on the QTc. COMMENTARY Clin Drug Investig 2010; 30 (1): 1-3 1173-2563/10/0001-0001/$49.95/0