[Early clinical drug development]. / Les phases précoces du développement clinique d'un médicament.

The first administrations of a molecule to humans, so-called phase I studies of drug development, follow experimental animal studies which allow to have a first assessment of the pharmacological effects and toxicity of the molecule under development. Typically, these studies are performed in "healthy" subjects or in relapsing patients with cancer. Participants' safety is a priority. Trained professionals administer single doses, followed by repeated doses, in authorized medical centres. They allow to study the pharmacokinetic and pharmacodynamic profile of tested molecules in humans and to explore some sources of variability of these parameters. These studies are highly regulated and their methodology is fairly standardized.

LES PHASES PRÉCOCES DU DÉVELOPPEMENT CLINIQUE D'UN MÉDICAMENT. Les premières administrations d'une molécule à des humains, dites études de phase I du développement font suite aux études expérimentales qui permettent d'avoir une première idée du profil de ses effets pharmacologiques et de sa toxicité. Ces études sont typiquement organisées avec des sujets « normaux ¼ ou, en oncologie, chez des patients en rechute. La sécurité des participants est une priorité. Des doses uniques, suivies de doses répétées, sont administrées par des professionnels formés dans des lieux médicalisés autorisés. Elles permettent d'étudier le profil pharmacocinétique et pharmacodynamique de la molécule chez les humains et d'explorer quelques sources de variabilité de ces paramètres. Elles sont très encadrées réglementairement et relativement stéréotypées méthodologiquement.

Fast, accurate and easy-to-teach QT interval assessment: The triplicate concatenation method.

BACKGROUND: The gold standard method for assessing the QTcF (QT corrected for heart rate by Fridericia's cube root formula) interval is the "QTcF semiautomated triplicate averaging method" (TAM), which consists of measuring three QTcF values semiautomatically, for each 10-second sequence of a triplicate electrocardiogram set, and averaging them to get a global and unique QTcF value. Thus, TAM is time consuming. We have developed a new method, namely the "QTcF semiautomated triplicate concatenation method" (TCM), which consists of concatenating the three 10-second sequences of the triplicate electrocardiogram set as if they were a single 30-second electrocardiogram, and measuring QTcF only once for the triplicate electrocardiogram set. AIM: To compare the TCM method with the TAM method. METHODS: Fifty triplicate electrocardiograms were read twice by an expert and a student using both methods (TAM and TCM). We plotted Bland-Altman plots to assess agreement between the two methods, and to compare the student and expert results. The time needed to read a set of 20 consecutive triplicate electrocardiograms was measured. RESULTS: Limits of agreement between TAM and TCM ranged from -8.25 to 6.75ms with the expert reader. TCM was twice as fast as TAM (17.38 versus 34.28min for 20 consecutive triplicate electrocardiograms). Bland-Altman plots comparing student and expert results showed limits of agreement ranging from -4.34 to 11.75ms for TAM, and -1.2 to 8.0ms for TCM. CONCLUSIONS: TAM and TCM show good agreement for QT measurement. TCM is less time consuming than TAM. After a learning session, an inexperienced reader can measure the QT interval accurately with both methods.

Assessment of the effect of a single oral dose of telithromycin on sotalol-induced qt interval prolongation in healthy women.

AIMS: Telithromycin belongs to ketolides, a new class of macrolide antibiotics. Macrolides are known to have the potential to prolong QT interval duration. Previous studies have shown that telithromycin did not induce significant QT interval prolongation in healthy subjects compared with placebo. The main objective of this study was to demonstrate the absence of amplification of QT interval prolongation induced by sotalol, when telithromycin and sotalol were co-administered. The secondary objective was to correlate the QT interval changes induced by the study drugs to plasma concentrations during the elimination phase. METHODS: Twenty-four women received sotalol (160 mg) together with placebo or telithromycin (800 mg) in a two-period, double-blind, randomized study. Electrocardiograms were recorded at rest. Comparison of maximal corrected QT interval (QTc(max)) with sotalol in the presence or absence of telithromycin was performed. The relation between sotalol concentration and QTc was studied using linear regression. RESULTS: Mean difference (95% CI) between QTc(max) with sotalol-placebo and QTc(max) with sotalol-telithromycin was -15.5 ms (-27.7 to -3.2 ms). QTc(max) interval prolongation was lower (P < 0.05) with sotalol-telithromycin than with sotalol-placebo, in relation to decreased sotalol plasma concentrations. Regression analysis showed that the relationship between sotalol plasma concentration and QTc interval duration was not modified by telithromycin co-administration. CONCLUSION: Our results do not support a potential synergistic effect on QT interval prolongation between sotalol and telithromycin. The decrease of mean QTc interval in subjects taking telithromycin and sotalol may be explained by a decrease of sotalol concentration.