Optimal design of QTc interval measurements for circadian rhythm determination
Marylore Chenel(1), Laetitia Canini(1), Kayode Ogungbenro(2) and Emmanuelle Foos-Gilbert(1)
(1). Institut de Recherches Internationales Servier, France. 2. CAPkR, School of Pharmacy, University of Manchester, United Kingdom
Introduction: Several classes of non-antiarrhythmic drugs induce lengthening of the QT interval. QT interval length is considered as a biomarker of ventricular tachiarrhythmia (Torsade de pointe). Regulatory agencies require QT/QTc studies to evaluate cardiac safety of non anti-arrhythmic drugs (1). The QT and RR intervals, as well as the QTc interval, are known to vary during the day (circadian rhythm) (2). Badly designed studies can miss this rhythmicity and the within-day variations can lead to a wrong conclusion concerning the cardiotoxic effect of the tested drug. It is thus important to reveal this phenomenon. As the number of electrocardiogram (ECG) is often limited, determining the minimum number and the location of QT measurement by an optimal design approach could be useful to take into account circadian QTc's variations in population pharmacokinetics/pharmacodynamics (PK/PD) analyses.
Objectives: Our aim was to determine the optimal ECG's record times to assess the best estimations of model parameters describing the QTc circadian rhythm.
Methods: QTc data coming from two phase I studies including a total of 160 healthy volunteers under placebo were used to build the population model for the QTc baseline. ECGs were recorded during 24h with an average 10 records per period and per subject. Estimation of the population parameters characterizing the QTc baseline was performed using NONMEM V with the FOCE-I method. Once, the population model was built and validated with an external study by visual predictive checks, ECG's record times were optimized by D-optimal design approach in PopDes version 3.0. The design domain consisted in times between 6 and 24h o'clock in order to save a sleep period. Only one group of 100 subjects was considered. The maximization procedure was based on a local exact design optimization performed using the modified Fedorov exchange algorithm (3) in PopDes version 3.0. At last, the optimal design was evaluated by simulations and estimations with NONMEM V.
Results: The circadian QTc rhythm was modeled as a mesor and a sum of three cosine terms (one amplitude and one lag-time per cosine term), representing three periods of 24, 12 and 6 h. Thus, the population model consisted of 7 fixed-effect parameters with inter-individual variability parameters and a proportional residual error model. The lag-time of the second cosine term was fixed to zero in the model. According to the coefficients of variation of the standard error (CVSEs) given by the population Fisher information matrix, the best design (i.e. with a minimum number of records) was obtained with 7 optimal record times. With this optimal design, CVSEs of fixed-effect parameters were all less than 20% except for the amplitude of the second cosine term, which was equal to 27%. At last, simulations and re-estimation with NONMEM showed that this design was able to correctly estimate fixed-effect parameters of this placebo QTc model.
Conclusions: A design with 7 ECG's records allows to well describe the circadian QTc rhythm taking into account clinical constraints. This optimized protocol could be applied in regular QTc studies in order to well estimate circadian QTc rhythm when data are analyzed by population PK/PD modeling and therefore correctly assessed the potential cardiotoxic effect of evaluated drug.
 International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; availability. Notice. Fed Regist. 70.202 (2005): 61134-35.
 Piotrovsky, V. "Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation." AAPS J 7.3 (2005): E609-E624.