Population pharmacokinetics-pharmacodynamics modeling of the QTc prolongation of Moxiflovoxacin and Levofloxacin in healthy volunteers: selection of the positive control in mandatory QT/QTc studies
Karl Brendel, Laetitia Canini and Marylore Chenel
Department of Clinical Pharmacokinetics, Institut de Recherches Internationales Servier,
Objectives: 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 . Because of multiple sources of variability in QTcI intervals for the investigation of any potential drug effect, population pharmacokinetics/pharmacodynamics (PK/PD) modelling approach is more and more used in order to split the overall variability into components . Moxifloxacin and levofloxacin are often used as positive control to validate the sensitivity of the QT/QTc studies. The positive control should have an effect on the mean QT/QTc interval of about 5ms.
The aim is to help to the choice of the positive control and the dose to be administered in thorough QT/QTc study, in comparing population QTc PKPD model parameter estimates after moxifloxacin and levofloxacin administrations.
Methods: QTc data coming from two phase I studies (moxifloxacin 400mg and levofloxacin 1000 or 1500mg) including a total of 160 healthy volunteers under placebo were used to build the population model for the QTc. 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 VI with the FOCE-I method. Then several models were investigated to evaluate any potential drug effect. Simulations will be performed to determine the optimal dose of moxifloxacine and/or levofloxacin allowing to have the best positive control in QT/QTc studies.
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. Moxifloxacin and levofloxacin effects were modeled as linear effects. In this model, the effect of mean moxifloxacin (400mg) predicted maximum concentration (mean Cmax=2.5mg/L) corresponded to a change of QTcI from baseline of 11.8ms. For Levofloxacin (mean Cmax=9.6mg/L for dose 1000mg and 13mg/L for 1500mg), the change of QTcI were 3.7 and 5ms, respectively.
Conclusions: This population PK/PD analyses allowed us to characterize the effects of moxifloxacin 400mg and levofloxacin 1000 or 1500mg on the QTc baseline. Simulations will be the next step to determine both the optimal dose and the number of subjects to assure a mean QT/QTc interval of about 5ms with each positive control.
 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.