Félix Jaminion (1), Darren Bentley (1), Michael Derks (2), Cheikh Diack (1)
(1) Roche Pharma Research and Early Development, Clinical Pharmacology, Roche Innovation Center Basel, F.Hoffmann-La Roche Ltd, Switzerland (2) Roche Pharma Research and Early Development, Clinical Pharmacology, Roche Innovation Center Welwyn, Roche Products, UK
Objectives: Assess the QT interval prolonging effect at supra-therapeutic exposure of a new molecular entity (NME) using a DDI study.
Methods: A clinical DDI study was conducted to evaluate the pharmacokinetics and QT prolonging effect of the NME (mainly metabolized by CYP3A4) with and without concomitant administration of the potent CYP3A inhibitor itraconazole. The study was a fixed sequence crossover. Subjects received dose D1 ( n = 4) or D2 (n = 8) of the NME b.i.d. for 10 days, 200 mg itraconazole b.i.d. for 5 days, and the NME b.i.d + 200 mg itraconazole qd for 10 days. ECGs were collected at baseline and serially paired with PK samples.
A nonlinear mixed effects modeling approach in NONMEM (version 7.2 Icon Development Solutions, Ellicott City, MD) were used for the parameters estimation and R Studio (v 0.98) and SAS (v 9.4) was used for graphical analyses of the results.
All data from the 3 treatment periods were used simultaneously to develop an exposure response model relating the different drug concentration to QT. The non-linear mixed effects modeling approach used here appropriately differentiated the drug-induced QT prolongation from other factors altering QT Interval duration. More specifically, the model uses an individualized correction of heart rate effect and incorporates oscillatory functions to describe the circadian rhythms observed in QT profiles. The potential impact of meal times which were not time-matched between baseline and post-dose was accounted by quantitating their effects on the parameters describing the diurnal variation of QT. Simulations were performed to check that the model adequately describe the data. The risk of QT prolongation for high concentrations of the NME was assessed using a PK model assuming 50% decrease of the clearance at supra-therapeutic doses.
Results: The model suggested a weak increasing effect on QT interval of the NME while Itraconazole had a slight decreasing effect. It was shown using VPC and PPC that the model describes adequately the data and that it is usable for prediction. It was shown by simulations that the upper bound of the 95% confidence interval of the mean double delta corrected QT interval would cross the 10 ms threshold only when the clearance of the NME is decrease of 50% at dose 10 fold higher than the maximum dose used in clinic.
Conclusions: A model that adequately evaluates the drug effects of the NME on cardiac repolarization was developed. It was shown that the magnitude of the NME effect on QT prolongation is unlikely to be of clinical concern even at high exposures.
References:
[1] ICH E14 Guidance. The clinical evaluation of QT/QTc interval prolongation andproarrhythmic potential for non-antiarrhythmic drugs. European Medicines Agency, November 2005
[2] Vladimir Piotrovsky. Pharmacokinetic-Pharamcodynamic Modeling in the Data Analysisand Interpretation of Drug-induced QT/QTc Prolongation., October 2005
Reference: PAGE 25 () Abstr 5772 [www.page-meeting.org/?abstract=5772]
Poster: Drug/Disease modeling - Safety