Translating QT interval prolongation from conscious dogs to humans.
In spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans.



Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between -0.98 ms μM-1and 6.1 ms μM-1in dogs and -10 ms μM-1and 90 ms μM-1in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species.



For compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x; R2= 0.989). These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs.



Together with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans.
Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.|Pharmacometrics, Grunenthal GmbH, Aachen, Germany.
Vincent F S
VF
Dubois
Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, UK.
Giovanni
G
Smania
Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
Huixin
H
Yu
Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, UK.
Ramona
R
Graf
Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
Anne S Y
AS
Chain
Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
Meindert
M
Danhof
Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, UK.|Clinical Pharmacology & Therapeutics, UCL, London, UK.
Oscar
O
Della Pasqua
D000818:Animals; D004285:Dogs; D015195:Drug Design; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis*; D004562:Electrocardiography; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis; D008954:Models, Biological; D013045:Species Specificity
PKPD modelling; QT interval prolongation; candidate screening; interspecies differences; predictive modelling; pro-arrhythmic effect