Model‐based evaluation of drug‐induced QT c prolongation for compounds in early development
Aims Significant differences between dogs and humans have been observed in the concentration– QTc effect relationship of compounds with known pro‐arrhythmic properties. These findings suggest that interspecies differences must be considered when evaluating drug effects. The aim of this study was to...
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Published in | British journal of clinical pharmacology Vol. 79; no. 1; pp. 148 - 161 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
01.01.2015
|
Online Access | Get full text |
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Summary: | Aims
Significant differences between dogs and humans have been observed in the concentration–
QTc
effect relationship of compounds with known pro‐arrhythmic properties. These findings suggest that interspecies differences must be considered when evaluating drug effects. The aim of this study was to evaluate the performance of a model‐based approach to assess the risk of
QT
c prolongation for three investigational compounds (
NCE01
,
NCE02
and
NCE03
).
Methods
Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and healthy subjects were included in this analysis. Pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each
QT
measurement. An integrated pharmacokinetic–pharmacodynamic (
PKPD
) model was then used to describe
QT
prolongation. A threshold of ≥10 ms was used to characterize the probability of
QTc
prolongation.
Results
The
PKPD
relationships of all three compounds were successfully described in both species. A strong effect was observed after administration of
NCE01
to dogs and humans, with a slope of 0.0061 and 0.0662 ms n
m
−1
, respectively, and maximal probability of
QT
c prolongation ≥10 ms at peak concentration. For
NCE02
and
NCE03
,
QT
c‐shortening and borderline
QT
effects were observed both in dogs and humans, as described by negative or very shallow slopes (
NCE02
, −0.00098 and −0.01 ms n
m
−1
;
NCE03
, 0.00064 and −0.0002 ms n
m
−1
).
Conclusions
Whilst
NEC01
shows clear pro‐arrhythmic effects, the liability for
QT/QTc
prolongation for
NCE02
and
NCE03
can be deemed low at the expected therapeutic exposure. Moreover, our results show the advantages of an integrated
PKPD
approach as the basis for translating pro‐arrhythmic effects from dogs to humans. |
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ISSN: | 0306-5251 1365-2125 |
DOI: | 10.1111/bcp.12482 |