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Commentary on: “ Levofloxacin ‐ Induced QTc Prolongation Depends on the Time of Drug Administration ”

View Article: PubMed Central - PubMed

ABSTRACT

Circadian variations in the corrected QT (QTc) interval have been documented in clinical trials. Animal models show circadian variations in expression of the cardiac ion channels that are necessary to maintain the heart's electrophysiological properties. Can these diurnal rhythms in QTc affect the ability of a drug to delay cardiac repolarization?

No MeSH data available.


Comparison of the observed dofetilide plasma concentrations (a) and ΔΔQTc (b) in two clinical studies where dofetilide was either administered at 8 am in the morning (Ref. 10, red) or at noon and at dinner (Ref. 9, blue). The concentration‐QTc relationships for the morning administration (c) and noon/dinner administration (d) show no difference in the slope of the concentration‐QTc relationship (slope (95% confidence interval) in ms per ng/mL in each panel).
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psp412128-fig-0001: Comparison of the observed dofetilide plasma concentrations (a) and ΔΔQTc (b) in two clinical studies where dofetilide was either administered at 8 am in the morning (Ref. 10, red) or at noon and at dinner (Ref. 9, blue). The concentration‐QTc relationships for the morning administration (c) and noon/dinner administration (d) show no difference in the slope of the concentration‐QTc relationship (slope (95% confidence interval) in ms per ng/mL in each panel).

Mentions: Circadian variation in K+ channel density, however, seems unlikely to explain a greater than 10‐fold increase in the slope estimate of the levofloxacin‐QTc relationship over the day (from −0.04 ms per mg/L at 6 am to 1.7 ms per mg/L at 2 pm; table 3 in Kervezee et al.1). If normal physiological variations in cardiac ion channel density profoundly affect the sensitivity to drug‐induced QTc prolongation, then these effects would be expected with other drugs that selectively inhibit the hERG K+ channel. With drugs that directly inhibit the hERG K+ channel, the extent of the PD response varies according to the proportion of channels that are blocked, until saturation. Levofloxacin inhibits the hERG K+ channel, with an IC50 of 915 µM8 and is not thought to affect other cardiac ion channels. Dofetilide, on the other hand, is a much more potent inhibitor of hERG, with an IC50 of ∼1.5 nM,9 prolonging the QTc interval by as much as 80 ms, and without showing any evidence of saturation.10 In two recent double‐blind clinical studies, dofetilide or placebo was administered in the morning10 or after lunch9; there was no significant difference in the slope estimate of the studies (Figure1). One would have expected a steeper slope following afternoon dosing compared to morning dosing if diurnal hERG K+ density affects drug‐induced QTc prolongation. A possible limitation of this counterexample is that the dosing and sampling timepoints were not optimal for observing potential diurnal differences in the slope estimate in either study. However, given the large variation in levofloxacin response at 6 am and 2 pm reported by the authors, one would expect dofetilide, an inhibitor that is over 4 orders of magnitude more potent than levofloxacin, to show enough variation to be evident even in these studies of morning vs. after lunch dosing.


Commentary on: “ Levofloxacin ‐ Induced QTc Prolongation Depends on the Time of Drug Administration ”
Comparison of the observed dofetilide plasma concentrations (a) and ΔΔQTc (b) in two clinical studies where dofetilide was either administered at 8 am in the morning (Ref. 10, red) or at noon and at dinner (Ref. 9, blue). The concentration‐QTc relationships for the morning administration (c) and noon/dinner administration (d) show no difference in the slope of the concentration‐QTc relationship (slope (95% confidence interval) in ms per ng/mL in each panel).
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psp412128-fig-0001: Comparison of the observed dofetilide plasma concentrations (a) and ΔΔQTc (b) in two clinical studies where dofetilide was either administered at 8 am in the morning (Ref. 10, red) or at noon and at dinner (Ref. 9, blue). The concentration‐QTc relationships for the morning administration (c) and noon/dinner administration (d) show no difference in the slope of the concentration‐QTc relationship (slope (95% confidence interval) in ms per ng/mL in each panel).
Mentions: Circadian variation in K+ channel density, however, seems unlikely to explain a greater than 10‐fold increase in the slope estimate of the levofloxacin‐QTc relationship over the day (from −0.04 ms per mg/L at 6 am to 1.7 ms per mg/L at 2 pm; table 3 in Kervezee et al.1). If normal physiological variations in cardiac ion channel density profoundly affect the sensitivity to drug‐induced QTc prolongation, then these effects would be expected with other drugs that selectively inhibit the hERG K+ channel. With drugs that directly inhibit the hERG K+ channel, the extent of the PD response varies according to the proportion of channels that are blocked, until saturation. Levofloxacin inhibits the hERG K+ channel, with an IC50 of 915 µM8 and is not thought to affect other cardiac ion channels. Dofetilide, on the other hand, is a much more potent inhibitor of hERG, with an IC50 of ∼1.5 nM,9 prolonging the QTc interval by as much as 80 ms, and without showing any evidence of saturation.10 In two recent double‐blind clinical studies, dofetilide or placebo was administered in the morning10 or after lunch9; there was no significant difference in the slope estimate of the studies (Figure1). One would have expected a steeper slope following afternoon dosing compared to morning dosing if diurnal hERG K+ density affects drug‐induced QTc prolongation. A possible limitation of this counterexample is that the dosing and sampling timepoints were not optimal for observing potential diurnal differences in the slope estimate in either study. However, given the large variation in levofloxacin response at 6 am and 2 pm reported by the authors, one would expect dofetilide, an inhibitor that is over 4 orders of magnitude more potent than levofloxacin, to show enough variation to be evident even in these studies of morning vs. after lunch dosing.

View Article: PubMed Central - PubMed

ABSTRACT

Circadian variations in the corrected QT (QTc) interval have been documented in clinical trials. Animal models show circadian variations in expression of the cardiac ion channels that are necessary to maintain the heart's electrophysiological properties. Can these diurnal rhythms in QTc affect the ability of a drug to delay cardiac repolarization?

No MeSH data available.