The effect of quinidine and its metabolites on the electrocardiogram and systolic time intervals: concentration‐effect relationships.

Holford, Nicholas H. G.; Coates, P. E.; Guentert, TW; Riegelman, Sidney; Sheiner, L. B.

doi:10.1111/j.1365-2125.1981.tb01123.x

Cited by 124 publications

(46 citation statements)

References 31 publications

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“…A linear model similar to that of Equation 8 was used by Holford et al 43 in their study of quinidine effects on QT intervals and other cardiovascular parameters after intravenous and oral administration. QT correction for RR was performed as in Whiting et al 29 using a linear relationship (Equation 7).…”

Section: Pharmacokinetic-pharmacodynamic Modeling Of Qt Prolongationmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation

Piotrovsky¹

2005

AAPS J

109

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A BSTRACTIn this review, factors affecting the QT interval and the methods that are currently in use in the analysis of drug effects on the QT interval duration are overviewed with the emphasis on (population) pharmacokinetic-pharmacodynamic (PK-PD) modeling. Among which the heart rate (HR) and the circadian rhythm are most important since they may interfere with the drug effect and need to be taken into account in the data analysis. The HR effect or the RR interval (the distance between 2 consecutive R peaks) effect is commonly eliminated before any further analysis, and many formulae have been suggested to correct QT intervals for changes in RR intervals. The most often used are Bazett and Fridericia formulae introduced in 1920. They are both based on the power function and differ in the exponent parameter. However, both assume the same exponent for different individuals. More recent fi ndings do not confi rm this assumption, and individualized correction is necessary to avoid under-or overcorrection that may lead to artifi cial observations of drug-induced QT interval prolongation. Despite the fact that circadian rhythm in QT and QTc intervals is a welldocumented phenomenon, it is usually overlooked when drug effects are evaluated. This may result in a false-positive outcome of the analysis as the QTc peak due to the circadian rhythm may coincide with the peak of the drug plasma concentration. In view of these effects interfering with a potential drug effect on the QTc interval and having in mind low precision of QT interval measurements, a preferable way to evaluate the drug effect is to apply a population PK-PD modeling. In the literature, however, there are only a few publications in which population PK-PD modeling is applied to QT interval prolongation data, and they all refer to antiarrhythmic agents. In this review, after the most important sources of variability are outlined, a comprehensive population PK-PD model is presented that incorporates an individualized QT interval correction, a circadian rhythm in the individually corrected QT intervals, and a drug effect. The model application is illustrated using real data obtained with 2 compounds differing in their QT interval prolongation potential. The usefulness of combining data of several studies is stressed. Finally, the standard approach based on the raw observations and formal statistics, as described in the Preliminary Concept paper of the International Conference on Harmonization, is briefl y compared with the method based on population PK-PD modeling, and the advantages of the latter are outlined.

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Section: Pharmacokinetic-pharmacodynamic Modeling Of Qt Prolongationmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation

Piotrovsky¹

2005

AAPS J

109

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“…Since quinidine and 3-hydroxyquinidine concentrations increased on average by 41% and 77% respectively, this may simply reflect moving up the sigmoid concentration-response curve under steady state conditions. Alternatively, the presence of higher concentrations of metabolites in serum as previously suggested (Holford et al, 1981), may account for this observation. In five of six volunteers the ratio of 3-hydroxyquinidine to quinidine was higher at steady state than after the single dose.…”

Section: Discussionmentioning

confidence: 67%

“…Effect was assessed as the change in the QTC interval from the baseline value. The relationship between serum concentrations (total and unbound) of quinidine and 3-hydroxyquinidine and ECG effect was described using a simple model describing effect as a linear function of concentration (Holford et al, 1981).…”

Section: Analytical Proceduresmentioning

confidence: 99%

The pharmacokinetics and pharmacodynamics of quinidine and 3‐ hydroxyquinidine.

Wooding-Scott

Smalley

Visco

et al. 1988

Brit J Clinical Pharma

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1 The pharmacokinetics and pharmacodynamics of quinidine and 3-hydroxyquinidine based upon measurements of total and unbound serum concentrations were determined after a single dose (400 mg) and at steady state (200 mg every 6 h).2 The oral clearance (7.6 ± 1.9 vs 4.8 ± 2.0 ml min-kg-'; P < 0.05) and renal clearance (1.2 ± 0.3 vs 0.63 ± 0.25 ml min' kg'-; P < 0.005) or quinidine were lower during steady state than after the single dose. 3 The area under the serum concentration vs time curve (AUC) of 3-hydroxyquinidine was greater at steady state than after the single dose (2.0 ± 0.7 vs 3.0 ± 0.6 mg 1-1 h; P < 0.05) and its renal clearance was less (3.0 ± 1.1 vs 1.54 ± 0.38 ml min-' kg-'; P < 0.05).4 The slope of the relationship between quinidine concentration and change in QTc interval was greater at steady state (40.1 ± 21.7 vs 72.2 ± 41.7 ms/(mg 1-1); P < 0.05).

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“…Risk of severe poisoning, mainly transient or permanent visual deficit, occurs only when serum levels exceeded 15 tg ml-' (Boland, 1985). Comparatively serum concentrations of quinidine that are recommended for treatment of cardiac dysrytmias ranged from 3 to 5 tLg ml-' with risk of severe blockade of auriculoventricular conduction above 8 tLg ml-' (Holford et al, 1981). In the study of Benson et al (1985), which evaluated the tolerance of verapamil given by continuous infusion (0.12 tg kg-' h-') in association with vinblastine, the maximal tolerated concentration was 0.29 jig ml-' in serum.…”

Section: Discussionmentioning

confidence: 99%

Potential usefulness of quinine to circumvent the anthracycline resistance in clinical practice

Chauffert

Pelletier²,

Corda³

et al. 1990

Br J Cancer

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Quinine, the widely used antimalaria agent, was found to increase the cytotoxicity of epideoxorubicin (epiDXR) in resistant DHD/K12 rat colon cancer cells in vitro. Quinine appeared as slightly less effective than quinidine or verapamil for anthracycline potentiation but its weaker cardiotoxicity could counterbalance this disadvantage in vivo. Serum from six patients treated by conventional doses of quinine (25-30 mg kg-1 day-1) was demonstrated to enhance the accumulation of epiDXR in DHD/K12 cells as judged by fluorescence microscopy and HPLC assay (1.6 to 6-fold compared with control serum). In this patients quinine concentrations in serum ranged from 4.4 to 10.1 micrograms ml-1. Our results suggest that quinine could be safely used as anthracycline resistance modifier in clinical practice. Images Figure 2

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The effect of quinidine and its metabolites on the electrocardiogram and systolic time intervals: concentration‐effect relationships.

Cited by 124 publications

References 31 publications

Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation

Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation

The pharmacokinetics and pharmacodynamics of quinidine and 3‐ hydroxyquinidine.

Potential usefulness of quinine to circumvent the anthracycline resistance in clinical practice

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