Comparative Pharmacokinetic and Pharmacodynamic Properties of Oral and Intravenous (+)-Sotalol in Healthy Volunteers

Uematsu, Toshihiko; Kanamaru, Mitsutaka; Nakashima, Mitsuyoshi

doi:10.1111/j.2042-7158.1994.tb03865.x

Cited by 28 publications

(33 citation statements)

References 15 publications

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“…(+)-Sotalol effects on QTc intervals in healthy male subjects were analyzed in the work by Uematsu et al 47 The authors did not report the correction method used. The drug was administered orally and intravenously, and in the latter case PK-PD modeling was attempted.…”

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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“…M-4 was mainly excreted in urine in healthy human volunteers (4). The excretion of M-4 in urine after the oral administration of BOF-4272 to the cynomolgus monkey was lower than that in healthy human volunteers (4), and was about 1/10 that after intravenous administration.However, it is thought that the low excretion of M-4 in urine after the oral administration of BOF-4272 to the cynomolgus monkey is not due to low biotransformationbut to low absorption from the gastrointestinal tract. These findings suggest that the cynomolgus monkey may be a suitable animal species for evaluating the clinical pharmacokinetics and biotransformation of BOF-4272.…”

Section: Preparation Of Urine Samples For Hplcmentioning

confidence: 99%

“…It has also been demonstrated that the linear range of absorption and/or elimination of BOF-4272 is very wide in the mouse and the rat (11). It has been shown that BOF-4272 is rapidly biotransformed to a main metabolite (M-4, a sulfoxidecontaining metabolite of BOF-4272), that M-4 is then mainly excreted in urine, and that BOF-4269 is a minor metabolite in plasma after oral administration to healthy volunteers (4). It has been suggested that we should clarify the metabolic pathways of BOF-4272 in the rat (12) and the dog (13).…”

Section: Introductionmentioning

confidence: 98%

“…BOF-4272, a derivative of pyrazolotriazine, is a new drug that has been developed for the treatment of hyperuricemia and ischemic reperfusion injury (1)(2)(3)(4). BOF-4272 inhibits the de novo biosynthesis of uric acid by blocking the xanthine oxidase/xanthine dehydrogenase system, which catalyses the last step of purine catabolism (1,4).…”

Section: Introductionmentioning

confidence: 99%

“…BOF-4272 inhibits the de novo biosynthesis of uric acid by blocking the xanthine oxidase/xanthine dehydrogenase system, which catalyses the last step of purine catabolism (1,4). The mechanism of the inhibitory action of BOF-4272 has been elucidated by an in vitro study using milk xanthine oxidase/xanthine dehydrogenase (5).…”

Section: Introductionmentioning

confidence: 99%

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Biotransformation of BOF-4272, a sulfoxide-containing drug, in the cynomolgus monkey

Naito

Nishimura

Jin³

1999

Eur. J. Drug Metab. Pharmacokinet.

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BOF-4272, (+/-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one), is a new drug intended for the treatment of hyperuricemia. This report describes the pharmacokinetics and detailed metabolic pathways of BOF-4272 in the cynomolgus monkey, which were investigated using the metabolites found in plasma, urine, and faeces after intravenous and oral administration. M-4 was the main metabolite in plasma after intravenous administration. M-3 and M-4 were the main metabolites in plasma after oral administration. The Cmax and AUC(0-t) of M-4 were the highest of all the metabolites after intravenous administration. The Cmax and AUC(0-t) of M-3 were the highest of all the metabolites, and those of M-4 were the second highest, after oral administration. M-4 and M-3 were the main metabolites detected in urine and faeces, respectively, after intravenous administration, with M-4 and M-3 at 47.2% in urine and 19.1% in faeces, respectively, within 120 h after administration. M-4 was the only metabolite detected in urine after oral administration, at about 5% within 120 h after administration. M-3 was detected in faeces at 17.0% within 120 h after oral administration. These results suggest that, in the cynomolgus monkey, BOF-4272 is rapidly biotransformed to a main metabolite (M-4, a sulphoxide-containing metabolite of BOF-4272) and that M-4 is mainly excreted in urine and possibly also in bile, with subsequent conversion to M-3 by the intestinal flora. It is expected that the biotransformation of BOF-4272 would be similar in healthy human volunteers.

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A Pharmacokinetic—Pharmacodynamic Model of d‐Sotalol Q‐Tc Prolongation During Intravenous Administration to Healthy Subjects

Salazar

Much

Nichola

et al. 1997

The Journal of Clinical Pharma

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The objective of this study was to assess the pharmacokinetics and pharmacodynamics of the dextro (d-) isomer of sotalol, a class III antiarrhythmic agent, in healthy young men and women after a single intravenous bolus dose. The design was open-label, randomized, parallel group. Each group (4 men and 4 women) received either 0.5, 1.5, or 3.0 mg/kg d-sotalol as an intravenous infusion for 2 minutes. Serial measurements of the d-sotalol plasma concentration and the Q-Tc interval data were recorded before, during, and for 72 hours after drug administration. The pharmacokinetics of d-sotalol were found to be well described by a three-compartment model with linear elimination clearance from the central compartment. There were no significant differences in the elimination clearance or volume of the central compartment between dose levels or between men and women. However, women were found to have a lower steady-state volume of distribution than men (1.20 L/Kg versus 1.43 L/Kg). The Q-Tc versus d-sotalol plasma concentration data were fitted to a model that assumed a distinct "effect compartment" and sigmoidal Emax response. The baseline Q-Tc, determined from the fittings, was found to be significantly higher in women (0.40 versus 0.38 seconds). The effect compartment clearance was found to be highly variable, with a median of 12.3 (range, 0.2-671,300) L/h. There were statistically significant differences in the effect compartment clearance by dose among men and by gender at a dose of 1.5 mg/kg. There were no significant differences detected between dose groups or genders for the d-sotalol effect site concentration at one half the maximum Q-Tc prolongation from baseline (EC50), EMAX, (the maximum Q-Tc prolongation from baseline) or the Hill coefficient. In conclusion, the pharmacokinetics of d-sotalol after intravenous administration are independent of dose and gender, because the difference between men and women in volume of distribution at steady-state is not clinically significant. The pharmacodynamics of Q-Tc prolongation produced by d-sotalol appear to be independent of dose and gender; however, there is considerable variability in the time course of effects on Q-Tc between individuals.

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Comparative Pharmacokinetic and Pharmacodynamic Properties of Oral and Intravenous (+)-Sotalol in Healthy Volunteers

Cited by 28 publications

References 15 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

Biotransformation of BOF-4272, a sulfoxide-containing drug, in the cynomolgus monkey

A Pharmacokinetic—Pharmacodynamic Model of d‐Sotalol Q‐Tc Prolongation During Intravenous Administration to Healthy Subjects

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