Antiarrhythmic efficacy of propafenone: Evaluation of effective plasma levels following single and multiple doses

Frabetti, L; Marchesini, B.; Capucci, Alessandro; Cavallini, C; Gubelli, S.; Ambrosioni, Ettore; Magnani, B

doi:10.1007/bf00608213

Cited by 19 publications

(3 citation statements)

References 11 publications

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“…The data of the present study confirm the nonlinear kinetics of propafenone reported previously [1,9,13,14], together with a high interindividual variability, either of propafenone concentrations or of the propafenone/5-hydroxy-propafenone ratio. This parameter was well correlated with the debrisoquine hydroxylation capacity.…”

Section: Discussionsupporting

confidence: 92%

“…Further studies documented that its electrophysiologic effects are quite similar to those of propafenone [8], and some clues in the clinical setting also suggest a direct antiarrhythmic action of the metabolite [6]. In spite of these observations, a clear-cut demonstration of a clinical antiarrhythmic effeet of 5-hydroxy-propafenone in humans is lacking thus far.In a previous study we demonstrated a wide interindividual variation in the effective plasma levels of propafenone during chronic therapy [9]. The purpose of this study was to evaluate the concentration-effect relationship of propafenone and 5-hydroxy-propafenone in individual patients during acute testing and chronic treatment.…”

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confidence: 98%

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Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy

Capucci

Boriani

Marchesini

et al. 1990

Cardiovasc Drug Ther

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We evaluated the antiarrhythmic efficacy and the minimal effective concentrations of propafenone and its metabolite 5-hydroxy-propafenone during a) acute intravenous infusion (1.5 mg/kg in bolus followed by 45 minutes infusion), b) an acute oral single-dose test (450 mg), and c) 14-day chronic therapy (300 mg tid) followed by a washout. Oxidative metabolism was assessed by a debrisoquine oral test in every patient. Eleven patients with stable ventricular premature beats (VPBs) greater than or equal to 300/hr and Lown class greater than or equal to 3 completed the study. The main results emphasized a certain discrepancy between the clinical effect of the acute intravenous infusion (efficacy in 5 out of 11 patients) and of the acute oral test and chronic therapy (efficacy in 11/11), with a time lag of the ECG changes during the acute intravenous infusion. The minimal effective concentrations were lower after acute oral administration compared with chronic treatment both for propafenone (200 +/- 189 ng/ml vs. 492 +/- 530 ng/ml; p less than 0.05) and for 5-hydroxy-propafenone (82 +/- 40 ng/ml vs. 149 +/- 80 ng/ml; p less than 0.02). A linear correlation was demonstrated between drug/metabolite ratios of propafenone and debrisoquine, either after acute oral (r = 0.91) or after chronic administration (r = 0.84). The pharmacokinetics of propafenone was nonlinear and showed wide interindividual variations.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 98%

Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy

Capucci

Boriani

Marchesini

et al. 1990

Cardiovasc Drug Ther

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“…In less than 10% of patients, metabolism is slow with an elimination half-life of 10–32 h because of their deficiency of CYP2D6 6 . In extensive metabolizers, propafenone also undergoes saturable presystemic biotransformation such that its bioavailability is both dose and dosage form dependent 7 , 8 , 9 , 10 . Propafenone exhibits a high degree of inter-subject variability in pharmacokinetic parameters following both single and multiple dose administration probably due to the wide range of CYP2D6 activity 11 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of propafenone hydrochloride sustained-release capsules in male beagle dogs

Pan

Qian

Cheng

et al. 2015

Acta Pharmaceutica Sinica B

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This paper describes the development and validation of a liquid chromatography–mass spectrometric assay for propafenone and its application to a pharmacokinetic study of propafenone administered as a new propafenone hydrochloride sustained-release capsule (SR-test), as an instant-release tablet (IR-reference) and as the market leader sustained-release capsule (Rythmol, SR-reference) in male beagle dogs (n=8). In Study A comparing SR-test with IR-reference in a crossover design Tmax and t1/2 of propafenone for SR-test were significantly higher than those for IR-reference while Cmax and AUC were lower demonstrating the sustained release properties of the new formulation. In Study B comparing SR-test with SR-reference the observed Cmax and AUC of propafenone for SR-test (124.5±140.0 ng/mL and 612.0±699.2 ng·h/mL, respectively) were higher than for SR-reference (78.52±72.92 ng/mL and 423.6±431.6 ng·h/mL, respectively) although the differences were not significant. Overall, the new formulation has as good if not better sustained release characteristics to the market leader formulation.

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Serum Digoxin Levels Related to Plasma Propafenone Levels During Concomitant Treatment

Bigot

Debruyne

Bonnefoy

et al. 1991

The Journal of Clinical Pharma

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Nine patients with supraventricular rhythm disorders were treated during 5-day periods with different oral doses (300, 450, 600, and 900 mg daily) of propafenone concomitantly to long-term digoxin treatment. A poor correlation (r = .398; P less than .05) was obtained when the difference between the mean digoxin serum level (calculated with the Cmin data determined each of the 5 days) observed during a given propafenone dose and the mean digoxin serum level observed before propafenone treatment, was correlated with the dose of propafenone; but an evident correlation (r = .778; P less than .01) was found when the difference in digoxin level was correlated with the plasma propafenone concentration. The propafenone effect of increasing digoxin blood levels was thus concluded to be poorly dose dependent but strongly concentration dependent. The association of propafenone to a long-term digoxin treatment can be considered with a low risk of toxicity when plasma propafenone concentration does not exceed about 1000 ng/mL. Propafenone plasma levels are unpredictable in view of their wide interindividual variation for a given dose, so their measurement is advised to detect high levels and consequently to prevent a rise in digoxin serum concentrations with the possibility of toxicity. In clinical practice, when propafenone concentration determinations are not readily available, digoxin serum levels at least have to be carefully monitored.

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Antiarrhythmic efficacy of propafenone: Evaluation of effective plasma levels following single and multiple doses

Cited by 19 publications

References 11 publications

Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy

Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy

Pharmacokinetics of propafenone hydrochloride sustained-release capsules in male beagle dogs

Serum Digoxin Levels Related to Plasma Propafenone Levels During Concomitant Treatment

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