European journal of clinical pharmacology · 2004
Absorption kinetics and pharmacodynamics of two oral dosage forms of flecainide in patients with an episode of paroxysmal atrial fibrillation.
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Deneer V H M, Lie-A-Huen L, Kingma J H, Proost J H, Gossen S A, Stuurman A, Uytdehaag G M M, Dunselman P H J M, Brouwers J R B J
Аннотация
OBJECTIVES: The objectives were to study the absorption kinetics and pharmacodynamics of two oral formulations of flecainide in patients with atrial fibrillation (AF) and to assess the relationship between pharmacokinetic parameters and the efficacy in restoring sinus rhythm.
METHODS: The data of 54 patients included in a randomised, open, parallel-group study were used. Patients received an oral solution containing 300 mg flecainide and 20 mg cisapride or three tablets each containing 100 mg flecainide. The pharmacokinetic profile of flecainide was fitted using a one-compartment model with lag-time and first-order absorption.
RESULTS: The tablets gave a maximum concentration (C (max\ fit)) of 0.43+/-0.14 mg/l at 2.37+/-1.20 h. The oral solution resulted in a much faster peak concentration at 1.05+/-0.71 h (P<0.0001). The C (max\ fit) of the oral solution of 0.60+/-0.17 mg/l was higher (P=0.0002) than that of the tablets, and interindividual variabilities of C (max\ fit) were 28% and 33%, respectively. The absorption rate constant (ka) of the oral solution was twofold larger (P<0.0001). A higher ka (P=0.04) and a duration of AF less than 24 h (P=0.006) increased the probability of cardioversion. If atrial fibrillation lasted less than 24 h, only ka (P=0.016) was obtained as a significant variable in multivariate analysis. The linear models of QRS interval changes versus flecainide concentrations of both formulations had similar slopes with similar interindividual variabilities.
CONCLUSIONS: The probability of cardioversion after an oral loading dose of flecainide in patients with AF is dependent on ka. Rapid loading of the effect compartment, i.e. the atria, appears to be critical to reach cardioversion. Higher flecainide serum concentrations and a more rapid absorption does not increase interindividual variability of pharmacokinetics and pharmacodynamics, which is important when safety is considered.
METHODS: The data of 54 patients included in a randomised, open, parallel-group study were used. Patients received an oral solution containing 300 mg flecainide and 20 mg cisapride or three tablets each containing 100 mg flecainide. The pharmacokinetic profile of flecainide was fitted using a one-compartment model with lag-time and first-order absorption.
RESULTS: The tablets gave a maximum concentration (C (max\ fit)) of 0.43+/-0.14 mg/l at 2.37+/-1.20 h. The oral solution resulted in a much faster peak concentration at 1.05+/-0.71 h (P<0.0001). The C (max\ fit) of the oral solution of 0.60+/-0.17 mg/l was higher (P=0.0002) than that of the tablets, and interindividual variabilities of C (max\ fit) were 28% and 33%, respectively. The absorption rate constant (ka) of the oral solution was twofold larger (P<0.0001). A higher ka (P=0.04) and a duration of AF less than 24 h (P=0.006) increased the probability of cardioversion. If atrial fibrillation lasted less than 24 h, only ka (P=0.016) was obtained as a significant variable in multivariate analysis. The linear models of QRS interval changes versus flecainide concentrations of both formulations had similar slopes with similar interindividual variabilities.
CONCLUSIONS: The probability of cardioversion after an oral loading dose of flecainide in patients with AF is dependent on ka. Rapid loading of the effect compartment, i.e. the atria, appears to be critical to reach cardioversion. Higher flecainide serum concentrations and a more rapid absorption does not increase interindividual variability of pharmacokinetics and pharmacodynamics, which is important when safety is considered.