Heart failure elevates serum levels of cibenzoline in arrhythmic patients.
BACKGROUND
Cibenzoline dosing is generally based on renal function, but serum concentrations might be greater than the expected therapeutic levels when standard oral dosing is used. Because heart failure might modify cibenzoline pharmacokinetics, the difference in cibenzoline pharmacokinetics between patients with and without heart failure was evaluated.


RESULTS
The study enrolled 368 patients (233 men, 135 women) that had been hospitalized and received cibenzoline therapy at the National Cardiovascular Center from January 2001 to May 2005. There were 89 patients with heart failure (51 men, 38 women) and 279 patients without heart failure (182 men, 97 women). They had therapeutic drug monitoring > or = 3 days after the beginning of treatment with cibenzoline. Brain natriuretic peptide (BNP) was measured in 81 patients (50 men, 31 women) concurrently with therapeutic drug monitoring of cibenzoline. The difference in serum cibenzoline concentration/(dose/weight) (C/D) values between patients with and without heart failure was analyzed using analysis of covariance (ANCOVA) with creatinine clearance (Ccr) serving as the covariate. The effects of dose/weight and the log-transformed BNP (log-BNP) values on serum cibenzoline concentrations were also assessed using ANCOVA. There were 135 and 361 measurements of serum cibenzoline concentration in patients with and without heart failure, respectively. Pearson's correlation coefficient analyses in the patients with and without heart failure revealed that the C/D values were significantly correlated with Ccr (with heart failure, y = -0.837x + 169, r = -0.211, p = 0.014; without heart failure, y = -0.789x + 132, r = -0.393, p < 0.001), and the ANCOVA model indicated that C/D values were significantly higher in patients with heart failure than without heart failure. The ANCOVA model also showed that dose/weight, Ccr and the log-BNP value were significant factors.


CONCLUSIONS
The selection of a cibenzoline dose based only on renal function may increase the risk of toxicity in patients with heart failure. Cardiac function should be taken into account in cibenzoline dosing. The log-BNP may be a useful index for predicting serum cibenzoline concentrations.
Kotake
Takeshi
T
Department of Pharmacy, National Cardiovascular Center, Suita, Japan. kotaket@hsp.ncvc.go.jp
Takada
Mitsutaka
M
Komamura
Kazuo
K
Kamakura
Shiro
S
Miyatake
Kunio
K
Kitakaze
Masafumi
M
Morishita
Hideki
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D001835:Body Weight; D004341:Drug Evaluation; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006334:Heart Function Tests; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies
D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; C032151:cifenline