Extremely prolonged elimination of cibenzoline at toxic plasma concentrations in patients with renal impairments

Three patients (age: 36, 68, and 80 years) treated with a standard oral dose of cibenzoline (300 mg/d) developed clinical symptoms being compatible with cibenzoline toxicity (e.g., prolonged QTc, wide QRS, arrhythmias, hypotension and hypoglycemia). Their plasma cibenzoline concentrations (i.e., 1944-2580 microg/L) were 5 to 10 times greater than the expected therapeutic levels. All patients had severe renal dysfunction (i.e., creatinine clearance: 10-16 mL/min) but had no severe liver damages. They received no drugs that might have inhibited hepatic drug metabolism. Intentional or accidental overdosing of the drug was ruled out in each patient. The elimination half-lives of cibenzoline monitored immediately after its withdrawal (i.e., 69, 116 and 198 hours) were 3-10 times longer than those reported in patients with end-stage renal failure of about 20 hours. In addition, two patients exhibited biphasic plasma drug decay curves. Our report indicates that not only reduced renal excretion but also non-linear kinetics of the drug via non-renal elimination at toxic concentrations may render renal failure patients more susceptible to cibenzoline toxicity.