Tolvaptan Administration Does Not Affect Steady State Amiodarone Concentrations in Patients With Cardiac Arrhythmias

Abstract

Tolvaptan coadministration does not alter steady-state amiodarone or desethylamiodarone concentrations. Tolvaptan concentrations did not appear to be different from historical controls. The most frequently reported adverse event was polyuria (15 of 21 subjects for amiodarone + 30 mg tolvaptan); an expected outcome due to the known potent aquaretic action of tolvaptan. The combination of amiodarone and tolvaptan was well tolerated.

Pharmacokinetics, Pharmacodynamics and Safety of Tolvaptan, A Novel, Oral, Selective Nonpeptide AVP V2-receptor Antagonist: Results of Single- and Multiple-Dose Studies in Healthy Japanese Male Volunteers

“…Since it has become clear that tolvaptan is primarily metabolized via CYP3A4 [11], it was expected that racial differences in pharmacokinetic parameters would be minor for tolvaptan [12]. Therefore, we compared the pharmacokinetic data for Japanese subjects in present single-dose study with those reported by Shoaf et al, which mainly comprised Caucasian subjects (83%) [8].…”

Pharmacology of vasopressin antagonists

“…Coadministration with ketoconazole increased maximal plasma concentration by 248% and the area under plasma concentration versus time curve by 440% [16]. Less than 1% of tolvaptan is excreted unchanged via the urine [16]. In a study evaluating the effect of tolvaptan 30 mg and 90 mg on amiodarone in otherwise healthy arrhythmia patients on chronic amiodarone therapy, tolvaptan did not affect amiodarone levels.…”

“…Tolvaptan is primarily eliminated by CYP3A4. Coadministration with ketoconazole increased maximal plasma concentration by 248% and the area under plasma concentration versus time curve by 440% [16]. Less than 1% of tolvaptan is excreted unchanged via the urine [16].…”

“…In a study evaluating the effect of tolvaptan 30 mg and 90 mg on amiodarone in otherwise healthy arrhythmia patients on chronic amiodarone therapy, tolvaptan did not affect amiodarone levels. In this study a single dose of tolvaptan 30 mg led to a maximal plasma concentration of 497 ± 230 (SD) ng/ml, the median time to maximal plasma concentration was 2.13 h (range 1.92-24.0), and the area under the curve from 0 to 24 h was 4212 ± 2008 ng h/ml [16]. It has also been Bars represent weighted averages ± standard error of the mean over an observation period of 9 h. * P \ 0.05.…”

Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

“…Less than 1% of the substance is eliminated unchanged via the urine [42]. In human, increases in tolvaptan concentrations (C max ) were less than doseproportional and plateaued at doses greater than 240 mg [43].…”