Lack of clinically significant interaction between steady state tolvaptan and digoxin in healthy volunteers

Abstract

Tolvaptan (TLV) is a selective vasopressin receptor (V2) antagonist being studied for several indications. Digoxin (DIG) is expected to be frequently co-administered with TLV. The objectives of this study were to determine the effect of TLV administration on steady state DIG pharmacokinetics (PK) and the effect of DIG on TLV PK. This study was an open-label, sequential design in 14 healthy men and women. Subjects received a single dose of 60 mg TLV on Day 1 followed by a 3-day washout. Following digoxin loading doses on Day 4, subjects received 0.25 mg DIG QD on Days 5 through 16. On Days 12 through 16, subjects also received 60 mg TLV QD. Plasma concentrations of TLV and metabolite were determined by HPLC-MS/MS. Serum and urine DIG were determined by turbidometric immunoassay. The table below summarizes the ratios of the Cmax and AUC0-24h geometric means and their 90% confidence intervals (90% CI) for steady state DIG+TLV vs. DIG alone and for a single oral dose of TLV with steady state DIG vs. TLV alone. Although plasma DIG concentrations were elevated, there were no clinically relevant changes in body weight, heart rate, systolic or diastolic blood pressure, ventricular rate or QTc (Bazett's) interval between Day 11 (DIG alone) and Day 16 (DIG + TLV). Therefore, there is no clinically significant interaction between DIG and TLV. Clinical Pharmacology & Therapeutics (2004) 75, P37–P37; doi: 10.1016/j.clpt.2003.11.139 Table 1. Analytes Parameter Cmax AUC0–24h Digoxin Day 16/Day 11 Ratio 1.27 1.18 90% CI 1.085–1.496 1.073–1.286 Tolvaptan Day 12/Day 1 Ratio 1.11 0.97 90% CI 0.885–1.395 0.758–1.251