In vitro P-glycoprotein interactions and steady-state pharmacokinetic interactions between tolvaptan and digoxin in healthy subjects

• Published in: Journal of clinical pharmacology Vol. 51; no. 5; p. 761
• Main Authors: Shoaf, Susan E, Ohzone, Yoshihiro, Ninomiya, Shin-ichi, Furukawa, Masayuki, Bricmont, Patricia, Kashiyama, Eiji, Mallikaarjun, Suresh
• Format: Journal Article
• Language: English
• Published: England 01.05.2011
• Subjects: Administration, Oral; Adolescent; Adult; Analysis of Variance; Animals; Antidiuretic Hormone Receptor Antagonists; Area Under Curve; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Benzazepines - administration & dosage; Benzazepines - blood; Benzazepines - pharmacokinetics; Benzazepines - urine; Cardiotonic Agents - administration & dosage; Cardiotonic Agents - blood; Cardiotonic Agents - pharmacokinetics; Cardiotonic Agents - urine; Digoxin - administration & dosage; Digoxin - blood; Digoxin - pharmacokinetics; Digoxin - urine; Drug Administration Schedule; Drug Interactions; Female; Florida; Hormone Antagonists - administration & dosage; Hormone Antagonists - blood; Hormone Antagonists - pharmacokinetics; Hormone Antagonists - urine; Humans; LLC-PK1 Cells; Male; Metabolic Clearance Rate; Models, Biological; Swine; Transfection; Young Adult
• ISSN: 1552-4604
• DOI: 10.1177/0091270010376193

Interactions between tolvaptan and digoxin were determined in an open-label, sequential study where 14 healthy subjects received tolvaptan 60 mg once daily (QD) on days 1 and 12 to 16 and digoxin 0.25 mg QD on days 5 to 16. Mean maximal concentrations (C(max)) and area under the curve during the dosing interval (AUC(τ)) for digoxin with tolvaptan (day 16) were increased 1.27- and 1.18-fold compared with digoxin alone (day 11); mean renal clearance of digoxin was decreased by 59% (P < .05). Tolvaptan C(max) and AUC(0-24h) for a single dose with digoxin (day 12) were each increased about 10% compared with tolvaptan alone (day 1). Tolvaptan did not accumulate upon multiple dosing. After a single dose of tolvaptan (day 1, day 12), 24-hour urine volume was about 7.5 L. As expected, after 5 days of tolvaptan, 24-hour urine volume decreased about 20%. In vitro studies in control and MDR1-expressing LLC-PK1 cells indicate that tolvaptan is a substrate of P-glycoprotein. Tolvaptan (50 µM) inhibited basolateral to apical digoxin secretion to the same extent as 30 µM verapamil; the IC50 of tolvaptan was determined to be 15.9 µM. The increase in steady-state digoxin concentrations is likely mediated by tolvaptan inhibition of digoxin secretion.