In Vitro P-Glycoprotein Interactions and Steady-State Pharmacokinetic Interactions Between Tolvaptan and Digoxin in Healthy Subjects

• Published in: Journal of clinical pharmacology 2011-05, Vol.51 (5), p.761-769
• Main Authors: Shoaf, Susan E., Ohzone, Yoshihiro, Ninomiya, Shin-ichi, Furukawa, Masayuki, Bricmont, Patricia, Kashiyama, Eiji, Mallikaarjun, Suresh
• Format: Article
• Language: English
• 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; 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; P-glycoprotein; pharmacodynamics; pharmacokinetics; Swine; Tolvaptan; Transfection; Urine; Young Adult
• ISSN: 0091-2700; 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 (Cmax) and area under the curve during the dosing interval (AUCτ) 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 Cmax and AUC0–24h 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.