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

Abstract

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.

Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes

“…While the cell+bile accumulation of digoxin was not affected by tolvaptan, cellular accumulation appeared to increase; the BEI of digoxin decreased by 65.9% compared with control ( Fig. 3B), consistent with P-gp inhibition as reported previously (Shoaf et al, 2011).…”

“…Previous studies demonstrated that tolvaptan is a substrate and an inhibitor of P-glycoprotein (P-gp) (Shoaf et al, 2011). Our recent studies in membrane vesicles and transfected cells revealed that tolvaptan and metabolites could inhibit several transporters, including sodium taurocholate (TCA) cotransporting polypeptide (NTCP), the bile salt export pump s This article has supplemental material available at dmd.aspetjournals.org.…”

Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial

“…In Trial 249 the mean change from baseline in 24‐hour urine volume also increased following all split‐dose regimens, but there was no evidence of a dose effect, again consistent with the U osm result. Following multiple doses, urine volume was approximately 20% lower on day 5 than on day 1, consistent with observations in healthy subjects and in patients with heart failure …”

Cerebrospinal Fluid Can Be Used as a Surrogate to Assess Brain Exposures of Breast Cancer Resistance Protein and P-Glycoprotein Substrates

“…Unlike dantrolene, digoxin blood exposures also increased in the presence of the Pgp inhibitors. The increased blood exposure of digoxin was most likely due to the reduced renal secretion, as it has been shown that Pgp at the luminal membrane of the renal tubule is involved in digoxin renal elimination Okamura et al, 1993;Shoaf et al, 2011). There are two major pathways to deliver drug to CSF, namely transport from brain to CSF by crossing the ependymal cell monolayers between the brain and CSF interface or transport from blood to CSF by crossing the BCSFB.…”