Abstract
Tolvaptan is an arginine vasopressin (AVP) antagonist that acts to increase excretion of free water (aquaresis) in patients without introducing electrolyte abnormalities or worsening renal function. It works via blockade of vasopressin-2 receptors at the renal collecting duct. Since the approval of tolvaptan for the treatment of hypervolemic and euvolemic hyponatremia in 2009, new studies have been reported to better characterize its pharmacokinetic and pharmacodynamic profile of tolvaptan. This paper is a review of both these clinical studies, as well as previous literature, in order to help guide appropriate clinical use of tolvaptan in patients. With appropriate monitoring of serum sodium, tolvaptan may be safely dose escalated from 15 mg once daily to a maximum effective dose of 60 mg once daily for multiple days, to achieve optimal aqauretic effects. In terms of drug interactions, co-administration of moderate to potent CYP3A4 inhibitors and inducers should be avoided. Tolvaptan should also be co-administered with caution and proper monitoring in the presence of P-glycoprotein substrate and strong inhibitors. Co-administration of tolvaptan with diuretic therapy did not appear to alter the aquaretic effect of tolvaptan; and was shown to be safe and well tolerated.
Highlights
IntroductionThe development of tolvaptan, an oral drug that is selective for vasopressin blockade at the
The development of tolvaptan, an oral drug that is selective for vasopressin blockade at theV2-receptors in the renal collecting duct, has changed the management of hypervolemic and euvolemic hyponatremia
Euvolemic hyponatremia often is associated with syndrome of inappropriate antidiuretic hormone (SIADH) [3], whereas hypervolemic hyponatremia commonly is associated with underlying conditions such as heart failure, cirrhosis, and renal failure [4,5,6,7,8]
Summary
The development of tolvaptan, an oral drug that is selective for vasopressin blockade at the. As the urine osmolality decreased with increasing tolvaptan dose, the mean serum sodium concentration increased from 1.5 to 8.0 mEq/L, with the maximal change from baseline seen at 6 to 8 hours post-dose. In the 120 mg tolvaptan group, mean plasma AVP concentration was significantly higher on Day 9 than that of a single 120 mg dose on Day 1, even at 24 hours post-dose. This indicates that tolvaptan’s effect retained potency after multiple-dosing. Review of tolvaptan PK/PD properties in detail suggest that increasing dose of the drug promotes an increase in the rate of aquaresis and extends the duration of effect, with the maximum urinary excretion rate plateauing at durations of greater than 8 hours post- a 60 mg dose. This review explored other studies in which tolvaptan concentrations could have been affected due to drug or food interactions
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