Tolvaptan 15 mg · Tablets

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times that for the V1a-receptor. Decreased binding of vasopressin to the V2-receptor in the kidney lowers adenylate cyclase activity resulting in a decrease in intracellular adenosine 3′, 5′-cyclic monophosphate (cAMP) concentrations. Decreased cAMP concentrations prevent aquaporin 2 containing vesicles from fusing with the plasma membrane, which in turn causes an increase in urine water excretion, an increase in free water clearance (aquaresis) and a decrease in urine osmolality. In human ADPKD cyst epithelial cells, tolvaptan inhibited AVPstimulated in vitro cyst growth and chloride-dependent fluid secretion into cysts. In animal models, decreased cAMP concentrations were associated with decreases in the rate of growth of total kidney volume and the rate of formation and enlargement of kidney cysts. Tolvaptan metabolites have no or weak antagonist activity for human V2-receptors compared with tolvaptan.

In healthy subjects, the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been studied. In ADPKD patients, single doses up to 120 mg and multiple split-doses up to 90/30 mg have been studied.

Absorption: — In healthy subjects, peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Peak concentrations increase less than dose proportionally with doses greater than 240 mg.

The absolute bioavailability of tolvaptan decreases with increasing doses. The absolute bioavailability of tolvaptan following an oral dose of 30 mg is 56% (range 42 to 80%).

Co-administration of 90 mg tolvaptan tablets with a high-fat meal (~1000 calories, of which 50% are from fat) doubles peak concentrations but has no effect on the AUC of tolvaptan; tolvaptan may be administered with or without food.

Distribution: — Tolvaptan binds to both albumin and α1-acid glycoprotein and the overall protein binding is greater than 98%; binding is not affected by disease state. The volume of distribution of tolvaptan is about 3 L/kg. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. When administered as multiple once-daily 300 mg doses to healthy subjects or as split-dose regimens to patients with ADPKD, tolvaptan’s accumulation factor is less than 1.2. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.

Metabolism and Elimination: — Tolvaptan is metabolized almost exclusively by CYP 3A. Fourteen metabolites have been identified in plasma, urine and feces; all but one were also metabolized by CYP 3A and none are pharmacodynamically active. After oral administration of radiolabeled tolvaptan, tolvaptan was a minor component in plasma representing 3% of total plasma radioactivity; the oxobutyric acid metabolite was present at 52.5% of total plasma radioactivity with all other metabolites present at lower concentrations than tolvaptan. The oxobutyric acid metabolite shows a plasma half-life of ~180 h. About 40% of radioactivity was recovered in urine (less than 1% as unchanged tolvaptan) and 59% in feces (19% as unchanged tolvaptan). Following intravenous infusion, tolvaptan half-life is approximately 3 hours. Following single oral doses to healthy subjects, the estimated half-life of tolvaptan increases from 3 hours for a 15 mg dose to approximately 12 hours for 120 mg and higher doses due to more prolonged absorption of tolvaptan at higher doses; apparent clearance is approximately 4 mL/min/kg and does not appear to change with increasing dose.

Age, Gender and Race — Age, gender and race have no effect on tolvaptan pharmacokinetics.

Hepatic Impairment — In studies involving patients with hepatic impairment (Child-Pugh class A-C), but without ADPKD; moderate (class A, B) or severe (class C) hepatic impairment decreases the clearance and increases the volume of distribution of tolvaptan.

Renal Impairment — In subjects with creatinine clearances ranging from 10 to 124 mL/min administered a single dose of 60 mg tolvaptan, the AUC and Cmax of plasma tolvaptan was increased 90% and 10%, respectively, for subjects with clearances of less than 30 mL/min compared to subjects with clearances greater than 60 mL/min [see Use in Special Populations (8.7)].

In ADPKD patients with estimated creatinine clearance greater than 60 mL/min, pharmacokinetics were similar to healthy subjects.

Strong CYP 3A Inhibitors — Tolvaptan’s Cmax and AUC were, respectively, 3.5 times and 5.4 times as high following ketoconazole 200 mg given one day prior to and concomitantly with 30 mg tolvaptan.

Moderate CYP 3A4 Inhibitors — Fluconazole: Fluconazole 400 mg given one day prior and 200 mg given concomitantly produced an 80% and 200% increase in tolvaptan Cmax and AUC, respectively.

Grapefruit Juice: When 60 mg tolvaptan was taken with 240 mL regular strength grapefruit juice, tolvaptan Cmax and AUC increased 90% and 60%, respectively.