Tolvaptan

Tolvaptan is a selective vasopressin V2-receptor antagonist that specifically blocks the binding of arginine vasopressin (AVP) at the V2-receptor of the distal portions of the nephron. Tolvaptan affinity for the human V2-receptor is 1.8 times that of native AVP.

In healthy adult subjects, oral administration of 7.5 to 120 mg doses of tolvaptan produced a increase in urine excretion rate within 2 hours of dosing. Following single oral doses of 7.5 to 60 mg, 24-hour urine volume increased dose dependently with daily volumes ranging from 3 to 9 litres. For all doses, urine excretion rates returned to baseline levels after 24 hours. For single doses 60 mg to 480 mg, a mean of about 7 litres was excreted during 0 to 12 hours, independent of dose. Markedly higher doses of tolvaptan produce more sustained responses without affecting the magnitude of excretion, as active concentrations of tolvaptan are present for longer periods of time.

Absorption

After oral administration, tolvaptan is rapidly absorbed with peak plasma concentrations occurring about 2 hours after dosing. The absolute bioavailability of tolvaptan is about 56%. Co-administration of a 60 mg dose with a high-fat meal increases peak concentrations 1.4 fold with no change in AUC and no change in urine output. Following single oral doses of ≥300 mg, peak plasma concentrations appear to plateau, possibly due to saturation of absorption.

Distribution

Tolvaptan binds reversibly (98%) to plasma proteins.

Biotransformation

Tolvaptan is extensively metabolised by the liver. Less than 1% of intact active substance is excreted unchanged in the urine.

Elimination

The terminal elimination half-life is about 8 hours and steady-state concentrations of tolvaptan are obtained after the first dose.

Radio labelled tolvaptan experiments showed that 40% of the radioactivity was recovered in the urine and 59% was recovered in the faeces where unchanged tolvaptan accounted for 32% of radioactivity. Tolvaptan is only a minor component in plasma (3%).

Linearity

Tolvaptan has linear pharmacokinetics for doses of 7.5 to 60 mg.

Pharmacokinetics in special patient groups

Age

Clearance of tolvaptan is not significantly affected by age.

Hepatic impairment

The effect of mildly or moderately impaired hepatic function (Child-Pugh classes A and B) on the pharmacokinetics of tolvaptan was investigated in 87 patients with liver disease of various origins. No clinically significant changes have been seen in clearance for doses ranging from 5 to 60 mg. Very limited information is available in patients with severe hepatic impairment (Child-Pugh class C).

In a population pharmacokinetic analysis in patients with hepatic oedema, AUC of tolvaptan in severely (Child-Pugh class C) and mildly or moderately (Child-Pugh classes A and B) hepatic impaired patients were 3.1 and 2.3 times higher than that in healthy subjects.

Renal impairment

In an analysis on population pharmacokinetics for patients with heart failure, tolvaptan concentrations of patients with mildly (creatinine clearance [C_cr] 50 to 80 mL/min) or moderately (C_cr 20 to 50 mL/min) impaired renal function were not significantly different to tolvaptan concentrations in patients with normal renal function (C_cr 80 to 150 mL/min). The efficacy and safety of tolvaptan in those with a creatinine clearance <10 mL/min has not been evaluated and is therefore unknown.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Teratogenicity was noted in rabbits given 1,000 mg/kg/day (up to 15 times the exposure in humans at the 60 mg dose, based on AUC). No teratogenic effects were seen in rabbits at 300 mg/kg/day (up to 5 times the exposure in humans at the 60 mg dose, based on AUC). In a peri-and post-natal study in rats, delayed ossification and reduced pup bodyweight were seen at the high dose of 1,000 mg/kg/day. Two fertility studies in rats showed effects on the parental generation (decreased food consumption and body weight gain, salivation), but tolvaptan did not affect reproductive performance in males and there were no effects on the foetuses. In females, abnormal oestrus cycles were seen in both studies. The no observed adverse effects level (NOAEL) for effects on reproduction in females (100 mg/kg/day) was about 8-times the total daily dose of 60 mg/day on a mg/m² basis.