PHARMACOKINETICS AND METABOLISM
Visken® (pindolol) is rapidly and reproducibly absorbed (greater than 95%), achieving peak plasma concentrations within 1 hour of drug administration. Visken® (pindolol) has no significant first-pass effect. The blood concentrations are proportional in a linear manner to the administered dose in the range of 5-20 mg. Upon repeated administration to the same subject, variation is minimal. After a single dose, intersubject variation for peak plasma concentrations was about 4fold (e.g., 45-167 ng/mL for a 20 mg dose). Upon multiple dosing, intersubject variation decreased to 2-2.5 fold. Visken® (pindolol) is only 40% bound to plasma proteins and is evenly distributed between plasma and red cells. The volume of distribution in healthy subjects is about 2 L/kg.
Visken® (pindolol) undergoes extensive metabolism in animals and man. In man, 35%-40% is excreted unchanged in the urine and 60%-65% is metabolized primarily to hydroxy-metabolites which are excreted as glucuronides and ethereal sulfates. The polar metabolites are excreted with a half-life of approximately 8 hours and thus multiple dosing therapy (q.8H) results in a less than 50% accumulation in plasma. About 6%-9% of an administered intravenous dose is excreted by the bile into the feces.
The disposition of Visken® (pindolol) after oral administration is monophasic with a half-life in healthy subjects or hypertensive patients with normal renal function of approximately 3-4 hours. Following t.i.d. administration (q.8H), no significant accumulation of Visken® (pindolol) is observed.
In elderly hypertensive patients with normal renal function, the half-life of Visken® (pindolol) is more variable, averaging about 7 hours, but with values as high as 15 hours.
In hypertensive patients with renal diseases, the half-life is within the range expected for healthy subjects. However, a significant decrease (50%) in volume of distribution (VD) is observed in uremic patients and VD appears to be directly correlated to creatinine clearance. Therefore, renal drug clearance is significantly reduced in uremic patients, resulting in a significant decrease in urinary excretion of unchanged drug. Uremic patients with a creatinine clearance of less than 20 mL/min generally excreted less than 15% of the administered dose unchanged in the urine.
In patients with histologically diagnosed cirrhosis of the liver, the elimination of Visken® (pindolol) was more variable in rate and generally significantly slower than in healthy subjects. The total body clearance of Visken® (pindolol) in cirrhotic patients ranged from about 50-300 mL/min and was directly correlated to antipyrine clearance. The half-life ranges from 2.5 hours to greater than 30 hours. These findings strongly suggest that caution should be exercised in dosage adjustments of Visken® (pindolol) in such patients.
The bioavailability of Visken® (pindolol) is not significantly affected by co-administration of food, hydralazine, hydrochlorothiazide or aspirin. Visken® (pindolol) has no effect on warfarin activity or the clinical effectiveness of digoxin, although small transient decreases in plasma digoxin concentrations were noted.
INDICATIONS AND USAGE
Visken® (pindolol) is indicated in the management of hypertension. It may be used alone or concomitantly with other antihypertensive agents, particularly with a thiazide-type diuretic.
|
