Diuretics are the most widely prescribed class of drugs. As renal function deteriorates in patients with chronic kidney disease (CKD) whose glomerular filtration rate falls below 60 ml/min (stages 3 to 5) they become more salt-sensitive and require a low BP goal to slow the progression of their disease and to prevent the associated cardiovascular disease (CV) complications. This mandates a predictably effective diuretic. However, at CKD >3-5, thiazides lose their efficacy. Patients are often switched to furosemide although this suffers from a number of limitations. Furosemide has a highly variable bioavailability (10 to 80%) that leads to unpredictable efficacy and its accumulation in advanced CKD leads to ototoxicity. It has a very short duration of action of about 4 hours that permit post- diuretic renal Na+ and fluid retention that limits the loss of body salt and water (efficacy) and t an abrupt action ("Niagara effect") that reduces the quality of life and causes neurohumoral activation, including aldosterone secretion, that are associated with bad clinical outcomes. Torsemide is a fully effective loop diuretic that is eliminated largely by hepatic metabolism and so does not accumulate in CKD. It has a high and constant bioavailability (80- 100%) in CKD, and blocks the secretion and action of aldosterone, thereby generally maintaining serum potassium concentrations. However, it too suffers from a limited duration of action (4 -8 hours). To address this unmet need and to provide a better diuretic for hypertensive CKD, we have formulated an extended release (ER) form of torsemide that releases the drugs over 8-10 hours in solution. This grant is a proposal for a phase 1 within - subject, cross over, single dose trialto contrast torsemide ER with torsemide immediate release (IR) in 8 normal individuals on fixed Na+ and K+ intakes.
Aims 1 will compare pharmakokinetics;
aim 2 pharmakodynamics (Na+ and K+ balances) and aim 3 neurohurmonal activation. If successful, this will lead to a similar phase 2 trial in patients with CKD 3-5. This would be followed by an efficacy and safety trial in patients with CKD 3-5 that includes the effects of torsemide ER compared with the standard-of-care drug, furosemide, comparing antihypertensive efficacy and safety in this population.
Loop diuretics such as torsemide are required to reduce body salt and water and to control hypertension in patients with chronic kidney disease. However, the duration of action of torsemide is short, which allows time for the kidney to regain the salt and water lost by the action of the drug. We are proposing a clinical trial of an extended release formulation of torsemide to confirm that this extended release formulation leads to a prolonged delivery of torsemide to the blood and thereby to a better salt and water loss. This is the first step in developing a new long-acting diuretic for the two million Americans that suffer from high blood pressure and chronic kidney disease.