KINETICS OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS IN RENAL-FAILURE

Although there is impressive documentation linking severe hypertension to renal insufficiency, corresponding data for mild-to-moderate hypertension are only now starting to emerge. As a result, it is only now becoming evident that a much larger portion of the hypertensive population could be susceptible to drug accumulation owing to renal insufficiency. Angiotensin-converting enzyme (ACE) inhibitor therapy routinely requires dosage adjustment in the instance of renal insufficiency, as all currently marketed ACE inhibitors are renally eliminated. Such dosage adjustments are usually considered a way to minimize side effects and to limit the duration of any induced hypotension. Dosage adjustment is usually considered at creatinine clearance levels between 30 and 60 ml/min. This is somewhat problematic, as physicians generally rely on serum creatinine determinations to assess renal function, and serum creatinine values are notoriously poor predictors of actual creatinine clearance. This is particularly true in the elderly population, where a greater disparity between the serum creatinine and creatinine clearance commonly exists, with moderate renal insufficiency frequently going unrecognized. Thus, the development of other ACE inhibitors eliminated via renal/hepatic routes may prove to be advantageous in that dosage adjustments might not be required in the setting of declining renal function, whether age-related or not. Fosinopril, a new phosphorus-containing ACE inhibitor, is administered as a prodrug and is hydrolyzed to the pharmacologically active diacid, fosinoprilat. It is distinguished from other ACE inhibitors in that in normal individuals it is equally eliminated via renal and hepatic routes; in addition, as renal elimination declines in the presence of renal insufficiency, fractional hepatic elimination increases. Thus, accumulation of the compound is minimal, and dosage adjustment may be unnecessary. This pharmacokinetic aspect of fosinopril was further explored in an open-label, randomized, parallel study comparing the serum levels of fosinoprilat, enalaprilat, and lisinopril following single and multiple doses of each in patients with moderate to severe renal insufficiency (creatinine clearance < 30 ml/min). Of the 29 evaluable patients (mean age of 62.8 years), there were no statistically significant differences between groups with regard to baseline creatinine clearance values. Mean accumulation indices [(AUC Day 10)/(AUC Day 1)] for fosinoprilat (n = 9), enalaprilat (n = 10), and lisinopril (n = 10) were 1.26 +/- 0.10, 1.77 +/- 0.17, and 2.62 +/- 0.32, respectively. Statistical analysis of these data showed fosinoprilat to accumulate significantly less than enalaprilat (p < 0.05) and lisinopril (p < 0.001). Thus, dosage adjustment in moderate to advanced renal insufficiency and/or the elderly population would appear unnecessary. This pharmacokinetic distinction should facilitate convenient dosing for fosinopril in that the same starting dose may be utilized in all patients.