Imipenem/cilastatin: rationale for a fixed combination

Imipenem is renally metabolized to the stable open-lactam metabolite by a dipeptidase, dehydropeptidase I, located at the lumenal surface of the proximal tubular cells. In humans the degree of hydrolysis shows marked intersubject variability but minimal intrasubject variability. In healthy subjects the urinary recovery of unchanged imipenem ranged from 5.5% to 42.5% of the dose. Cilastatin inhibits the metabolism of imipenem and increases the urinary recovery of active imipenem to about 70% of the dose when a combination of imipenem and cilastatin in a 1:1 ratio is used. In healthy volunteers, the pharmacokinetics of imipenem and cilastatin are similar, but in patients with renal impairment, cilastatin is eliminated more slowly than imipenem. Both compounds have a high degree of safety. However, very high doses of imipenem induce tubular toxicity in rabbits. That effect can be blocked by using a combination of imipenem and cilastatin. The use of a fixed combination of imipenem and cilastatin is motivated by the increases in urinary recovery of imipenem with the combination and by the elimination of the nephrotoxic potential associated with the administration of imipenem alone.