Vexpinem 500 Mechanism of Action

Pharmacological Classification: Carbapenems β-lactam antibiotics. ATC Code: J01D H51.
Pharmacology: Pharmacodynamics: Mechanism of action: Imipenem is a potent inhibitor of bacterial cell wall synthesis and is highly reactive towards penicillin-binding protein. Imipenem is more potent in its bactericidal effect than other antibiotics studied.
Cilastatin sodium is a competitive, reversible, and specific inhibitor of dehydropeptidase-1, the renal enzyme which metabolises and inactivates Imipenem. Cilastatin sodium is devoid of intrinsic antibacterial activity itself and does not affect the antibacterial activity of Imipenem.
PK/PD relationship: Imipenem exhibits primarily time-dependent killing. In common with other beta-lactams, the main PK/PD parameter that correlates with therapeutic efficacy is the time that concentrations in serum and tissue are above the MIC for the pathogens (>MIC).
Mechanism(s) of resistance: Imipenem is effectively stable to hydrolysis by most classes of beta-lactamases, including penicillinases, cephalosporinases and extended spectrum beta-lactamases, but not metallo-beta-lactamases. Resistance is generally due to a combination of decreased permeability and low- level beta-lactamase hydrolysis.
The mechanism of action of Imipenem differs from that of other classes of antibiotics, such as quinolones, aminoglycosides, macrolides and tetracyclines. There is no target-based cross-resistance between Imipenem and these substances. However, micro-organisms may exhibit resistance to more than one class of antibacterial agents when the mechanism is, or includes, impermeability to some compounds.
Pharmacokinetics: After oral administration, imipenem is not significantly absorbed. After I.V. administration of 500 mg, maximale plasma levels of about 36 mg/ml are observed. Multiple dosing has no effect on the pharmacokinetics of either imipenem or cilastatin, and no accumulation of imipenem/cilastatin is observed.
Distribution: Imipenem is bound to plasma proteins for about 20% and cilastatin for about 40%. The volume of distribution is approximately 10 L for both drugs.
Metabolism: Imipenem is mainly metabolised in the proximal renal tubuli by dehydropeptidase 1 into the inactive open ring metabolite, resulting in relative low urinary imipenem concentrations. Imipenem systemic metabolism accounts for about 30%. Cilastatin, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem, resulting in higher imipenem urinary concentrations.
Cilastatin is partly metabolised to N-acetyl-cilastatin in the kidneys.
Elimination: The plasma clearance of imipenem is 225 mL/min and that of cilastatin about 200 mL/min. Concomitant administration results in a decrease of the imipenem plasma clearance to about 195 mL/min, and an increase in renal clearance, urinary recovery and urinary concentrations. The plasma clearance of cilastatin is not affected. The elimation half-life is about 1 h for imipenem as well as for cilastatin. Approximately 70% of the administered imipenem dose is excreted intact in urine, and approximately 70-80% of the cilastatin dose.
Special patient groups: Elderly: In healthy elderly volunteers (65 to 75 years of age with normal renal function for their age), the pharmacokinetics of a single dose of imipenem 500 mg and cilastatin 500 mg administered intravenously over 20 minutes are consistent with those expected in subjects with slight renal impairment for which no dosage alteration is considered necessary.
Patients with renal impairment: Imipenem plasma clearance is decreased approximately 40% in subjects with moderate renal impairment to 70% in patients with severe renal impairment. In addition, the elimination half-life is increased to approximately 2.5 hours. Haemodialysis patients have an elimination half-life of about 3.4 hours. Cilastatin clearance is decreased approximately 50% in subjects with moderate renal impairment to 80% in patients with severe renal impairment. In addition, the elimination half-life is increased to approximately 4 hours. Haemodialysis patients have an elimination half-life of about 12 hours. During haemodialysis a higher clearance is observed for imipenem and cilastatin.
Children: The volume of distribution of imipenem and cilastatin in children is slightly higher than in adults. The elimination half-life for imipenem is about 1 h, and that for cilastatin about 40 min. 50-70% of the administered imipenem/cilastatin dose is excreted in urine.