Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment

Abstract

The pharmacokinetics of meropenem (ICI 194,660) and its open-ring metabolite (ICI 213,689) were studied in 6 healthy volunteers and 16 patients with moderate to severe renal impairment after a single intravenous dose of 500 mg given as a 30-min infusion. Concentrations of unchanged meropenem in plasma and urine were measured by both microbiological and high-pressure liquid chromatographic (HPLC) assays. A good correlation was found between the two techniques. Pharmacokinetic parameters of unchanged meropenem were determined by using the HPLC data. The terminal half-lfe of unchanged meropenem increased in relation to the degree of renal impairment, being 1.2 h in subjects with normal renal function and 10 h in patients with end-stage renal failure. Total body clearance and renal clearance of unchanged meropenem are lnearly related to creatinine clearance. The concentrations of the metabolite in plasma, which are very low in healthy subjects, signcantl increased in uremic patients. The apparent half-life of ICI 213,689 increased in uremic patients and was about 35 h in patients with severe renal insufficiency. Meropenem and its metabolite are effectively removed by hemodialysis. The dialysis clearance of the unchanged drug was 81 J 22 ml/min. Dosage adjustments of meropenem will be necessary in patients with severe renal impairment.Meropenem (ICI 194,660) is a new parenteral carbapenem antibiotic characterized by a broad antibacterial spectrum. It has been shown to have activity against both gram-positive and gram-negative pathogens, including anaerobes such as Bacteroidesfragilis. Meropenem is more active in vitro than imipenem against members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Unlike imipenem, meropenem shows a good stability against human renal dehydropeptidase I and does not require the coadministration of a dehydropeptidase I enzyme inhibitor such as cilastatin (4,7,(9)(10)(11).The purpose of this study was to investigate the pharmacokinetics of meropenem (ICI 194,660) and of its open-ring metabolite (ICI 213,689) in patients with moderate or severe renal impairment after a single intravenous (i.v.) dose of 500 mg given as a 30-min infusion.

Role of Therapeutic Drug Monitoring in Pulmonary Infections: Use and Potential for Expanded Use of Dried Blood Spot Samples

“…Ciprofloxacin is used in more common 301 infections, while moxifloxacin is used for infections caused by less common or resistant pathogens, 302 for example Mycobacterium tuberculosis. Most fluoroquinolones need dose adjustments in patients 303 with decreased renal function [25,[37][38][39]. These drugs are not extensively metabolised in the liver, 304 so no dose adjustments are required for patients with impaired liver function [37,40].…”

“…Y ciprofloxacin oral/IV Y(R), N(H) [22,22,24] Cmax and trough [23] P-gp [19] ST [21] levofloxacin oral/IV Y(R) [25], N(H) [23] Cmax [23] P-gp [19] ST moxifloxacin oral/IV N(R) [6], AUC [23] Al/Mg, Antacids, Fe [23] LT and ST N(H) [26] ofloxacin oral Y(R) [22], N(H)ᵠ No data CYP3A4, P-gp [19] ST…”

“…For clindamycin, dose adjustments are not required for patients with impaired renal functions [25]. 363…”

“…Duration of treatment with these 291 drugs is often short (one or two weeks). Dose adjustments are normally not required for 292 tetracyclines in patients with renal (except for tetracycline) or hepatic impairment [25,34]. 293…”

“…For beta-lactam antibiotics it has been shown that dose adjustment is recommended for most drugs 271 in patients with renal impairment, especially when combined with β-lactamase inhibitors [24][25][26][27][28][29][30]. 272…”