Pharmacokinetics and dose proportionality of cefmetazole in healthy young and elderly volunteers

Abstract

The pharmacokinetics and dose proportionality of cefmetazole were studied in 24 healthy volunteers (12 young and 12 elderly). Each volunteer received single 0.5-, 1-, and 2-g doses of cefmetazole administered intravenously over 5 min according to a three-way crossover design. Serial plasma and urine samples were collected over a 24-h period following dosing and assayed for cefmetazole by a high-performance liquid chromatography method. Results of the dose proportionality portion of the study indicated that cefmetazole pharmacokinetics are linear and proportional with dose in both age groups. Comparisons of pharmacokinetic parameters between the young and elderly groups indicated that the systemic clearance was significantly lower in elderly than in young volunteers (92.4 versus 112 ml/min). Additionally, creatinine clearance was significantly lower in elderly (74.1 ml/min) than in young (92.9 ml/min) subjects. No significant differences between age groups were observed for volume of distribution, urinary recovery, terminal half-life, nonrenal clearance, or renal clearance, although half-life was slightly prolonged in elderly volunteers relative to that in young volunteers (1.54 versus 1.34 h), and renal clearance was slightly lower in elderly than in young volunteers (83.7 versus 96.1 ml/min). Both systemic and renal clearance were significantly correlated with creatinine clearance. These results indicate that the observed age-related differences in the pharmacokinetics of cefmetazole are most likely due to differences in renal function between the two age groups. The small reduction in cefmetazole elimination in the elderly would not warrant dose adjustment in this population.Cefmetazole sodium is a parenteral cephamycin antibiotic having a broad antibacterial spectrum in vitro which includes many strains of both gram-positive and gram-negative aerobic and anaerobic bacteria (6,12,14,19,21). Clinical studies have shown its effectiveness in the treatment of a number of infections and in prophylactic use prior to surgery (8,19,23).Pharmacokinetic studies of healthy young volunteers following intravenous administration of cefmetazole sodium have demonstrated that cefmetazole is eliminated primarily by renal mechanisms resulting in greater than 70% recovery of intact cefmetazole in urine (13,15). Cefmetazole pharmacokinetics have also been studied in patients with various degrees of renal insufficiency (13,20). In these patients, the elimination half-life of cefmetazole was found to increase progressively with decreasing renal function.Physiological changes associated with aging which can affect drug disposition include decreases in lean body mass and body water and an increase in body fat, which can result in altered drug distribution, and a decrease in serum albumin levels, which can lead to changes in drug binding (7,26). Reductions in glomerular filtration rate and renal tubular function in the elderly are also well documented and can result in decreased elimination of drugs which are primarily renally excreted...

Optimal dosage of cefmetazole for intraoperative antimicrobial prophylaxis in patients undergoing surgery for colorectal cancer

“…These findings were considered reasonable because more than 85% of CMZ is excreted as the unchanged compound in the urine, and excretion is mainly renal. A CL CMZ of 7.04 L/h (Ccr : 100 mL/min) and a Vd CMZ of 10.4 ± 1.6 L (Bw : 47.5 to 89.0 kg) were generally consistent with the results of Borin et al (CL : 6.96 L/h, Vd : 11.9 ± 4.2 L) [7] and Wong-Beringer et al (Vd : 0.14 to 0.28 L/kg) [8]. …”

Pharmacokinetic–pharmacodynamic analysis of cefmetazole against extended-spectrum β-lactamase-producing Enterobacteriaceae in dogs using Monte Carlo Simulation

“…We investigated the PK parameters of CMZ in dogs based on the results of blood concentration transition after bolus administration. Borin et al ( 25 ) determined the corresponding PK data in young adult humans, ranging in age from 21 to 40 years, when intravenously administered, as follows: the mean residence time (MRT) was 1.78 h, the elimination half-life (T1/2) was 1.34 h, total body clearance (CL) was 0.10 L/h/kg, and the volume of distribution (Vd) was 0.17 L/kg. Our study indicates the shorter MRT and T1/2, higher CL, and larger Vd in dogs administered with CMZ, compared with the PK data in humans.…”

Considerations in Dosage Selection for Third Generation Cephalosporins

“…Cephalosporin dosage regimens and serum half-lives (t'l2) in neonates, children and the elderly. Dosages listed do not reflect those for life-threatening infection or meningitis (data from Andritz et al 1984;Blouin et al 1989;Borin et al 1990;Faulkner et al 1988b;Hayton 1986;LeBel et al 1985;Meyers et al 1987Meyers et al , 1989Sugihara et al 1988 Nilsson-Ehle 1987; Meyers et al 1989;Montamat et al 1989). Pharmacokinetic studies of ceftazidime, ceftizoxime, and cefmenoxime conducted in elderly populations showed a doubling of tl/, by the age of 70, indicating the need for dosage reduction for these renally eliminated cephalosporins in this age group.…”

“…Reductions in CLR and protein binding often present in this population lead to no apparent change in the t'l2 of ceftriaxone (Hayton & Stoeckel 1986). Dosage adjustment in the elderly is not indicated for cefetamet ), cefmetazole (Borin et al 1990) or cefixime (Faulkner et al 1988b) if the renal function remains normal other than the usual CLCR decline with aging [to CLCR 30 mlfmin (1.8 L/h)].…”