Pharmacokinetics and tolerance of N-formimidoyl thienamycin (MK0787) in humans

Abstract

The pharmacokinetics of intravenously administered N-formimidoyl thienamycin (MK0787) were studied in 14 healthy male subjects in a single-dose study, in which the volunteers received N-formimidoyl thienamycin with and without probenecid, and in a multiple-dose study, in which the subjects were given 250 or 500 mg every 8 h for 10 doses. High dose-related plasma concentrations of Nformimidoyl thienamycin were achieved; co-administration with probenecid resulted in only minor increases in these concentrations. No accumulation in plasma was seen after multiple doses. The plasma half-life of N-formimidoyl thienamycin was slightly less than 1 h and did not increase significantly with the coadministration of probenecid. The urinary recovery of N-formimidoyl thienamycin varied between 6.0 and 38.4% of the dose with a marked intersubject variability. Variations in individual subjects were small, however, when the urinary recoveries after repeated doses were compared. These results were in agreement with previous animal studies showing a renal metabolism of Nformimidoyl thienamycin. Probenecid administration resulted in a marked decrease in N-formimidoyl thienamycin urinary recovery. In vitro experiments showed that the decay of N-formimidoyl thienamycin in spiked pretreatment urine samples was 2 to 5%/h with more rapid degradation at acidic than at basic pH. N-Formimidoyl thienamycin (MK0787) is a stable derivative of thienamycin, a carbapenem antibiotic produced by Streptomyces cattleya (5). Its antibacterial spectrum is unusually broad and includes many commonly antibiotic-resistant bacterial species, e.g., Pseudomonas aeruginosa and enterococci (2, 3, 9). The antibacterial activity is bactericidal, and N-formimidoyl thienamycin is extremely resistant to degradation by bacterial P-lactamases (1,8).In animals, N-formimidoyl thienamycin is rapidly excreted via the kidneys (3). However, urinary recovery varies with the species, and a renal metabolism of N-formimidoyl thienamycin has been demonstrated. The present studies were undertaken to investigate the pharmacokinetics of N-formimidoyl thienamycin in healthy volunteers after the administration of single doses (with or without the prior administration of probenecid) and after multiple doses.(These studies were presented at the 21st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 111., 1981.) MATERIALS AND METHODS Subjects. Fourteen healthy male Caucasian subjects were recruited for the two studies. The mean age was 22 years (range, 19 to 28 years), and the mean body weight was 71.6 kg (range, 62.3 to 77.4 kg). Written informed consent was obtained, and the studies were approved by the Ethical Committee at

Pharmacokinetics of imipenem and cilastatin in patients with cystic fibrosis

“…In addition, over the three dosage schedules studied, a linear relationship was observed between drug dose and AUC (Table 4). Both of these findings have been reported previously in unaffected adults (17,18). A total of 50 and 78% of the administered doses of imipenem and cilastatin, respectively, were recovered in the urine over the 6-h study period (Fig.…”

“…Arvidsson and colleagues (1), in are similar to imipenem profiles observed in unaffected adult assessing the urinary clearance of cefsulodin in cystic fivolunteers (18). Norrby et al (17,18) have shown that the brosis patients and unaffected individuals, found comparable coadministration of either probenecid or dehydropeptidase results, although the actual renal elimination pathway(s) was inhibitors only mildly affect the systemic biodisposition of different in patients with cystic fibrosis. imipenem.…”

“…Preliminary biodisposition studies of imipenem in animals and humans have demonstrated stable systemic profiles accompanied by variable amounts of renal degradation of the compound (13,18). This finding is a result of the rapid renal hydrolysis of the imipenem ,B-lactam ring by the brush border enzyme dehydropeptidase I (13,17,18).…”

“…This finding is a result of the rapid renal hydrolysis of the imipenem ,B-lactam ring by the brush border enzyme dehydropeptidase I (13,17,18). To circumvent the renal inactivation of imipenem, cilastatin, a competitive inhibitor of renal dehydropeptidase I, is currently being evaluated for concomitant administration (17).…”

Prospective evaluation of effects of broad-spectrum antibiotics on gastrointestinal yeast colonization of humans

“…On the other hand, antibiotics with poor anaerobic activity, like ceftazidime (7,8,23) and aztreonam (13,25,35), or with low concentrations in the G.I. contents, like imipenem (22,26,27), were associated with smaller increases in the yeast flora of the gut.…”