Pharmacokinetics and tolerability of teicoplanin in healthy volunteers after single increasing doses

Abstract

In this double-blind, randomized study, five healthy subjects per group received doses of 15, 20, or 25 mg of teicoplanin per kg of body weight, and one subject per group received a 0.9% NaCl placebo as single intravenous infusion over 30 min. Serial blood samples and urine were collected for 13 days postadministration, and concentrations of teicoplanin were determined by microbiological assay. The pharmacokinetic data were analyzed by noncompartmental and compartmental analyses. Laboratory safety tests, audiometry, and serum creatinine clearance measurements were done prior to day 1 and on days 2 and 14. In the three groups, peak levels at the end of the infusion averaged 194, 197, and 253 mg/liter, respectively. Mean concentrations in plasma 24 h after the administration were 10.5, 13.6, and 19.8 mg/liter, respectively. Mean values of volume of distribution at steady state were 0.80, 0.87, and 0.87 liters/kg, respectively. Terminal half-lives averaged 88, 83, and 92 h. Mean total clearance values were 10.9, 11.0, and 11.3 mg/h/kg, respectively, with renal clearance accounting for 75, 81, and 78%, respectively, of the total. The 13-day cumulative mean urinary recovery ranged from 71 to 78% of the dose within the groups. The pharmacokinetics of teicoplanin appears to be linear in the range of administered doses. Teicoplanin was generally well tolerated. Side effects, appearing in five subjects, were represented by fevers, chills, and skin reactions; these adverse reactions were mild, but one episode of rash necessitated the interruption of infusion, and one episode of chills necessitated treatment with corticosteroids. There was no indication of drug-related modifications of laboratory test results.The pharmacokinetics of teicoplanin has been extensively investigated in numerous studies (17) carried out with both healthy volunteers and patients, with a range of doses from 2 to 6 mg/kg of body weight. In healthy volunteers, teicoplanin shows a triexponential plasma kinetic profile. Concentrations of around 70 mg/liter have been observed 5 min after the intravenous (i.v.) administration of 6 mg/kg (4, 5, 17). The apparent terminal half-life ranged in different studies from 34 to 163 h after a single dose, depending on the length of sampling (4-6, 13, 16-19, 21). A preliminary analysis of experience in the United States of the treatment of endocarditis due to Staphylococcus aureus, mainly in drug addicts, indicates that dosages of less than 12 mg/kg/ day did not approach the anticipated efficacy for this patient population, thus suggesting that the daily dose of teicoplanin for this specific condition would have to be increased. Since earlier studies on the tolerability of increasing doses of teicoplanin among normal volunteers did not include such a high dose, this study was carried out in order to obtain information on the tolerability and pharmacokinetics of teicoplanin among volunteers in a dose range of 15 to 25 mg/kg.(This work has been previously presented in part at the 29th Interscience Conference on Antim...

Daptomycin or teicoplanin in combination with gentamicin for treatment of experimental endocarditis due to a highly glycopeptide-resistant isolate of Enterococcus faecium

“…To evaluate whether the synergistic effect observed in killing curves between teicoplanin, which was used at an inhibitory concentration, and gentamicin could be relevant in vivo, HiD teicoplanin was evaluated. Such a regimen, which provided very high peak and trough levels in serum, would not be readily recommendable for humans, because it has previously been reported to induce adverse reactions in healthy volunteers (6,19). Its poor efficacy in rabbits, even when used in combination with gentamicin, might be explained by (i) the high degree of protein binding of the drug, as suggested by the killing curves, which showed a lack of the bactericidal effect observed with teicoplanin at VOL.…”

Teicoplanin versus vancomycin in the empirical treatment of febrile neutropenic patients

“…Infections due to Gram-positive organisms, such as staphylococci and streptococci, have become increasingly prevalent in febrile neutropenic patients with underlying neoplasia (1). Vancomycin is commonly used for such patients either during viously established in the authors' laboratory (6). This assay gave reproducible results (mean coefficient of variation, 8.8%) regardless of the presence of tobramycin, amikacin, piperacillin, ceftazidime, or amphotericin B. Serum tobramycin concentrations, monitored every 3-7 days before and at 1 h after the end of infusion, were measured by the fluorescence polarization immunoassay method (TDX; Abbott Laboratories, North Chicago, Illinois, USA).…”

“…This assay gave reproducible results (mean coefficient of variation, 8.8%) regardless of the presence of tobramycin, amikacin, piperacillin, ceftazidime, or amphotericin B. Serum tobramycin concentrations, monitored every 3-7 days before and at 1 h after the end of infusion, were measured by the fluorescence polarization immunoassay method (TDX; Abbott Laboratories, North Chicago, Illinois, USA). Pharmacokinetic parameters for both glycopeptides and tobramycin were estimated at steady state after multiple dosing according to standard procedures (6). tial advantages, including low toxicity, better tolerability with intravenous or intramuscular administration, and a longer elimination half-life (60-80 h compared with [4][5][6] h for vancomycin) (3)(4)(5)(6)(7).…”

“…Pharmacokinetic parameters for both glycopeptides and tobramycin were estimated at steady state after multiple dosing according to standard procedures (6). tial advantages, including low toxicity, better tolerability with intravenous or intramuscular administration, and a longer elimination half-life (60-80 h compared with [4][5][6] h for vancomycin) (3)(4)(5)(6)(7).…”

Randomized Comparison of Serum Teicoplanin Concentrations following Daily or Alternate Daily Dosing in Healthy Adults

“…A computer simulation of various intravenous administration schedules was performed by using the equation described by Rowland (16) (4,16) were assumed to be linear (no dose or time dependency), and the final concentration was the sum of all concentrations reached with all preceding administrations.…”