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...

Teicoplanin is a new antibiotic consisting of closely related glycopeptides. Following an iv bolus of 400 mg teicoplanin, the pharmacokinetics of the individual components A3-1, A2-1, A2-2, A2-3, A2-4, and A2-5 was studied in five healthy volunteers by HPLC. For each subject, plasma and urine data of the individual components were simultaneously fitted by a triexponential disposition model. No significant differences were observed between the components of the A2 group in the initial volume of distribution, 0.05-0.06 L/kg, and the half-life of the second disposition phase, 2.5-3.0 hr. Significant differences were found in the volume of distribution at steady state (Vss 0.42-0.92 L/kg), the half-lives of the first (0.18-0.26 hr) and the third (48.1-66.8 hr) disposition phases, the total clearance (CL 5.4-19.3 ml/hr per kg), the renal clearance (CLR 2.8-16.1 ml/hr per kg), and the percentage of the administered dose excreted in urine (Ae 53-85%). A highly significant correlation was found between the lipophilicity of the individual components increasing from A2-1 to A2-5, and the values of the kinetic parameters. As the lipophilicity increases the fraction unbound in plasma, Vss, CL, CLR, and Ae decrease, whereas the unbound steady state volume of distribution and the unbound nonrenal clearance increase. A modest degree of accumulation of each teicoplanin component in plasma is predicted to occur at steady state following repeated administration of teicoplanin given daily, with accumulation slightly higher for the more lipophilic components A2-4 and A2-5.

The pharmacokinetics of teicoplanin have been studied in 13 pediatric male patients from 2 to 12 years of age. Patients were given a single 3-mg/kg intravenous dose of teicoplanin for prophylaxis. Blood and urine samples were collected for 8 days after administration, and teicoplanin levels were determined by microbiological assay. Pharmacokinetic parameters were estimated from a three-compartment open pharmacokinetic model and from a noncompartmental analysis. Levels in plasma 1 h after the administration averaged 14.8 mg/liter. The half-lives of the two distribution phases were 1.3 and 9.7 h. The half-life of the terminal phase averaged 57.9 h, with similar estimates obtained from the noncompartmental analysis and from data from urine. The volume of distribution of the central compartment was 0.15 liter/kg, whereas the volumes of distribution at steady state and during the elimination phase were 0.80 and 1.25 liters/kg. The total teicoplanin clearance averaged 14.8 ml/h per kg, with renal clearance accounting for about 60% of the total. The average cumulative recovery of teicoplanin in urine over 8 days was 59% of the dose, similar to the value obtained in adult volunteers. There was no significant linear correlation between elimination half-life and age. Preliminary data after repeated administration support the reliability of the model used and the validity of the mean estimated parameters. There were no local or systemic adverse reactions to teicoplanin.

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The pharmacokinetic profile of teicoplanin was studied in 12 elderly patients with a moderate degree of renal impairment (mean creatinine clearance, 51.3 ml/h/kg before treatment), after a single 6 mg/kg iv dose. Pharmacokinetic parameters were estimated both by a three-compartment open pharmacokinetic model and by non-compartmental analysis; peak plasma levels, 15 min after administration, averaged 45 mg/l. The half-lives of two distributive phases were 0.39 and 7.3 h, respectively. The elimination half-life averaged 107 h, with similar estimates obtained from the three-compartment analysis and from urinary data. The volume of distribution from the central compartment was 0.09 l/kg while the volumes of distribution at steady state and during the elimination phase were 1.3 and 1.6 l/kg, respectively. The total teicoplanin clearance averaged 10.6 ml/h/kg, with renal clearance accounting for about 40% of the total. There was a linear correlation between teicoplanin total or renal clearance and endogenous creatinine clearance. The average total recovery of teicoplanin in urine over eight days was 28%. There were no local or systemic adverse reactions to teicoplanin.