The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, was studied in 5 healthy male volunteers and 29 adult patients with various degrees of renal impairment, given a single 3 mg/kg intravenous dose. Teicoplanin was assayed in plasma and urine specimens by a microbiological method. Pharmacokinetic parameters for teicoplanin were estimated both by a 3-compartment open pharmacokinetic model and by non-compartmental analysis. Elimination half-life increased with the decrease in creatinine clearance and mean values ranged from 41 hours in volunteers to 163 hours in anuric patients. Renal failure did not affect either the volume of distribution of the central compartment (mean approximately 0.09 L/kg) or the steady-state volume of distribution (mean approximately 0.9 L/kg). Both total and renal clearance decreased with severity of disease, particularly the latter, while non-renal clearance was unaffected by renal failure. Average values were from 19 to 6 ml/min for total clearance and from 12 to 0.4 ml/min for renal clearance. There was a linear correlation between the total clearance of teicoplanin and creatinine clearance, as well as between renal clearance and creatinine clearance. The total urinary excretion of active teicoplanin averaged 65% of the administered dose in normal subjects, but was significantly reduced in the presence of renal insufficiency. Guidelines for administration of teicoplanin in patients with renal failure are given.

Five healthy male volunteers received over 60 sec a single intravenous injection of 400 mg of teicoplanin labelled with 41 microCi of 14C. Plasma and urine total radioactivity was measured up to 10 and 16 days, respectively. Teicoplanin was assayed in plasma and urine also by a microbiological method, with similar results. Pharmacokinetic parameters were estimated by model-independent analysis and the following mean values were obtained: elimination half-life 77 h; total body clearance 9.8 ml/h/kg; renal clearance 7.81 ml/h/kg; volume of distribution at steady-state 0.759 l/kg. Similar estimates were obtained by a compartmental analysis. A total of 80% of the administered dose was recovered in urine in 16 days; 2.7% of the dose was recovered in faeces collected for eight days after administration. The mean total recovery of the drug was 83 +/- 0.6%. The plasma and urine concentrations of teicoplanin observed after a single 400 mg iv dose exceeded the MIC for most pathogens for at least one day, and this suggests that a daily dosage regimen would be satisfactory for patients with normal renal function.

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.

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...