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

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.

Teicoplanin binding in plasma following administration of increasing intravenous doses to healthy volunteers.

Teicoplanin is a new long half-life glycopeptide antibiotic active against Gram-positive bacteria. Binding to plasma protein can significantly affect the pharmacokinetics of drugs with low extraction ratio, such as teicoplanin; clearance, volume of distribution and half-life of the drug change as the fraction of drug unbound (fu) varies, with obvious clinical implications. In this study, the linearity of teicoplanin binding to plasma protein was studied in healthy volunteers receiving single increasing intravenous doses of 15, 20 and 25 mg/Kg teicoplanin. Unbound fraction of teicoplanin in human plasma was determined by ultrafiltration. Unbound and total teicoplanin concentrations, Cu and Cp, were measured by microbiological assay. The results indicate that Cu was linearly correlated to Cp in the Cp range from 7 to 280 mg/L, according to the following regression model: Cu = 0.105 Cp - 0.234 (r = 0.9947) in which the coefficient 0.105 represents the average fu. Individual estimates of fu were calculated for every sample as the ratio between Cu and Cp; mean fu values were 0.100 +/- 0.002 (SE), 0.101 +/- 0.002 and 0.097 +/- 0.002, after 15, 20 and 25 mg/Kg, respectively. No statistical difference was found between groups. We conclude that the binding of teicoplanin to plasma protein is linear up to about 300 mg/L and fu value is not dose-dependent from 15 to 25 mg/Kg dose. These conclusions are in keeping with the observation that the pharmacokinetics of teicoplanin is linear in the dose range from 15 to 25 mg/Kg. These estimates of teicoplanin unbound fraction using ultrafiltration are also in agreement with previously reported values obtained by equilibrium dialysis. A mathematical model is proposed to predict changes of fu as the total plasma concentration increases.

Model choice for teicoplanin kinetics in man.

Teicoplanin is a new long half life antibiotic, characterized by a polyexponential profile. A pharmacokinetic study was made in healthy volunteers receiving 15, 20 and 25 mg/Kg iv doses of Teicoplanin. Plasma concentration-time data were fitted by a polyexponential equation, consisting of two, three, four and five terms. The software was PCNONLIN, using the Gauss-Newton method with Harley's and Levenberg's modification and 1/Y2 as a weighting factor, where Y is the predicted concentration. The increase of the number of exponential terms from two to five resulted in a continuous minimization of the sum of the weighted squared residuals. To test whether or not this sum had been sufficiently reduced to justify the fitting with additional exponential terms, Akaike, Gallant and F-ratio test criteria were used. The four exponential equation best fit most of the data sets. However, the estimates of the main parameters (AUC, V, Vss, CL, Css min, Css max, number of doses to reach 95%ss) calculated according to tri and four-exponential models did not significantly differ. In the dose range studied teicoplanin pharmacokinetics are linear. In conclusion, an additional exponential term in the equation can significantly improve the best fit of teicoplanin plasma curves according to the above criteria, but it may not lead to a significant variation of the main pharmacokinetic parameters and derived values. This indicated that for clinical purposes a tri exponential model suffices for describing the kinetics of Teicoplanin in man.

Pharmacokinetics of teicoplanin in pediatric patients.

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 volume 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.

Pharmacokinetics of intraperitoneal teicoplanin in patients with chronic renal failure on continuous ambulatory peritoneal dialysis.

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, is described in five patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). A single 3 mg kg-1 dose was given intraperitoneally in the dialysate during a 6 h dwell time. The drug appeared in the plasma within 15 min at 1.00-0.28 mg l-1 (mean +/- s.d. = 0.70 +/- 0.45) in all five subjects, and peak serum concentrations ranged from 5.53 to 2.80 mg l-1 (4.84 +/- 1.43) at 6 h. Approximately 70% (71 +/- 12) of teicoplanin was absorbed from the peritoneal dialysis fluid during a single 6 h dwell time. The rate constant for peritoneal transfer (lambda d) averaged 0.318 h-1 and the half-life (t1/2 lambda d) was 2.18 h. Further values were serum elimination half-life 114-173 h; total body clearance 263-532 ml h-1; steady-state volume of distribution 68-93 l. This drug profile closely agrees with data reported after intravenous injection in patients on CAPD and suggests that teicoplanin has bidirectional exchange characteristics through the peritoneal membrane, although transfer from the systemic circulation to peritoneal fluid is consistently low. Instillation of teicoplanin in CAPD fluid may be a useful route of administration for treatment of peritonitis and exit site infections in CAPD patients.

Pharmacokinetics of a single intravenous dose of teicoplanin in subjects with various degrees of renal impairment.

The pharmacokinetic profile of teicoplanin after single 3 mg/kg doses in adults with different degrees of renal failure was reviewed. The disposition of teicoplanin was adequately described by a three-compartment open pharmacokinetic model and it appears to be primarily related to the degree of renal function. Teicoplanin total body clearance was less and the terminal elimination half-life progressively prolonged in association with renal failure, but the volume of distribution at steady-state did not change. Highly significant relationships between teicoplanin total body and renal clearance and creatinine clearance have been reported and serve as a basis for adjusting dosage in patients with renal failure. In patients on continuous ambulatory peritoneal dialysis teicoplanin, administered either intravenously or intraperitoneally, showed bidirectional exchange characteristics through the peritoneal membrane, although transfer from the systemic circulation to peritoneal fluid was consistently low. Haemodialysis made no significant contribution to total body clearance of teicoplanin. Guidelines for administration of teicoplanin in patients with renal failure are discussed.

Pharmacokinetics of teicoplanin in the elderly.

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.

Teicoplanin pharmacokinetics in patients with chronic renal failure.

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.

Pharmacokinetics of teicoplanin in patients on continuous ambulatory peritoneal dialysis.

We have studied the pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, in five patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). Although teicoplanin was eliminated in the peritoneal fluid, relatively little was recovered (6.8 +/- 1.2% of the given dose). The following values were obtained: elimination half-time 102-347 h; total body clearance 4.16-7.38 ml X h-1 X kg-1, peritoneal clearance 0.31-0.37 ml X h-1 X kg-1. Because the elimination of teicoplanin is about four times less in patients undergoing CAPD compared with subjects with normal renal function, the dose of teicoplanin should be reduced appropriately in such cases.

Prolactin-releasing effect of zetidoline, a new neuroleptic agent, in the rat.

The effect of a new neuroleptic agent, zetidoline, 1-(3-chlorophenyl)-3-[2-(3,3-dimethyl-l-azetidinyl)ethyl]imidaz olidin-2-one (ZET), on prolactin release was studied in both male and female rats and compared to that of the classic antipsychotic drugs chlorpromazine and haloperidol. Time-course and dose-effect studies showed that ZET induces a rapid and short lasting increase in plasma prolactin levels, with a significant increase after a dose as low as 0.33 mg/kg, i.p.. The overall patterns of prolactin release appeared to be similar in both sexes but the response was markedly greater in females than in males. The prolactin-releasing effect of ZET was counteracted by apomorphine and L-dopa, which indicates that blockade of dopamine receptors is the basis of its neuroendocrine action. As a prolactin-releaser, ZET was found to be about 5 times as potent as chlorpromazine and about one-ninth as potent as haloperidol.