Pharmacokinetic Profile of Two Different Administration Schemes of Teicoplanin: Single 400mg Intravenous Dose vs Double-Refracted 200mg Intramuscular Doses in Healthy Volunteers (original) (raw)
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Pharmacokinetic Profile of Two Different Administration Schemes of Teicoplanin
Clinical Drug Investigation, 1999
Objective: To evaluate the pharmacokinetic appropriateness of a possible switch in dosing schedule for outpatients after hospital discharge, i.e. the bioequivalence of a single 400mg intravenous daily dose versus double-refracted 200mg intramuscular doses. Subjects and Methods: This study was conducted in 10 normal healthy volunteers using a two-way randomised, open-label, two-period crossover design. Each subject received two different drug regimens of teicoplanin: a single 400mg intravenous daily dose versus double daily refracted 200mg intramuscular doses. Teicoplanin serum concentrations were analysed by means of a fluorescence polarisation immunoassay system in samples collected for up to 72 hours after each regimen. Pharmacokinetic evaluations were performed by means of a 3compartment open model with first-order elimination using the WinNonlin pharmacokinetic software package. Results: Teicoplanin peak serum concentrations were 97.96 ± 23.49 mg/L, 3.47 ± 1.00 mg/L and 6.99 ± 1.52 mg/L after a single 400mg intravenous dose, and after the first and second intramuscular administrations, respectively. The trough level at 24 hours (C24)was 4.55 ± 1.04 mg/L after the 400mg intravenous dose, and 6.67 ± 1.75 mg/L after double 200mg intramuscular doses. The ratio between C24 intramuscular and intravenous treatment was 1.46 ± 0.17. Total body exposure (AUC0-∞) was 474.22 ± 111.77 mg/L • h post-intravenous dose, and 424.84 ± 113.53 mg/L • h post-intramuscular doses. Intramuscular bioavailability suggested substantial bioequivalence with intravenous administration (89.58 ± 14.35%). Dose-normalised data indicated that the intersubject variability was mainly related to interindividual differences in bodyweight. Conclusion: These findings indicated that a total daily dosage of teicoplanin 400mg administered in two refracted doses by the intramuscular route could produce steady-state trough levels that are even higher than those achievable after once-daily intravenous administration during maintenance treatment. Since the time during which the serum concentration persists above MIC is actually thought to be a possible major determinant for the outcome of treatment with glycopeptides, this intramuscular schedule could enhance the pharmacokinetic exposure CLINICAL PHARMACOKINETICS
Journal of Pharmaceutical Sciences, 1991
0 Pharmacokinetics, bioavailability, and local tolerance (at the site of intramuscular administration) of a new formulation of teicoplanin (400 mg/3 mL) were investigated in 24 normal, healthy, male volunteers. A single dose of 6 mglkg was administered intravenously and intramuscularly using a randomized crossover design. Volunteers and investigator were blinded as to the route of administration; placebo was administered by the other route. Blood and urine samples were collected for 21 days and were analyzed for microbiological activity. The median (range) pharmacokinetic parameters of teicoplanin following single-dose iv administration were as follows: steady-state volume of distribution of 1.6 (1.2-2.8) Ukg; total clearance of 10.2 (8.G15.1) mUh/kg; renal clearance of 10.0 (7.9-1 3.8) mUh/kg; and terminal disposition half-life of 168 (1 1 1-278) h. Following single-dose im administration, significantly more subjects complained of pain following administration of teicoplanin (58%) compared with placebo (4%). Teicoplanin was completely absorbed with a median (range) peak serum concentration of 12.3 (6.6-37.5) @/mL occurring at a median (range) time of 4.1 (0.7-6.1) h. Since the 90% confidence interval for the ratio of areas under the serum concentrationtime curve falls within the range of 80 to 120%, the extent of systemic absorption of teicoplanin following im administration is equivalent to that following iv administration. curve were calculated using the linear trapezoidal rule up to the last
Clinical Microbiology and Infection, 2017
Objectives: To describe the population pharmacokinetics of teicoplanin in adult patients with haematological malignancies receiving higher than standard doses, and to perform Monte Carlo simulations to determine dosing regimens associated with optimal teicoplanin concentrations. Methods: This was a hospital-based clinical trial (EudraCT 2013e004535e72). Nine blood samples were collected on Day 3, plus single trough samples on Days 7 and 10, and 24 and 48 hours after the last dose. Teicoplanin minimum inhibitory concentrations were determined for Gram-positive isolates from study patients. Population pharmacokinetic analyses and Monte Carlo dosing simulations were undertaken using Pmetrics. Results: Thirty adult haematological malignancy patients were recruited with a mean (SD) loading dose, age, total body weight, and creatinine clearance of 9.5 (1.9) mg/kg, 63 (12) years, 69.1 (15.8) kg, and 72 (41) mL/min, respectively. A three-compartment linear pharmacokinetic model best described the teicoplanin concentration data. Covariates supported for inclusion in the final model were creatinine clearance for clearance and total body weight for volume of the central compartment. The median (IQR) area under the concentration-time curve from 48 to 72 hours (AUC 48e72h) was 679 (319) mg.h/L. There was a strong correlation between the AUC 48e72h and trough concentration at 72 hours (Pearson correlation coefficient 0.957, p <0.001). Dosing simulations showed that administration of five loading doses at 12-hourly intervals, stratified by total body weight and creatinine clearance, increased the probability of achieving target concentrations within 72 hours. Conclusions: To increase the number of patients achieving optimal teicoplanin concentrations an individualized dosing approach, based on body weight and creatinine clearance, is recommended.
European Journal of Pharmaceutical Sciences, 1998
The population pharmacokinetics of teicoplanin in plasma and tonsillar tissue in children was determined following intramuscular administration. Thirty seven patients in all received either a single 5 mg / kg dose; 2 doses of 5 mg / kg, 12 h apart; 3 doses of 5 mg / kg, 12 h apart; or, a single 10 mg / kg dose. Limited data, comprising a maximum of 2 blood samples and 1 tonsillar sample were taken from each patient, with the maximum time being 48 h after the first dose of teicoplanin (in the 335 mg / kg dosing schedule). All plasma data were analyzed simultaneously by a maximum likelihood method employing a modified EM algorithm. A first-order absorption, one-compartment disposition model was fitted to the data. Mean parameter values (with lower and upper 95% confidence intervals) were: 21 21 21 clearance / bioavailability, 0.024 L h kg (0.020-0.027); volume of distribution / bioavailability, 0.61 L kg (0.54-0.70); absorption 21 rate constant, 0.43 h (0.31-0.61). A first-order transfer model for distribution of teicoplanin between plasma and tonsillar tissue was fitted to the tonsil data. The mean parameter values (95% confidence intervals) were: transfer rate constant between plasma and tonsils 21 21 0.49 h (0.35-0.67); transfer rate constant between tonsils and plasma 0.73 h (0.52-1.03)
BMC Clinical Pharmacology, 2020
Background: A trough concentration (C min) ≥20 μg/mL of teicoplanin is recommended for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. However, sufficient clinical evidence to support the efficacy of this target C min has not been obtained. Even though the recommended high C min of teicoplanin was associated with better clinical outcome, reaching the target concentration is challenging. Methods: Pharmacokinetics and adverse events were evaluated in all eligible patients. For clinical efficacy, patients who had bacteremia/complicated MRSA infections were analyzed. The primary endpoint for clinical efficacy was an early clinical response at 72-96 h after the start of therapy. Five dosed of 12 mg/kg or 10 mg/kg was administered as an enhanced or conventional high loading dose regimen, respectively. The C min was obtained at 72 h after the first dose. Results: Overall, 512 patients were eligible, and 76 patients were analyzed for treatment efficacy. The proportion of patients achieving the target C min range (20-40 μg/mL) by the enhanced regimen was significantly higher than for the conventional regimen (75.2% versus 41.0%, p < 0.001). In multivariate analysis, C min ≥ 20 μg/mL was an independent factor for an early clinical response (odds ratio 3.95, 95% confidence interval 1.25-12.53). There was no significant difference in the occurrence of adverse events between patients who did or did not achieve a C min ≥ 20 μg/mL. Conclusion: A target C min ≥ 20 μg/mL might improve early clinical responses during the treatment of difficult MRSA infections using 12 mg/kg teicoplanin for five doses within the initial 3 days.
Intensive Care Medicine, 2003
Objective: To compare the pharmacokinetic parameters of sequential intravenous and subcutaneous teicoplanin in the plasma of surgical intensive care unit patients. Design and setting: Prospective, randomized, crossover study in the surgical ICU of a university hospital. Patients: Twelve patients with a suspected nosocomial infection, a serum albumin level higher than 10 g/l, body mass index less than 28 kg/m 2 , and estimated creatinine clearance higher than 70 ml/min. Interventions: Teicoplanin was first administered intravenously as a loading dose of 6 mg/kg per 12 h for 48 h and then continued at a daily dose of 6 mg/kg. On the fourth day patients were randomized in two groups according to the order of the pharmacokinetic studies. Measurements and results: Serial plasma samples were obtained to measure teicoplanin levels. Compared with a 30-min intravenous infusion the peak concentration of teicoplanin after a 30-min subcutaneous administration occurred later (median 7 h, range 5-18) and was lower (16 µg/ml, 9-31; vs. 73, 53-106). Despite large and unpredictable interindividual differences no significant differences between subcutaneous and intravenous administration were observed in: trough antibiotic concentrations (10 µg/ml, 6-24; vs. 9, 5-30), the area under the teicoplanin plasma concentration vs. time curves from 0 to 24 h (AUC 0-24h ; 309 µg/ml per minute, 180-640; vs. 369, 171-955), the proportion of the dosing interval during which the plasma teicoplanin concentration exceeded 10 µg/ml (96%, 0-100%; vs. 79%, 13-100%), and the ratio of AUC 0-24h to 10 (77, 45-160; vs. 92, 43-239). Conclusions: In critically ill patients without vasopressors a switch to the subcutaneous teicoplanin after an initial intravenous therapy seems to give comparable pharmacodynamic indexes of therapeutic success.
In vitro activity and human pharmacokinetics of teicoplanin
Antimicrobial Agents and Chemotherapy, 1984
The in vitro activity of teicoplanin, a new antibiotic related to vancomycin, was determined against 456 gram-positive cocci. The activity of teicoplanin in comparison with that of vancomycin was similar against staphylococci but 4 to 40 times higher against enterococci and beta-hemolytic and viridans streptococci. The single-dose pharmacokinetics of teicoplanin were studied in six healthy volunteers after administration of 3 and 6 mg/kg intravenously and of 3 mg/kg intramuscularly. The kinetic parameters after both intravenous doses were very similar. The curves for concentration in plasma for the 3- and 6-mg/kg intravenous doses showed a triexponential decline with elimination half-lives of 47.3 and 44.1 h, respectively. The percentages of the doses recovered in urine (0 to 102 h) were 43.2 and 44.1%, respectively. The areas under the plasma curves were dose related: 256.5 and 520.9 micrograms/h per ml, respectively. The bioavailability of teicoplanin after injection of 3 mg/kg in...
Pharmacokinetics of teicoplanin in critically ill patients with various degrees of renal impairment
Antimicrobial Agents and Chemotherapy, 1987
The pharmacokinetics of teicoplanin were studied in 15 adult patients in the acute phase of severe infections caused by gram-positive cocci. All the subjects were given a daily intravenous bolus dose of 6 mg of teicoplanin kg-l (body weight). The pharmacokinetic study was performed over a 48-h period after injection 4. The subjects were categorized according to their mean creatinine clearances (ml min-1 kg-') during the study period: group 1 (n = 3), >1.6; group 2 (n = 6), 0.8 to 1.6; and group 3 (n = 6), 0.15 to 0.8. Mean concentrations of teicoplanin in serum at 1, 24, and 48 h were 33 8, 9 + 3, and 6 2.5 ,ug ml-l, respectively. The mean half-lives of the concentration-time curve from 12 to 48 h were 28 4, 44 ± 24, and 48 ± 14 h in groups 1, 2, and 3, respectively (group 3 versus group 1: P < 0.05). The mean area under the serum concentration-time curve from time zero to 24 h was 344 ± 92 mg. h-liter-', and the mean hybrid volume of distribution was 1.09 ± 0.46 liter. kg-'. These values were similar for the three groups, with a trend for larger areas under the curve in group 3. Creatinine clearance correlated directly with the total body clearance of teicoplanin (r = 0.70) and with the renal clearance of teicoplanin (r = 0.82). However, in critically ill patients, the wide interindividual variations in pharmacokinetic parameters are more relevant than those related to the variations in renal function when creatinine clearance is above 0.30 ml min-' kg-'. We concluded that, in such conditions, monitoring of concentrations of teicoplanin in serum is mandatory.
Pharmacokinetics of Teicoplanin in An ICU Population of Children and Infants
Pharmaceutical Research, 2004
Purpose. Better dosing is needed for antibiotics, including teicoplanin (TEI), to prevent emergence of resistant bacterial strains. Here, we assess the TEI pharmacokinetics (PK) related to a 10 mg/l minimum inhibitory concentration (MIC) target in ICU children (4 to 120 months; n ס 20) with gram+ infections. Methods. Standard administration of TEI was with three 10 mg/kg Q12h, loading infusions, and maintainance with 10 mg/kg or 15 mg/kg Q24h. During maintenance, 9 samples (3/day) were collected per patient and the PK analyzed with Nonlinear Mixed Effects Model (NONMEM). Results. Thirty-five percent of concentrations in older children (Ն2 months) vs. 8% in younger infants (<12 months) were below the target MIC. The global bicompartmental population PK parameters were [mean (interindividual CV%)] CL ס 0.23 l/h [72%], V ס 3.16 l [58%], k 12 ס 0.23 h −1 , and k 21 ס 0.04 h −1 . Two PK subpopulations were identified. The older children had CL ס 0.29 [23%] l/h, V ס 3.9 l and the younger infants, CLס 0.09 [37%] l/h, V ס 1.05 l. Residual error was reduced from 52% to around 30% in the final models. Conclusions. Older children in the ICU may require relatively higher doses of teicoplanin. However, a study in a larger population is needed.
Data obtained as part of our routine drug monitoring of teicoplanin therapy (therapeutic drug monitoring, TDM) in adult critically ill patients being treated for suspected or documented Grampositive multiresistant infections were assessed, retrospectively. Data were available for 202 patients (146 male, 56 female; age 58 ± 16 years) with a total number of 829 teicoplanin trough plasma levels (C min ) assessed. The percentage of patients with adequate teicoplanin concentrations (C min ≥ 10 mg/L) during the treatment period substantially increased from 3.2% on day 2, to 35%, 70%, 90% and ∼95% on days 4, 7, 11 and 15, respectively. The findings suggest that optimal teicoplanin therapy was achieved only after at least 4, and probably 7, days of therapy in most cases, mainly because of a failure to use an appropriate loading dose. Among the possible causes for the reluctance to use a loading dose, concern over the potential nephrotoxicity of teicoplanin was a major factor. We conclude that loading doses of teicoplanin (6 mg/kg every 12 h for at least three doses) must be considered mandatory in all patients, regardless of their renal function, to enable optimal drug concentrations to be achieved early in the treatment period. Subsequently, TDM is important to ensure that dose regimens are optimized to the individual requirements of the patients.