Population pharmacokinetics of teicoplanin and attainment of pharmacokinetic/pharmacodynamic targets in adult patients with haematological malignancy (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 Antimicrobial Chemotherapy, 2017
Objectives: To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens. Methods: This was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics V R. Target total and unbound trough concentrations were !20 and !1.5 mg/L, respectively. Results: Thirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CL CR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration-time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CL CR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CL CR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated. Conclusions: Standard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CL CR and serum albumin concentration are important considerations for appropriate dosing.
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
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.
Antimicrobial agents and chemotherapy, 2017
Objectives: To explore the following aspects of teicoplanin use in patients with haematological malignancy: early attainment of target trough concentrations with current high dose teicoplanin regimens; variability in unbound teicoplanin fractions; factors associated with observed total and unbound trough concentrations; efficacy and toxicity; and renal function estimation.Methods: This was a single-centre, prospective study. Trough samples were taken on Days 3, 4, 7 and 10. Total and unbound teicoplanin concentrations were determined using validated HPLC methods. Regression analyses were used to identify factors associated with trough concentration.Results: Thirty teicoplanin-treated adults with haematological malignancy were recruited. Despite higher than conventional dosages, the proportions of patients with a trough concentration ≥20 mg/L at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations...
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.
Population pharmacokinetic study of teicoplanin in severely neutropenic patients
Antimicrobial agents and chemotherapy, 1996
The teicoplanin pharmacokinetics (PK) of 30 febrile and severely neutropenic patients (polymorphonuclear count, < 500/mm3) with hematologic malignancies were compared with those determined for five healthy volunteers (HV). Neutropenic patients were given piperacillin combined with amikacin, and teicoplanin was added to the regimen the day fever developed in patients suspected of having a staphylococcal infection or 48 h later. Teicoplanin was given intravenously at a dosage of 6 mg/kg of body weight at 0, 12, and 24 h and once a day thereafter. Five to eleven blood samples per patient were collected. Teicoplanin concentrations were measured by liquid chromatography. A bicompartmental model was fitted to the data by a nonlinear mixed-effect-model approach. Multiple-linear regression analysis was applied in an attempt to correlate PK parameters to nine covariates. The mean trough concentrations of teicoplanin 48 h after the onset of treatment and 24 h after the last injection (last...
European Journal of Clinical Microbiology & Infectious Diseases, 2016
We evaluated the clinical efficacy and safety of teicoplanin according to the pharmacokinetics (PK) therapeutic level achieved in patients with renal dysfunction. Target trough concentration (C min) was ≥15-30 μg/ml which has been recommended in patients with normal renal function. Adult patients (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m 2) who were treated by teicoplanin were included in the study. We adopted two types of regimen for the initial 3 days: the conventional regimen, and the enhanced loading regimen (10 mg/kg twice daily on the 1st day, followed by 6.7-10 mg/kg once daily for the 2nd and 3rd days]. Two hundred and eighty-eight patients were evaluated for safety, and 106 patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were evaluated for clinical efficacy. A significantly higher success rate was obtained in patients who achieved the target initial C min compared with those that did not (75.0 % vs 50.0 %, p = 0.008). In a multivariate analysis, initial C min ≥15 μg/ml was an independent factor for clinical success (adjusted odds ratio: 4.20, 95 % confidence interval: 1.34-13.15). In patients with 15-30 μg/ml of maximal C min during therapy, nephrotoxicity occurred in 13.1 %, and hepatotoxicity in 2.6 %, and these incidences were not significantly higher compared with those patients with <15 μg/ml. In conclusion, achievement of C min of 15-30 μg/ml without delay was necessary to improve clinical outcomes for the treatment by teicoplanin in patients with renal dysfunction. Further investigation is required regarding the optimal loading regimen to achieve the therapeutic levels in those patients.
High-dose regimen to achieve novel target trough concentration in teicoplanin
Journal of Infection and Chemotherapy, 2014
In the treatment of severe MRSA infections such as endocarditis, more than 20 mg/L of plasma trough concentration (C min) is recommended for teicoplanin; however, in the treatment of common MRSA infections, recommended C min remains more than 10 mg/L. In this study, we set C min as 15e30 mg/L to obtain a favorable clinical outcome in the treatment of common MRSA infections, and investigated the optimal loading regimen that achieved the target C min in patients with normal renal function. Seventyeight patients received the high-dose regimen A (6 mg/kg every 12-h for initial two days) and 60 patients received the high-dose regimen B (the first five loading doses of 10e12 mg/kg at 12-h intervals for initial three days, followed by 6 mg/kg once daily). The mean C min on the 4th day was 13.7 AE 5.3 mg/L in regimen A, and 20.0 AE 6.6 mg/L in regimen B (P < 0.001), and the proportion of patients achieving the 15 e30 mg/L was 25.6% and 68.3% (P < 0.001). Clinical response at end-of treatment were 66.7% and 85.0% (P ¼ 0.014). The patients of initial C min with !15 mg/L had tended to be higher clinical response than those with <15 mg/L (80.9% vs 68.6%, P ¼ 0.084). There were no significant differences in the occurrence of adverse effects in regimen A and B (nephrotoxicity; 1.3% vs 3.3%, P ¼ 0.413, hepatotoxicity; 5.1% vs 3.3%, P ¼ 0.608). In conclusion, to obtain C min 15e30 mg/L, the first five loading doses of 10e12 mg/kg at 12-h intervals was required in patients with normal renal function.