scholarly journals Comparative Assessment of Tedizolid Pharmacokinetics and Tissue Penetration between Diabetic Patients with Wound Infections and Healthy Volunteers via In Vivo Microdialysis

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Sean M. Stainton ◽  
Marguerite L. Monogue ◽  
Arlinda Baummer-Carr ◽  
Ashley K. Shepard ◽  
James F. Nugent ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Subcutaneous Tissue ◽  
Extracellular Fluid ◽  
Pharmacokinetic Parameters ◽  
Diabetic Patients ◽  
Tissue Penetration ◽  
Time Curve ◽  
Dosing Interval ◽  
Concentration Time

ABSTRACT Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200 mg every 24 h for 3 doses to achieve steady state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the third dose, 12 blood and 14 dialysate fluid samples were collected over 24 h to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean ± standard deviation (SD) tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were as follows: maximum concentration (C max), 1.5 ± 0.5 versus 2.7 ± 1.1 mg/liter (P = 0.005); time to C max (T max) (median [range]), 5.9 (1.2 to 8.0) versus 2.5 (2.0 to 3.0 h) (P = 0.003); half-life (t1/2), 9.1 ± 3.6 versus 8.9 ± 2.2 h (P = 0.932); and plasma area under the concentration-time curve for the dosing interval (AUC p ), 18.5 ± 9.7 versus 28.7 ± 9.6 mg · h/liter (P = 0.004). The tissue area under the concentration-time curve (AUC t ) for the dosing interval was 3.4 ± 1.5 versus 5.2 ± 1.6 mg · h/liter (P = 0.075). Tissue penetration median (range) was 1.1 (0.3 to 1.6) versus 0.8 (0.7 to 1.0) (P = 0.351). Despite lower plasma C max and delayed T max values for patients with DFI relative to healthy volunteers, the penetration into and exposure to tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200 mg once-daily regimen are suitable for further study in treatment of DFI.

scholarly journals Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Marguerite L. Monogue ◽  
Sean M. Stainton ◽  
Arlinda Baummer-Carr ◽  
Ashley K. Shepard ◽  
James F. Nugent ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Subcutaneous Tissue ◽  
Free Drug ◽  
Free Time ◽  
Pharmacokinetic Parameters ◽  
Diabetic Patients ◽  
Total Plasma ◽  
Tissue Penetration ◽  
Gram Negative ◽  
Time Zero

ABSTRACT Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients (n = 10) with DFI were compared with those in healthy volunteers (n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (C max), 55.2 μg/ml (range, 40.9 to 169.3 μg/ml); half-life (t 1/2), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC0–8), 191.6 μg · h/ml (range, 147.1 to 286.6 μg · h/ml). The median AUC for tissue (AUCtissue; where AUCtissue was the AUC0–8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (fAUCplasma) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 μg/ml (the Pseudomonas aeruginosa susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: C max, 14.2 μg/ml (range, 7.6 to 64.2 μg/ml); t 1/2, 2.0 h (range, 0.7 to 2.4 h); and AUC0–8, 27.1 μg · h/ml (range, 15.0 to 70.0 μg · h/ml). The AUCtissue (where AUCtissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/fAUCplasma for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: C max, 91.5 μg/ml (range, 65.7 to 110.7 μg/ml); t 1/2, 1.9 h (range, 1.6 to 2.1 h); and AUC0–8, 191.3 μg · h/ml (range, 118.1 to 274.3 μg · h/ml). The median AUCtissue/fAUCplasma was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 μg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: C max, 17.5 μg/ml (range, 15.4 to 27.3 μg/ml); t 1/2, 0.7 h (range, 0.6 to 0.8 h); and AUC0–8, 22.2 μg · h/ml (range, 19.2 to 36.4 μg · h/ml). The AUCtissue/fAUCplasma for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.)

scholarly journals Tissue Penetration and Pharmacokinetics of Tigecycline in Diabetic Patients with Chronic Wound Infections Described by Using In Vivo Microdialysis

2010 ◽  
Vol 54 (12) ◽  
pp. 5209-5213 ◽  
Author(s):  
Catharine C. Bulik ◽  
Dora E. Wiskirchen ◽  
Ashley Shepard ◽  
Christina A. Sutherland ◽  
Joseph L. Kuti ◽  
...  
Keyword(s):  
Steady State ◽  
Protein Binding ◽  
Subcutaneous Tissue ◽  
Diabetic Patients ◽  
Tissue Penetration ◽  
Tissue Concentrations ◽  
Time Curve ◽  
The Mean

ABSTRACT Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent in vivo recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 ± 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC0-24) were 2.65 ± 0.33, 2.52 ± 1.15, and 2.60 ± 1.02 μg·h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (P = 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 ± 0.02 μg/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue fAUC/plasma fAUC) were 99% in the thigh and 100% in the wound (P = 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity.

scholarly journals Domestic Cat Model for Predicting Human Nucleoside Analogue Pharmacokinetics in Blood and Seminal Plasma

2001 ◽  
Vol 45 (7) ◽  
pp. 2173-2176 ◽  
Author(s):  
Holly L. Jordan ◽  
Arlene S. Pereira ◽  
Myron S. Cohen ◽  
Angela D. M. Kashuba
Keyword(s):  
Seminal Plasma ◽  
Nucleoside Analogue ◽  
Domestic Cat ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Feline Model ◽  
Cat Model ◽  
Male Genital

ABSTRACT To establish whether a feline model can predict nucleoside analogue behavior in human semen, zidovudine (ZDV) and lamivudine (3TC) pharmacokinetic parameters (PKs) were determined in the blood and seminal plasma of healthy cats. Our results show considerable similarity in ZDV and 3TC PKs between cats and humans. As in humans, ZDV and 3TC tend to accumulate in feline seminal plasma. Area under the blood plasma concentration-time curve was predictive of seminal plasma excretion. The felid model offers a unique in vivo experimental alternative for investigating the pharmacokinetics of nucleoside analogues in the male genital tract.

scholarly journals Penetration of Linezolid into Soft Tissues of Healthy Volunteers after Single and Multiple Doses

2005 ◽  
Vol 49 (6) ◽  
pp. 2367-2371 ◽  
Author(s):  
Pejman Dehghanyar ◽  
Cornelia Bürger ◽  
Markus Zeitlinger ◽  
Florian Islinger ◽  
Florian Kovar ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Soft Tissues ◽  
In Vivo Microdialysis ◽  
Time Curve ◽  
Concentration Time ◽  
Multiple Doses ◽  
Muscle Tissues ◽  
Subcutaneous Adipose ◽  
Free Plasma

ABSTRACT The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously. All following doses were self-administered orally. The tissue penetration of linezolid was assessed by use of in vivo microdialysis. In the single-dose experiments the ratios of the area under the concentration-time curve from 0 to 8 h (AUC0-8) for tissue to the AUC0-8 for free plasma were 1.4 ± 0.3 (mean ± standard deviation) and 1.3 ± 0.4 for subcutaneous adipose and muscle tissue, respectively. After multiple doses, the corresponding mean ratios were 0.9 ± 0.2 and 1.0 ± 0.5, respectively. The ratios of the AUC from 0 to 24 h (AUC0-24) for free linezolid in tissues to the MIC were between 50 and 100 for target pathogens with MICs between 2 and 4 mg/liter. In conclusion, the present study showed that linezolid penetrates rapidly into the interstitial space fluid of subcutaneous adipose and skeletal muscle tissues in healthy volunteers. On the basis of pharmacokinetic-pharmacodynamic calculations, we suggest that linezolid concentrations in soft tissues can be considered sufficient to inhibit the growth of many clinically relevant bacteria.

scholarly journals Effects of Silymarin on the In Vivo Pharmacokinetics of Simvastatin and Its Active Metabolite in Rats

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1666
Author(s):  
Ying Li ◽  
Yin Wu ◽  
Ya-Jing Li ◽  
Lu Meng ◽  
Cong-Yang Ding ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Compartmental Model ◽  
Elimination Rate ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Simultaneous Quantification ◽  
Concentration Time ◽  
Significant Difference ◽  
In Vivo Pharmacokinetics

Herein, the effect of silymarin pretreatment on the pharmacokinetics of simvastatin in rats was evaluated. To ensure the accuracy of the results, a rapid and sensitive UPLC–MS/MS method was established for simultaneous quantification of simvastatin (SV) and its active metabolite simvastatin acid (SVA). This method was applied for studying the pharmacokinetic interactions in rats after oral co-administration of silymarin (45 mg/kg) and different concentrations of SV. The major pharmacokinetic parameters, including Cmax, tmax, t1/2, mean residence time (MRT), elimination rate constant (λz) and area under the concentration-time curve (AUC0–12h), were calculated using the non-compartmental model. The results showed that the co-administration of silymarin and SV significantly increased the Cmax and AUC0–12h of SVA compared with SV alone, while there was no significant difference with regards to Tmax and t1/2. However, SV pharmacokinetic parameters were not significantly affected by silymarin pretreatment. Therefore, these changes indicated that drug-drug interactions may occur after co-administration of silymarin and SV.

scholarly journals A Rapid and Sensitive UHPLC-MS/MS Method for Determination of 2, 3, 8-Trimethylellagic, a Potent Active Compound from Sanguisorba officinalis L., and Its Application in the Pharmacokinetic Study within Thrombocytopenia Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yuqing Wang ◽  
Jianming Wu ◽  
Yunxia Li ◽  
Jing Yang ◽  
Long Wang ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Maximum Concentration ◽  
High Performance ◽  
Internal Standard ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Relative Standard ◽  
Plasma Concentration Time Curve

To investigate the pharmacokinetics of 2, 3, 8-trimethylellagic (TMEA) in rats in vivo and determine the possible effects of the pathological conditions and compatibility, a rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for quantitative determination was developed. TMEA and Artemetin (internal standard, IS) were separated on an Acquity Shim-pack GIST column with a total running time of 7 min using gradient elution at a flow rate of 0.3 mL/min. The intraday and interday relative standard deviations were <9.50%, and the relative error of accuracy was between −5.70% and 2.96%. The calibration curve of TMEA demonstrated good linearity with r2 = 0.9996, with the average recovery changing from 94.77% to 102.47% and the matrix effect from 93.16% to 100.15%. Compared with the normal group, the area under the plasma concentration-time curve from time 0 to the last time of quantifiable concentration (AUC(0 − t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0 − ∞)), and the maximum concentration (Cmax) of TMEA increased, whereas the time of maximum concentration (Tmax) and apparent clearance (CL/F) remarkably decreased in the TMEA group. With significantly reduced CL/F, AUC(0 − t), AUC(0 − ∞), and Cmax for TMEA were increased approximately one time after combining with 3, 7-Di-O-methylducheside A (DOMA). AUC(0 − t) and Cmax for TMEA in the 2, 3, 8-trimethylellagic-3, 8-dimethoxyellagic acid-2-oxyglucoside (TMEA-DMAG) group were significantly lower than that in the TMEA group with clearly prolonged Tmax and increased CL/F. These findings indicate that the changes in the pharmacokinetic parameters of TMEA may be caused by pathological and combination conditions.

Calibration of a Wearable Glucose Sensor

1992 ◽  
Vol 15 (1) ◽  
pp. 55-61 ◽  
Author(s):  
F.J. Schmidt ◽  
A.L. Aalders ◽  
A.J.M. Schoonen ◽  
H. Doorenbos
Keyword(s):  
Blood Glucose ◽  
Healthy Volunteers ◽  
Glucose Oxidase ◽  
Glucose Sensor ◽  
Subcutaneous Tissue ◽  
The Body ◽  
Diabetic Patients ◽  
Type I

Calibration of glucose sensors proved difficult for electrodes with immobilized glucose-oxidase. The correlation between the sensitivity of the electrodes in vitro and in vivo appeared to be poor. We developed a new type of glucose sensor, based on a microdialysis system, in which an oxygen electrode is used as detector outside the body and the enzyme glucose-oxidase dissolved in water is used as a dynamic selector. The enzyme solution is pumped through a hollow fiber placed subcutaneously, before the fluid passes the detector. The glucose sensor was tested in the subcutaneous abdominal tissue of 12 healthy volunteers and 12 type I diabetic patients. Blood glucose was clamped at two levels to permit a two-point calibration of the sensor in vivo. These values correlated well with the in vitro calibration factors (r=0.949). In subcutaneous tissue the sensor measures 43 ± 9% of the blood glucose value, using the in vitro calibration factor. No differences were detected between healthy volunteers and diabetic patients.

scholarly journals Simplified Equations Using Two Concentrations To Calculate Area under the Curve for Antimicrobials with Concentration-Dependent Pharmacodynamics: Daptomycin as a Motivating Example

2014 ◽  
Vol 58 (6) ◽  
pp. 3162-3167 ◽  
Author(s):  
Manjunath P. Pai ◽  
Alessandro Russo ◽  
Andrea Novelli ◽  
Mario Venditti ◽  
Marco Falcone
Keyword(s):  
Healthy Volunteers ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Antimicrobial Agents ◽  
Population Pharmacokinetic ◽  
Good Precision ◽  
Time Data ◽  
Time Curve ◽  
Dosing Interval ◽  
Concentration Time

ABSTRACTThe effects of several antimicrobial agents are predicted by the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). Peak (Cp) and trough (Ct) concentrations are often measured clinically as surrogates of AUC because actual computation of AUC from 1 or 2 samples requires sophisticated mathematical methods. Given that the effects of daptomycin are predicted by AUC/MIC, our objective was to compare simple equation calculated AUC based onCpandCtto model integrated AUC. A standard population pharmacokinetic model was used to simulate 5,000 daptomycin concentration-time profiles after 5 doses of 6 mg/kg of body weight/day (0.5-h infusions). The AUC for the 24-h period was computed by integration and by equations with 110Cp-Ctcombination pairs. TheCptime points were in 15-min increments between 0.5 h and 3 h andCtin 15-min increments within an hour of the end of the dosing interval for each dose. The precision and bias of the calculated AUC relative to the integrated AUC were determined to identifyCp-Ctpairs associated with the lowest bias and highest precision. The equations were further validated using two daptomycin concentration-time data sets from healthy volunteers and critically ill patients. The precision and bias of calculated AUC were based primarily onCp, and use of a daptomycinCp1.5 h to 3 h from the start of infusion was associated with a bias of <10% and anR2of >0.95. Data from the healthy volunteers and critically ill patients also demonstrated declining bias with use ofCp≥1.5 h from the start of infusion with relatively good precision. Simplified equations using a daptomycinCpapproximately 2 h from the start of infusion and aCtwithin an hour of the end of the dosing interval should yield precise and unbiased estimates of daptomycin AUC.

scholarly journals Continuous versus Short-Term Infusion of Cefuroxime: Assessment of Concept Based on Plasma, Subcutaneous Tissue, and Bone Pharmacokinetics in an Animal Model

2014 ◽  
Vol 59 (1) ◽  
pp. 67-75 ◽  
Author(s):  
Mikkel Tøttrup ◽  
Bo M. Bibby ◽  
Tore F. Hardlei ◽  
Mats Bue ◽  
Sigrid Kerrn-Jespersen ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Subcutaneous Tissue ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Tissue Penetration ◽  
Short Term ◽  
Concentration Data ◽  
Time Curve ◽  
Infusion Group ◽  
Tissue Pharmacokinetic

ABSTRACTThe relatively short half-lives of most β-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two-compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. For short-term infusion, the tissue penetration ratios were 0.97 (95% confidence interval [CI], 0.67 to 1.39), 0.61 (95% CI, 0.51 to 0.73), and 0.45 (95% CI, 0.36 to 0.56) for subcutaneous tissue, cancellous bone, and cortical bone, respectively. For continuous infusion, they were 0.53 (95% CI, 0.33 to 0.84), 0.38 (95% CI, 0.23 to 0.57), and 0.27 (95% CI, 0.13 to 0.48) for the same tissues, respectively. The absolute areas under the concentration-time curve were also lower in the continuous infusion group. Nevertheless, a significantly longer time with concentrations above the MIC was found for continuous infusion up until MICs of 4, 2, 2, and 0.5 μg/ml for plasma and the same three tissues mentioned above, respectively. For drugs with a short half-life, like cefuroxime, continuous infusion seems to be favorable compared to short-term infusion; however, incomplete tissue penetration and high MIC strains may jeopardize the continuous infusion approach.

Sign in / Sign up

Export Citation Format

Share Document