scholarly journals Single-dose pharmacokinetics of temocillin in plasma and soft tissues of healthy volunteers after intravenous and subcutaneous administration: a randomized crossover microdialysis trial

2020 ◽  
Vol 75 (9) ◽  
pp. 2650-2656 ◽  
Author(s):  
Peter Matzneller ◽  
Perrin Ngougni Pokem ◽  
Arnaud Capron ◽  
Edith Lackner ◽  
Beatrix Wulkersdorfer ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Protein Binding ◽  
Healthy Volunteers ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Soft Tissues ◽  
Therapeutic Option ◽  
Subcutaneous Administration ◽  
Intravenous Route ◽  
Drug Concentrations

Abstract Background The antibiotic temocillin has recently been rediscovered as a promising therapeutic option against MDR Gram-negative bacteria. However, some aspects of the pharmacokinetic (PK) profile of the drug are still to be elucidated: subcutaneous administration of temocillin might be of interest as an alternative to the intravenous route in selected patients. Similarly, information on the penetration of temocillin into human soft tissues is lacking. Objectives To investigate the feasibility and plasma PK of subcutaneous dosing as well as soft tissue PK of temocillin after intravenous administration to healthy volunteers. Methods Eight healthy volunteers received 2 g of temocillin both as intravenous and subcutaneous infusion in a randomized two-period crossover study. Concentration–time profiles of total temocillin in plasma (after both routes) and of unbound temocillin in plasma, muscle and subcutis (only after intravenous dosing) were determined up to 12 h post-dose. Results Subcutaneous dosing caused some infusion site discomfort but resulted in sustained drug concentrations over time with only slightly decreased overall exposure compared with intravenous dosing. Plasma protein binding of temocillin showed concentration-dependent behaviour and was higher than previously reported. Still, unbound drug concentrations in muscle and subcutis determined by microdialysis markedly exceeded those in plasma, suggesting good tissue penetration of temocillin. Conclusions The subcutaneous administration of temocillin is a valid and feasible alternative to intravenous dosing. With the description of plasma protein binding and soft tissue PK of temocillin in healthy volunteers, this study provides important information that adds to the ongoing characterization of the PK profile of temocillin and might serve as input for PK/PD considerations.

Apparent Valproic Acid Neurotoxicity in a Hypoalbuminemic Patient

1993 ◽  
Vol 27 (1) ◽  
pp. 32-35 ◽  
Author(s):  
Barry E. Gidal ◽  
D. Michael Collins ◽  
Brad R. Beinlich
Keyword(s):  
Valproic Acid ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Plasma Concentrations ◽  
Free Fraction ◽  
Laboratory Evaluation ◽  
Neurologic Symptoms ◽  
Drug Concentrations ◽  
Dependent Protein

OBJECTIVE: To report a case of possible neurotoxicity caused by markedly elevated free valproic acid (VPA) plasma concentrations. CASE SUMMARY: A patient with a history of a mixed-type seizure disorder that had been treated with oral VPA 1000 mg four times daily for the previous two years was admitted to the neurology service with the chief complaint of increasing difficulty in walking and involuntary muscle jerks that were new in onset. The patient was hypersomnolent and dysarthric. The total plasma VPA concentration was 103 μg/mL, which was only slightly above the recommended therapeutic range (50–100 μg/mL). VPA free fraction and free plasma concentrations, however, were unexpectedly elevated (26 percent, 26.8 μg/mL, respectively). Further laboratory evaluation revealed a serum albumin concentration of 33 g/L. The neurologic symptoms resolved upon VPA dosage reduction. DISCUSSION: VPA displays concentration-dependent protein binding, resulting in disproportionate increases in drug free fraction with increasing drug concentration. This effect may be magnified in patients with decreased plasma protein-binding capacity. The plasma protein-binding kinetics of VPA are reviewed and the implications for therapeutic drug monitoring are discussed. CONCLUSIONS: It is likely that the markedly elevated free VPA plasma concentrations contributed to the neurologic symptoms displayed in this patient. In patients with decreased albumin concentrations, failure to recognize concentration-dependent protein binding, as well as exclusive reliance upon total drug concentrations, may lead to erroneous pharmacokinetic and therapeutic interpretations.

scholarly journals Artificial Neural Network Modeling for Drug Dialyzability Prediction

2013 ◽  
Vol 16 (5) ◽  
pp. 665 ◽  
Author(s):  
Kahina Daheb ◽  
Mark L. Lipman ◽  
Patrice Hildgen ◽  
Julie J Roy
Keyword(s):  
Neural Network ◽  
Artificial Neural Network ◽  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Neural Network Modeling ◽  
Ann Model ◽  
Drug Concentrations ◽  
Drug Removal ◽  
Artificial Neural

Purpose. The purpose of this study was to develop an artificial neural network (ANN) model to predict drug removal during dialysis based on drug properties and dialysis conditions. Nine antihypertensive drugs were chosen as model for this study. Methods. Drugs were dissolved in a physiologic buffer and dialysed in vitro in different dialysis conditions (UFRmin/UFRmax, with/without BSA). Samples were taken at regular intervals and frozen at -20ºC until analysis. Extraction methods were developed for drugs that were dialysed with BSA in the buffer.  Drug concentrations were quantified by high performance liquid chromatography (HPLC) or mass spectrometry (LC/MS/MS). Dialysis clearances (CLDs) were calculated using the obtained drug concentrations.  An ANOVA with Scheffe’s pairwise adjustments was performed on the collected data in order to investigate the impact of drug plasma protein binding and ultrafiltration rate (UFR) on CLD. The software Neurosolutions® was used to build ANNs that would be able to predict drug CLD (output). The inputs consisted of dialysis UFR and the herein drug properties: molecular weight (MW), logD and plasma protein binding. Results. Observed CLDs were very high for the majority of the drugs studied. The addition of BSA in the physiologic buffer statistically significantly decreased CLD for carvedilol (p= 0.002) and labetalol (p<0.001), but made no significant difference for atenolol (p= 0.100). In contrast, varying UFR does not significantly affect CLD (p>0.025). Multiple ANNs were built and compared, the best model was a Jordan and Elman network which showed learning stability and good predictive results (MSEtesting = 129). Conclusion. In this study, we have developed an ANN-model which is able to predict drug removal during dialysis. Since experimental determination of all existing drug CLDs is not realistic, ANNs represent a promising tool for the prediction of drug CLD using drug properties and dialysis conditions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding

1995 ◽  
Vol 16 (6) ◽  
pp. 443-460 ◽  
Author(s):  
D. M. F. Edwards ◽  
C. Pellizzoni ◽  
H. P. Breuel ◽  
A. Berardi ◽  
M. G. Castelli ◽  
...  
Keyword(s):  
Protein Binding ◽  
Healthy Volunteers ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Oral Doses

scholarly journals Concentrations of Gemifloxacin at the Target Site in Healthy Volunteers after a Single Oral Dose

2004 ◽  
Vol 48 (11) ◽  
pp. 4246-4249 ◽  
Author(s):  
Florian Islinger ◽  
Rene Bouw ◽  
Mathias Stahl ◽  
Edith Lackner ◽  
Petra Zeleny ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Soft Tissue ◽  
Oral Dose ◽  
Healthy Volunteers ◽  
Single Oral Dose ◽  
Soft Tissues ◽  
Therapeutic Option ◽  
The Mean

ABSTRACT Free gemifloxacin concentrations in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were measured by means of in vivo microdialysis to characterize the ability of gemifloxacin to penetrate human soft tissues. Twelve healthy volunteers received a single oral dose of 320 mg of gemifloxacin. The mean areas under the concentration-time curves from 0 to 10 h (AUC0-10) were significantly higher for soft tissue than for unbound gemifloxacin in plasma (P < 0.05). The ratios of the mean AUC0-10 for tissue to the AUC0-10 for free gemifloxacin in plasma were 1.7 ± 0.7 (mean ± standard deviation) for skeletal muscle and 2.4 ± 1.0 for adipose tissue. The AUC0-24 ratios for free gemifloxacin in tissues to the MIC at which 90% of frequently isolated bacteria are inhibited were close to or higher than 100 h. Therefore, based on pharmacokinetic and pharmacodynamic calculations, we conclude that gemifloxacin might be a useful therapeutic option for the treatment of soft tissue infections.

scholarly journals In Vivo Microdialysis Study of the Penetration of Daptomycin into Soft Tissues in Diabetic versus Healthy Volunteers

2008 ◽  
Vol 52 (11) ◽  
pp. 3941-3946 ◽  
Author(s):  
Aryun Kim ◽  
Larry A. Suecof ◽  
Christina A. Sutherland ◽  
Lihong Gao ◽  
Joseph L. Kuti ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Healthy Volunteers ◽  
Healthy Subjects ◽  
Soft Tissues ◽  
In Vivo Microdialysis ◽  
Free Drug ◽  
Target Tissue ◽  
Drug Concentrations ◽  
Complicated Skin

ABSTRACT Daptomycin is approved for the treatment of complicated skin and soft tissue infections, including diabetic wounds of the lower extremities, at a dose of 4 mg/kg of body weight once daily. For such localized tissue infections, drug concentrations in the interstitial space are an important determinant of successful therapy. In the diabetic population, peripheral arterial disease may limit antibiotic penetration into the target tissue. The objective of this study was to describe and compare the pharmacokinetic profiles of daptomycin in the interstitial fluid of soft tissues in diabetic and healthy volunteers by using in vivo microdialysis. Twelve subjects (six diabetic and six healthy) received a single 4-mg/kg dose of daptomycin intravenously. Samples of plasma and tissue were simultaneously collected over 24 h. Diabetic and healthy groups were matched in mean age (±10 years), gender ratio, mean weight (±10 kg), and creatinine clearance rate (±20 ml/min/1.73 m2). Pharmacokinetic parameters for plasma were similar between groups (P > 0.05). The mean peak drug concentrations ± standard deviations in tissue were 4.3 ± 3.3 μg/ml and 3.8 ± 1.4 μg/ml for diabetic and healthy subjects, respectively. The degree of tissue penetration, defined as the ratio of the area under the free drug concentration-time curve for tissue to that for plasma, was 0.93 ± 0.61 for diabetic subjects and 0.74 ± 0.09 for healthy subjects (P = 0.46). Daptomycin at 4 mg/kg penetrated well into the soft tissue, reaching concentrations approximately 70 to 90% of those of the free drug in plasma. Moreover, these free, bioactive concentrations in tissue exceeded the MICs for staphylococci and streptococci over the 24-h dosing interval.

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