scholarly journals Synovial and Systemic Pharmacokinetics of Florfenicol and PK/PD Integration against Streptococcus suis in Pigs

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 109
Author(s):  
Zoltán Somogyi ◽  
Patrik Mag ◽  
Dóra Kovács ◽  
Ádám Kerek ◽  
Pál Szabó ◽  
...  

Florfenicol is a member of the phenicol group, a broad-spectrum antibacterial agent. It has been used for a long time in veterinary medicine, but there are some factors regarding its pharmacokinetic characteristics that have yet to be elucidated. The aim of our study was to describe the pharmacokinetic profile of florfenicol in synovial fluid and plasma of swine after intramuscular (i.m.) administration. In addition, the dosage regimen of treatment of arthritis caused by S. suis was computed for florfenicol using pharmacokinetic/pharmacodynamic (PK/PD) indices. As the first part of our investigation, the pharmacokinetic (PK) parameters of florfenicol were determined in the plasma and synovial fluid of six pigs. Following drug administration (15 mg/kgbw, intramuscularly), blood was drawn at the following times: 10, 20, 30, 40, 50 and 60 min, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48 and 72 h; synovial fluid samples were taken after 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h. The concentration of florfenicol was determined by a validated liquid chromatography-mass spectrometry (LC-MS/MS) method via multiple reaction monitoring (MRM) modes. As the second part of our research, minimum inhibitory concentration (MIC) values of florfenicol were determined in 45 S. suis strains isolated from clinical samples collected in Hungary. Furthermore, a strain of S. suis serotype 2 (SS3) was selected, and killing-time curves of different florfenicol concentrations (0.5 µg/mL, 1 µg/mL and 2 µg/mL) were determined against this strain. Peak concentration of the florfenicol was 3.58 ± 1.51 µg/mL in plasma after 1.64 ± 1.74 h, while it was 2.73 ± 1.2 µg/mL in synovial fluid 3.4 ± 1.67 h after administration. The half-life in plasma was found to be 17.24 ± 9.35 h, while in synovial fluid it was 21.01 ± 13.19 h. The area under the curve (AUC24h) value was 54.66 ± 23.34 μg/mL·h for 24 h in plasma and 31.24 ± 6.82 μg/mL·h for 24 h in synovial fluid. The drug clearance scaled by bioavailability (Cl/F) in plasma and synovial fluid was 0.19 ± 0.08 L/h/kg and 0.29 ± 0.08 L/h/kg, respectively. The mean residence time (MRT) in plasma and synovial fluid was 24.0 ± 13.59 h and 27.39 ± 17.16 h, respectively. The steady-state volume of distribution (Vss) in plasma was calculated from Cl/F of 0.19 ± 0.08 L/h/kg, multiplied by MRT of 24.0 ± 13.59 h. For the PK/PD integration, average plasma and synovial fluid concentration of florfenicol was used in a steady-state condition. The obtained MIC50 value of the strains was 2.0 µg/mL, and MIC90 proved to be 16.0 µg/mL. PK/PD integration was performed considering AUC24h/MIC breakpoints that have already been described. This study is the first presentation of the pharmacokinetic behavior of florfenicol in swine synovia as well as a recommendation of extrapolated critical MICs of S. suis for therapeutic success in the treatment of S. suis arthritis in swine, but it should be noted that this requires a different dosage regimen to that used in authorized florfenicol formulations.

1998 ◽  
Vol 16 (7) ◽  
pp. 2494-2499 ◽  
Author(s):  
A M Langevin ◽  
D T Casto ◽  
P J Thomas ◽  
S D Weitman ◽  
C Kretschmar ◽  
...  

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.


1987 ◽  
Vol 15 (1) ◽  
pp. 7-14 ◽  
Author(s):  
D. R. Stanski

Pharmacokinetic concepts describe the relationship between drug dose and resulting plasma concentration. A drug's pharmacokinetic profile can be described by distribution and elimination half-lives, initial volume of distribution, steady-state distribution volume, and metabolic and distributional clearance. After initiating a fixed rate of drug infusion, four to five terminal elimination half-lives are required to reach a steady state of constant plasma concentration. If a loading dose is given, a steady state can be achieved more rapidly. The most rapid method of achieving a constant plasma concentration involves using a variable rate of drug infusion that adjusts for the metabolic clearance and distribution of the drug. Computer-driven infusion pumps can be used to rapidly achieve, then maintain, constant plasma concentrations of a drug.


1999 ◽  
Vol 87 (5) ◽  
pp. 1813-1822 ◽  
Author(s):  
A. Gastaldelli ◽  
A. R. Coggan ◽  
R. R. Wolfe

The most common approach for estimating substrate rate of appearance (Ra) is use of the single-pool model first proposed by R. W. Steele, J. S. Wall, R. C. DeBodo, and N. Altszuler. ( Am. J. Physiol. 187: 15–24, 1956). To overcome the model error during highly non-steady-state conditions due to the assumption of a constant volume of distribution (V), two strategies have been proposed: 1) use of a variable tracer infusion rate to minimize tracer-to-tracee ratio (TTR) variations (fixed-volume approach) or 2) use of two tracers of the same substrate with one infused at a constant rate and the other at a variable rate (variable-volume approach or approach of T. Issekutz, R. Issekutz, and D. Elahi. Can. J. Physiol. Pharmacol. 52: 215–224, 1974). The goal of this study was to compare the results of these two strategies for the analysis of the kinetics of glycerol and glucose under the non-steady-state condition created by a constant infusion of epinephrine (50 ng ⋅ kg−1 ⋅ min−1) with the traditional approach of Steele et al., which uses a constant infusion and fixed volume. The results showed that for glucose and glycerol the estimates of Raobtained with the constant and the variable tracer infusion rate and the equation of Steele et al. were comparable. The variable tracer infusion approach was less sensitive to the choice of V in estimating Ra for glycerol and glucose, although the advantage of changing the tracer infusion rate was greater for glucose than for glycerol. The model of Issekutz et al. showed instability when the ratio TTR1/TTR2approaches a constant value, and the model is more sensitive to measurement error than the constant-volume model for glucose and glycerol. We conclude that the one-tracer constant-infusion technique is sufficient in most cases for glycerol, whereas the one-tracer variable-infusion technique is preferable for glucose. Reasonable values for glucose Ra can be obtained with the constant-infusion technique if V = 145 ml/kg.


2015 ◽  
Vol 59 (7) ◽  
pp. 3956-3965 ◽  
Author(s):  
Julie Ann Justo ◽  
Stockton M. Mayer ◽  
Manjunath P. Pai ◽  
Melinda M. Soriano ◽  
Larry H. Danziger ◽  
...  

ABSTRACTThe pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m2and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of ≥40 kg/m2compared to those <30 kg/m2. A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCLCR) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is ≥90% when the MIC is ≤1 μg/ml irrespective of TBW or eCLCR. No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCLCR. Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.)


1994 ◽  
Vol 28 (6) ◽  
pp. 703-707
Author(s):  
Larry H. Danziger ◽  
Stephen C. Piscitelli ◽  
Donna J. Occhipinti ◽  
Daniel J. Resnick ◽  
Keith A. Rodvold

OBJECTIVE: To determine the steady-state pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to patients with acute appendicitis. METHODS: Six patients with normal renal and hepatic function received cefoperazone 2 g with sulbactam 1 g prior to appendectomy and then every 12 hours. Serial blood samples were collected after each patient received at least three doses of cefoperazone/sulbactam. RESULTS: Cefoperazone and sulbactam could be best described by a two-compartment model. Mean ± SD values for cefoperazone steady-state volume of distribution (Vssd), elimination half-life (t1/2β), clearance (Cl), and area under the curve (AUC0-t) were 19.8 ± 8.0 L, 3.97 ± 1.06 h, 62.6 ± 16.3 mL/min, and 556.9 ± 122.0 mg·h/L, respectively. Sulbactam Vssd, t1/2β, Cl, and AUC0-t were 34.7 ± 13.9 L, 1.39 ± 0.4 h, 288.6 ± 68.2 mL/min, and 64.8 ± 24.5 mg·h/L, respectively. CONCLUSIONS: Compared with data from healthy volunteers, cefoperazone exhibited a decreased Cl and increased Vssd and t1/2β in patients with acute appendicitis. An increased Vssd also was observed for sulbactam. The disposition of cefoperazone/sulbactam is altered in this group of patients; however, these changes are not likely to warrant a dosage reduction.


1996 ◽  
Vol 40 (8) ◽  
pp. 1903-1909 ◽  
Author(s):  
D E Uehlinger ◽  
F Schaedeli ◽  
M Kinzig ◽  
F Sörgel ◽  
F J Frey

The pharmacokinetic profile of fleroxacin was studied in eight noninfected patients receiving regular hemodialysis (four women and four men; mean age, 63 years; age range, 48 to 73 years). Dialysis clearances (mean +/- standard deviation) calculated from the amount of drug recovered in the dialysate exceeded those calculated from rates of extraction from plasma for fleroxacin (126 +/- 29 versus 73 +/- 11 ml/min) and its metabolite N-demethylfleroxacin (103 +/- 31 versus 72 +/- 15 ml/min) but not that for the metabolite fleroxacin N-oxide (100 +/- 25 versus 100 +/- 12 ml/min). Data were fitted to a two-compartment model over the total observation period of 8 days (six oral daily doses of 200 mg of fleroxacin on days 1 to 6 and hemodialysis treatments on day 1,3, and 6) by nonlinear mixed-effects modeling. The random variability of plasma fleroxacin concentrations was 13% about its prediction. The estimated metabolic clearance was 25 ml/min (coefficient of variation, 43%), and the calculated steady-state volume of distribution was 84 liters (coefficient of variation, 16%). The model was expanded for the two major metabolites by the addition of a two-compartment metabolite distribution. Formation clearances of N-demethylfleroxacin and fleroxacin N-oxide were estimated to be 54 and 33% of fleroxacin's metabolic clearance, respectively. The conclusions were as follows. Because of the slow metabolic clearance and intermittent dialysis treatment, steady-state conditions were not reached after 1 week of oral fleroxacin therapy, and there was relevant accumulation of fleroxacin as well as that of fleroxacin N-oxide in our patients with end-stage renal disease. We recommend that infected hemodialysis patients be treated with an initial oral dose of 400 mg of fleroxacin and then daily oral doses of 200 mg. One cannot recommend the treatment of this patient population with fleroxacin over prolonged time periods until more date about the levels of accumulation of fleroxacin and its metabolites in infected patients with renal disease are available.


2020 ◽  
Vol 10 (4) ◽  
pp. 242
Author(s):  
Giulia Di Prima ◽  
Giuseppina Campisi ◽  
Viviana De Caro

Nowadays the therapeutic strategies to manage Parkinson’s Disease are merely symptomatic and consist of administering L-DOPA and/or dopamine receptor agonists. Among these, Ropinirole (ROP) is a widely orally-administered molecule, although it is extensively susceptible to hepatic metabolism. Since literature reports the buccal mucosa as a potentially useful route to ROP administration, the development of novel, effective, and comfortable oromucosal formulations should prove desirable in order to both enhance the therapeutic efficacy of the drug and allow a personalized therapeutic strategy able to meet the patient’s needs. The results of the proposed ROP film as a new dosage form show that it is flexible; uniform; and characterized by suitable surface pH; good mucoadhesiveness; low swelling degree; and fast, complete drug release. Moreover, after ex vivo evaluation on a film having an area of 0.282 cm2 and dose of 2.29 mg, the results of drug flux through the buccal mucosa are closely comparable to the amount of ROP that reaches the bloodstream at the steady-state condition after ROP-PR 4 mg oral administration, calculated according to the literature (0.237 mg/cm2·h−1 vs. 0.243 mg/h, respectively). Moreover, drug flux and ROP dose could be accurately modulated time-by-time depending on the patient’s need, by varying the administered disk area. In addition, the proposed ROP film displays no lag time, producing an immediate drug input in the bloodstream, which could result in a prompt therapeutic response. These findings make ROP film a potentially comfortable and patient-friendly formulation, and a promising candidate for further clinical trials.


Computation ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 65
Author(s):  
Aditya Dewanto Hartono ◽  
Kyuro Sasaki ◽  
Yuichi Sugai ◽  
Ronald Nguele

The present work highlights the capacity of disparate lattice Boltzmann strategies in simulating natural convection and heat transfer phenomena during the unsteady period of the flow. Within the framework of Bhatnagar-Gross-Krook collision operator, diverse lattice Boltzmann schemes emerged from two different embodiments of discrete Boltzmann expression and three distinct forcing models. Subsequently, computational performance of disparate lattice Boltzmann strategies was tested upon two different thermo-hydrodynamics configurations, namely the natural convection in a differentially-heated cavity and the Rayleigh-Bènard convection. For the purposes of exhibition and validation, the steady-state conditions of both physical systems were compared with the established numerical results from the classical computational techniques. Excellent agreements were observed for both thermo-hydrodynamics cases. Numerical results of both physical systems demonstrate the existence of considerable discrepancy in the computational characteristics of different lattice Boltzmann strategies during the unsteady period of the simulation. The corresponding disparity diminished gradually as the simulation proceeded towards a steady-state condition, where the computational profiles became almost equivalent. Variation in the discrete lattice Boltzmann expressions was identified as the primary factor that engenders the prevailed heterogeneity in the computational behaviour. Meanwhile, the contribution of distinct forcing models to the emergence of such diversity was found to be inconsequential. The findings of the present study contribute to the ventures to alleviate contemporary issues regarding proper selection of lattice Boltzmann schemes in modelling fluid flow and heat transfer phenomena.


2021 ◽  
Vol 14 (2) ◽  
pp. 162
Author(s):  
Félicien Le Louedec ◽  
Fanny Gallais ◽  
Fabienne Thomas ◽  
Mélanie White-Koning ◽  
Ben Allal ◽  
...  

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUCIBRU) instead of trough concentration (Cmin,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUCIBRU associated with Bayesian estimation. The actual AUCIBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUCIBRU were derived considering combinations of one to four sampling times. The T0–1–2–4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUCIBRU and Cmin,ss was poor (r2 = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUCIBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.


Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1407
Author(s):  
Matyas Bukva ◽  
Gabriella Dobra ◽  
Juan Gomez-Perez ◽  
Krisztian Koos ◽  
Maria Harmati ◽  
...  

Investigating the molecular composition of small extracellular vesicles (sEVs) for tumor diagnostic purposes is becoming increasingly popular, especially for diseases for which diagnosis is challenging, such as central nervous system (CNS) malignancies. Thorough examination of the molecular content of sEVs by Raman spectroscopy is a promising but hitherto barely explored approach for these tumor types. We attempt to reveal the potential role of serum-derived sEVs in diagnosing CNS tumors through Raman spectroscopic analyses using a relevant number of clinical samples. A total of 138 serum samples were obtained from four patient groups (glioblastoma multiforme, non-small-cell lung cancer brain metastasis, meningioma and lumbar disc herniation as control). After isolation, characterization and Raman spectroscopic assessment of sEVs, the Principal Component Analysis–Support Vector Machine (PCA–SVM) algorithm was performed on the Raman spectra for pairwise classifications. Classification accuracy (CA), sensitivity, specificity and the Area Under the Curve (AUC) value derived from Receiver Operating Characteristic (ROC) analyses were used to evaluate the performance of classification. The groups compared were distinguishable with 82.9–92.5% CA, 80–95% sensitivity and 80–90% specificity. AUC scores in the range of 0.82–0.9 suggest excellent and outstanding classification performance. Our results support that Raman spectroscopic analysis of sEV-enriched isolates from serum is a promising method that could be further developed in order to be applicable in the diagnosis of CNS tumors.


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