Volume of Distribution for Dosing Interval by Fraction

2020 ◽  
Author(s):  
Keyword(s):  
Volume Of Distribution ◽  
Dosing Interval

scholarly journals Amikacin Pharmacokinetics To Optimize Dosing in Neonates with Perinatal Asphyxia Treated with Hypothermia

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Sinziana Cristea ◽  
Anne Smits ◽  
Aida Kulo ◽  
Catherijne A. J. Knibbe ◽  
Mirjam van Weissenbruch ◽  
...  
Keyword(s):  
Perinatal Asphyxia ◽  
Volume Of Distribution ◽  
Stochastic Simulations ◽  
Therapeutic Drug ◽  
Published Data ◽  
Data Set ◽  
Dosing Interval ◽  
Proposed Model ◽  
Dosing Regimens ◽  
The Impact

ABSTRACT Aminoglycoside pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed for treating neonates with (suspected) septicemia; however, none provide adjustments for cases of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations. Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published data set, we assessed the impact of PATH on amikacin PK by using population modeling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines. Amikacin clearance was decreased 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that increasing the dosing interval by 12 h results in a decrease in the percentage of neonates reaching toxic trough levels (>5 mg/liter), from 40 to 76% to 14 to 25%, while still reaching efficacy targets compared to the results of current dosing regimens. Based on this study, a 12-h increase in the amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required, as their clearance may also be impaired.

scholarly journals Pharmacokinetic and Pharmacodynamic Modeling of Anidulafungin (LY303366): Reappraisal of Its Efficacy in Neutropenic Animal Models of Opportunistic Mycoses Using Optimal Plasma Sampling

2001 ◽  
Vol 45 (10) ◽  
pp. 2845-2855 ◽  
Author(s):  
Andreas H. Groll ◽  
Diana Mickiene ◽  
Ruta Petraitiene ◽  
Vidmantas Petraitis ◽  
Caron A. Lyman ◽  
...  
Keyword(s):  
Animal Models ◽  
Volume Of Distribution ◽  
Pharmacodynamic Modeling ◽  
Pulmonary Aspergillosis ◽  
Dosing Interval ◽  
Disseminated Candidiasis ◽  
Drug Concentrations ◽  
Infection Models ◽  
The Mean ◽  
Antifungal Efficacy

ABSTRACT The compartmental pharmacokinetics of anidulafungin (VER-002; formerly LY303366) in plasma were characterized with normal rabbits, and the relationships between drug concentrations and antifungal efficacy were assessed in clinically applicable infection models in persistently neutropenic animals. At intravenous dosages ranging from 0.1 to 20 mg/kg of body weight, anidulafungin demonstrated linear plasma pharmacokinetics that fitted best to a three-compartment open pharmacokinetic model. Following administration over 7 days, the mean (± standard error of the mean) peak plasma concentration (C max) increased from 0.46 ± 0.02 μg/ml at 0.1 mg/kg to 63.02 ± 2.93 μg/ml at 20 mg/kg, and the mean area under the concentration-time curve from 0 h to infinity (AUC0–∞) rose from 0.71 ± 0.04 to 208.80 ± 24.21 μg · h/ml. The mean apparent volume of distribution at steady state (V ss) ranged from 0.953 ± 0.05 to 1.636 ± 0.22 liter/kg (nonsignificant [NS]), and clearance ranged from 0.107 ± 0.01 to 0.149 ± 0.00 liter/kg/h (NS). Except for a significant prolongation of the terminal half-life and a trend toward an increased V ssat the higher end of the dosage range after multiple doses, no significant differences in pharmacokinetic parameters were noted in comparison to single-dose administration. Concentrations in tissue at trough after multiple dosing (0.1 to 10 mg/kg/day) were highest in lung and liver (0.85 ± 0.16 to 32.64 ± 2.03 and 0.32 ± 0.05 to 43.76 ± 1.62 μg/g, respectively), followed by spleen and kidney (0.24 ± 0.65 to 21.74 ± 1.86 and <0.20 to 16.92 ± 0.56, respectively). Measurable concentrations in brain tissue were found at dosages of ≥0.5 mg/kg (0.24 ± 0.02 to 3.90 ± 0.25). Implementation of optimal plasma sampling in persistently neutropenic rabbit infection models of disseminated candidiasis and pulmonary aspergillosis based on the Bayesian approach and model parameters from normal animals as priors revealed a significantly slower clearance (P < 0.05 for all dosage groups) with a trend toward higher AUC0–24 values, higher plasma concentrations at the end of the dosing interval, and a smaller volume of distribution (P < 0.05 to 0.193 for the various comparisons among dosage groups). Pharmacodynamic modeling using the residual fungal tissue burden in the main target sites as the primary endpoint and C max, AUC0–24, time during the dosing interval of 24 h with plasma drug concentration equaling or exceeding the MIC or the minimum fungicidal concentration for the isolate, and tissue concentrations as pharmacodynamic parameters showed predictable pharmacokinetic-pharmacodynamic relationships in experimental disseminated candidiasis that fitted well with an inhibitory sigmoid maximum effect pharmacodynamic model (r 2, 0.492 to 0.819). However, no concentration-effect relationships were observed in experimental pulmonary aspergillosis using the residual fungal burden in lung tissue and survival as parameters of antifungal efficacy. Implementation of optimal plasma sampling in discriminative animal models of invasive fungal infections and pharmacodynamic modeling is a novel approach that holds promise of improving and accelerating our understanding of the action of antifungal compounds in vivo.

A Calculator Program for Adjusting Aminoglycoside Regimens That Accounts for Tissue Accumulation in Children and Adolescents

1982 ◽  
Vol 16 (7-8) ◽  
pp. 563-568 ◽  
Author(s):  
M. Vance Loertscher
Keyword(s):  
Half Life ◽  
Serum Levels ◽  
Volume Of Distribution ◽  
Drug Elimination ◽  
Hewlett Packard ◽  
Dosing Interval ◽  
Tissue Accumulation ◽  
Trough Serum ◽  
The Given ◽  
True Peak

The author has developed a program for the Hewlett Packard HP 41C calculator that is used in the analysis of aminoglycoside serum levels for the purpose of generating a personalized dosage regimen. Although other programs have been published, until now none has made adjustments in the half-life of drug elimination due to the tissue accumulation that occurs in the initial phases of dosing. Many of these same programs fail to locate the true peak and trough serum levels, which are essential in the calculation of the volume of distribution of the aminoglycosides. This article is not meant as a method of initial dosing, but rather assumes that the physician has chosen one of the readily usable methods of dosing, such as various nomograms. Patient data taken from published studies were used in generating individual patient parameters. These parameters were compared to those calculated in the studies for means of comparison. While correlation in all parameters was not ideal, the correlation of dose and dosing interval was exact and correlation of predicted peaks and troughs with the given regimen of dosing was excellent.

scholarly journals Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers

2012 ◽  
Vol 56 (5) ◽  
pp. 2627-2634 ◽  
Author(s):  
Seth T. Housman ◽  
J. Samuel Pope ◽  
John Russomanno ◽  
Edward Salerno ◽  
Eric Shore ◽  
...  
Keyword(s):  
Correction Method ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Dosing Interval ◽  
Drug Concentrations ◽  
Liquid Chromatography Tandem Mass ◽  
Adult Volunteers

ABSTRACTThis study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC0–24) for ELF and AM relative to the free AUC0–24(fAUC0–24) in plasma. The half-life and volume of distribution in plasma were 9.23 ± 2.04 h and 108.25 ± 20.53 liters (means ± standard deviations), respectively. Total AUC0–24in plasma was 25.13 ± 5.78 μg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a meanfAUC0–24of 2.65 ± 0.72 μg · h/ml in plasma. Mean concentrations (μg/ml) at 2, 6, 12, and 24 h were 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 in ELF and 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.

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