scholarly journals Comparative Pharmacokinetics, Tissue Distributions, and Effects on Renal Function of Novel Polymeric Formulations of Amphotericin B and Amphotericin B-Deoxycholate in Rats

2000 ◽  
Vol 44 (4) ◽  
pp. 898-904 ◽  
Author(s):  
Iciar Echevarría ◽  
Celia Barturen ◽  
María Jesús Renedo ◽  
Iñaki F. Trocóniz ◽  
M. Carmen Dios-Viéitez
Keyword(s):  
Renal Function ◽  
Amphotericin B ◽  
High Performance ◽  
Drug Exposure ◽  
Compartment Model ◽  
Drug Uptake ◽  
Parameter Estimates ◽  
Tissue Samples ◽  
Plasma Creatinine Level ◽  
Male Wistar Rats

ABSTRACT The pharmacokinetic profiles of a traditional formulation of amphotericin B (Fungizone) and novel nanosphere and mixed micelle delivery systems developed for amphotericin B were compared and described. Six groups of male Wistar rats received intravenous injections of the different formulations. Plasma and tissue samples were obtained at 11 different times after dosing, with three animals used each time. The amphotericin B concentrations in plasma and tissues were analyzed by high-performance liquid chromatography. The plasma drug concentration-time profiles were best described by a two-compartment model. Models that described the observed single or double peak disposition kinetics in kidney, liver, and spleen were also developed. Parameter estimates from those models show that components of the formulation such as poloxamer 188, which is present in all new formulations, seem to play an important role in the rate of drug uptake by the tissues; in general, the levels of amphotericin B in tissues were increased after the administration of the new formulations compared with those after the administration of Fungizone. The increment in the baseline plasma creatinine level was used as an index of renal function. All formulations increased this baseline value, but the novel formulations exhibited fewer renal effects than Fungizone did. However, a direct relationship between drug exposure in the kidneys and development of renal damage could not be found.

Kinetics of dodecanedioic acid triglyceride in rats

1999 ◽  
Vol 276 (3) ◽  
pp. E497-E502
Author(s):  
A. de Gaetano ◽  
G. Mingrone ◽  
M. Castagneto ◽  
G. Benedetti ◽  
A. V. Greco ◽  
...  
Keyword(s):  
High Performance ◽  
Compartment Model ◽  
High Performance Liquid Chromatographic ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Parameter Estimates ◽  
Tissue Uptake ◽  
Male Wistar Rats ◽  
Dodecanedioic Acid ◽  
Kinetics Of

The kinetics of the triglyceride of dodecanedioic acid (TGDA) has been investigated in 30 male Wistar rats after a rapid intravenous bolus injection. TGDA and its product of hydrolysis, nonesterified dodecanedioic acid (NEDA), were measured in plasma samples taken at different times using an improved high-performance liquid chromatographic method. The 24-h urinary excretion of TGDA was 1.54 ± 0.37 μmol, corresponding to ∼0.67% of the administered amount. Several kinetics models were considered, including central and peripheral compartments for the triglyceride and the free forms and expressing transports between compartments with combinations of linear, carrier-limited, or time-varying mechanisms. The parameter estimates of the kinetics of TGDA and of NEDA were finally obtained using a three-compartment model in which the transfer of TGDA to NEDA was assumed to be linear, through a peripheral compartment, and the tissue uptake of NEDA was assumed to be carrier limited. TGDA had a large volume of distribution (∼0.5 l/kg body wt) with a fast disappearance rate from plasma (0.42 min−1), whereas NEDA had a very small volume of distribution (∼0.04 l/kg body wt) and a tissue uptake with maximal transport rate of 0.636 mM/min. In conclusion, this first study on the triglyceride form of dodecanedioic acid indicates that it is rapidly hydrolyzed and that both triglyceride and nonesterified forms are excreted in the urine to a very low extent. The tissue uptake rate of NEDA is consistent with the possibility of achieving substantial energy delivery, should it be added to parenteral nutrition formulations. Furthermore, the amount of sodium administered with the triglyceride form is one-half of that necessary with the free diacid.

scholarly journals Population Pharmacokinetics of Liposomal Amphotericin B in Immunocompromised Children

2016 ◽  
pp. AAC.01427-16 ◽  
Author(s):  
Jodi M. Lestner ◽  
Andreas H. Groll ◽  
Ghaith Aljayyoussi ◽  
Nita L. Seibel ◽  
Aziza Shad ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
High Performance ◽  
Drug Exposure ◽  
Compartment Model ◽  
Invasive Fungal Disease ◽  
Volume Of Distribution ◽  
Liposomal Amphotericin B ◽  
Time Curve ◽  
Maximum Serum

BackgroundLiposomal amphotericin B (LAmB) is widely used in the treatment of invasive fungal disease (IFD) in adults and children. There are relatively limited PK data to inform optimal dosing in children that achieves systemic drug exposures comparable to those of adults.ObjectivesTo describe the pharmacokinetics of LAmB in children aged 1-17 years with suspected or documented IFD.MethodsThirty-five children were treated with LAmB at dosages of 2.5-10 mg kg-1daily. Samples were taken at baseline and at 0.5-2.0 hourly intervals for twenty-four hours after receipt of the first dose (n=35 patients) and on the final day of therapy (n=25 patients). LAmB was measured using high performance liquid chromatography (HPLC). The relationship between drug exposure and development of toxicity was explored.ResultsAn evolution in PK was observed during the course of therapy resulting in a proportion of patients (n=13) having significantly higher maximum serum concentration (Cmax) and area under the concentration time curve (AUC0-24) later in the course of therapy, without evidence of drug accumulation (Cminaccumulation ratio, AR < 1.2). The fit of a 2-compartment model incorporating weight and an exponential decay function describing volume of distribution best described the data. There was a statistically significant relationship between mean AUC0-24and probability of nephrotoxicity (OR 2.37; 95% CI 1.84-3.22, p=0.004).ConclusionsLAmB exhibits nonlinear pharmacokinetics. A third of children appear to experience a time-dependent change in PK, which is not explained by weight, maturation or observed clinical factors.

scholarly journals Population Pharmacokinetics of Levetiracetam and Dosing Evaluation in Critically Ill Patients with Normal or Augmented Renal Function

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1690
Author(s):  
Idoia Bilbao-Meseguer ◽  
Helena Barrasa ◽  
Eduardo Asín-Prieto ◽  
Ana Alarcia-Lacalle ◽  
Alicia Rodríguez-Gascón ◽  
...  
Keyword(s):  
Renal Function ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Parameter Estimates ◽  
Population Modelling ◽  
Two Compartment Model ◽  
Relative Standard

Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.

scholarly journals Population Pharmacokinetics of Amphotericin B Lipid Complex in Neonates

2005 ◽  
Vol 49 (12) ◽  
pp. 5092-5098 ◽  
Author(s):  
Gudrun Würthwein ◽  
Andreas H. Groll ◽  
Georg Hempel ◽  
Felice C. Adler-Shohet ◽  
Jay M. Lieberman ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Gestational Age ◽  
High Performance ◽  
Interindividual Variability ◽  
Age Groups ◽  
Compartment Model ◽  
Multicenter Trial ◽  
Volume Of Distribution ◽  
Lipid Complex ◽  
Amphotericin B Lipid Complex

ABSTRACT The pharmacokinetics of amphotericin B lipid complex (ABLC) were investigated in neonates with invasive candidiasis enrolled in a phase II multicenter trial. Sparse blood (153 samples; 1 to 9 per patient, 1 to 254 h after the dose) and random urine and cerebrospinal fluid (CSF) samples of 28 neonates (median weight [WT], 1.06 kg; range, 0.48 to 4.9 kg; median gestational age, 27 weeks; range, 24 to 41 weeks) were analyzed. Patients received intravenous ABLC at 2.5 (n = 15) or 5 (n = 13) mg/kg of body weight once a day over 1 or 2 h, respectively, for a median of 21 days (range, 4 to 47 days). Concentrations of amphotericin B were quantified as total drug by high-performance liquid chromatography. Blood data for time after dose (TAD) of <24 h fitted best to a one-compartment model with an additive-error model for residual variability, WT0.75 (where 0.75 is an exponent) as a covariate of clearance (CL), and WT as a covariate of volume of distribution (V). Prior amphotericin B, postnatal age, and gestational age did not further improve the model. The final model equations were CL (liters/h) = 0.399 × WT0.75 (interindividual variability, 35%) and V (liters) = 10.5 × WT (interindividual variability, 43%). Noncompartmental analysis of pooled data with a TAD of >24 h revealed a terminal half-life of 395 h. Mean concentrations in the urine after 1, 2, and 3 weeks ranged from 0.082 to 0.430 μg/ml, and those in CSF ranged from undetectable to 0.074 μg/ml. The disposition of ABLC in neonates was similar to that observed in other age groups: weight was the only factor that influenced clearance. Based on these results and previously published safety and efficacy data, we recommend a daily dosage between 2.5 and 5.0 mg/kg for treatment of invasive Candida infections in neonates.

Renal function measurements from MR renography and a simplified multicompartmental model

2007 ◽  
Vol 292 (5) ◽  
pp. F1548-F1559 ◽  
Author(s):  
Vivian S. Lee ◽  
Henry Rusinek ◽  
Louisa Bokacheva ◽  
Ambrose J. Huang ◽  
Niels Oesingmann ◽  
...  
Keyword(s):  
Low Dose ◽  
Random Noise ◽  
Compartment Model ◽  
Parameter Estimates ◽  
Imaging Data ◽  
Tracer Injection ◽  
Multicompartmental Model ◽  
Enhancement Curve ◽  
Reference Measurements ◽  
Single Kidney

The purpose of this study was to determine the accuracy and sources of error in estimating single-kidney glomerular filtration rate (GFR) derived from low-dose gadolinium-enhanced T1-weighted MR renography. To analyze imaging data, MR signal intensity curves were converted to concentration vs. time curves, and a three-compartment, six-parameter model of the vascular-nephron system was used to analyze measured aortic, cortical, and medullary enhancement curves. Reliability of the parameter estimates was evaluated by sensitivity analysis and by Monte Carlo analyses of model solutions to which random noise had been added. The dominant sensitivity of the medullary enhancement curve to GFR 1–4 min after tracer injection was supported by a low coefficient of variation in model-fit GFR values (4%) when measured data were subjected to 5% noise. These analyses also showed the minimal effects of bolus dispersion in the aorta on parameter reliability. Single-kidney GFR from MR renography analyzed by the three-compartment model (4.0–71.4 ml/min) agreed well with reference measurements from 99mTc-DTPA clearance and scintigraphy ( r = 0.84, P < 0.001). Bland-Altman analysis showed an average difference of 11.9 ml/min (95% confidence interval = 5.8–17.9 ml/min) between model and reference values. We conclude that a nephron-based multicompartmental model can be used to derive clinically useful estimates of single-kidney GFR from low-dose MR renography.

scholarly journals 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S670-S671
Author(s):  
Ronald G Hall ◽  
Jotam Pasipanodya ◽  
William C Putnam ◽  
John Griswold ◽  
Sharmila Dissanaike ◽  
...  
Keyword(s):  
Human Plasma ◽  
Kidney Injury ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Population Parameter ◽  
Full Thickness ◽  
Severe Burns

Abstract Background Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. Methods A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. Results The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities Summary of pharmacokinetic parameters Conclusion C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. Disclosures Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)

scholarly journals Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

2014 ◽  
Vol 58 (8) ◽  
pp. 4718-4726 ◽  
Author(s):  
Ping Liu ◽  
Diane R. Mould
Keyword(s):  
Invasive Aspergillosis ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Institutional Review Boards ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
First Order ◽  
Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

Noradrenergic activity in rat brain during rapid eye movement sleep deprivation and rebound sleep

1995 ◽  
Vol 268 (6) ◽  
pp. R1456-R1463 ◽  
Author(s):  
T. Porkka-Heiskanen ◽  
S. E. Smith ◽  
T. Taira ◽  
J. H. Urban ◽  
J. E. Levine ◽  
...  
Keyword(s):  
Sleep Deprivation ◽  
Eye Movement ◽  
Rem Sleep ◽  
High Performance ◽  
Locus Ceruleus ◽  
Rapid Eye Movement ◽  
Rem Sleep Deprivation ◽  
Large Platform ◽  
Male Wistar Rats ◽  
Th Mrna

Noradrenergic locus ceruleus neurons are most active during waking and least active during rapid eye movement (REM) sleep. We expected REM sleep deprivation (REMSD) to increase norepinephrine utilization and activate the tyrosine hydroxylase (TH) gene critical for norepinephrine production. Male Wistar rats were deprived of REM sleep with the platform method. Rats were decapitated after 8, 24, or 72 h on small (REMSD) or large (control) platforms or after 8 or 24 h of rebound sleep after 72 h of the platform treatment. During the first 24 h, norepinephrine concentration, measured by high-performance liquid chromatography/electrochemical detection, was lower in the neocortex, hippocampus, and posterior hypothalamus in REMSD rats than in large-platform controls. After 72 h of REMSD, TH mRNA, measured by in situ hybridization, was increased in the locus ceruleus and norepinephrine concentrations were increased. Polygraphy showed that small-platform treatment caused effective and selective REMSD. Serum corticosterone measurement by radioimmunoassay indicated that the differences found in norepinephrine and TH mRNA were not due to differences in stress between the treatments. The novel finding of sleep deprivation-specific increase in TH gene expression indicates an important mechanism of adjusting to sleep deprivation.

Identification of tissue insulin receptors: use of a unique in vivo radioreceptor assay

1985 ◽  
Vol 249 (6) ◽  
pp. E561-E567 ◽  
Author(s):  
D. C. Whitcomb ◽  
T. M. O'Dorisio ◽  
S. Cataland ◽  
M. A. Shetzline ◽  
M. T. Nishikawara
Keyword(s):  
Adrenal Glands ◽  
Insulin Receptors ◽  
Compartment Model ◽  
Radioreceptor Assay ◽  
Male Rats ◽  
Differential Distribution ◽  
Tissue Samples ◽  
Polypeptide Hormones ◽  
Tissue Receptors

An in vivo radioreceptor assay for polypeptide hormones has been developed and applied to the identification of tissue insulin receptors. The theoretical basis for this assay is presented elsewhere in this issue. 125I-insulin and 131I-albumin were infused into male rats with increasing amounts of unlabeled insulin. Plasma samples were taken at 1-min intervals until the animals were killed at 5 min. Tissue samples were excised and weighed and the activity due to each isotope counted. By comparing the differential distribution of the labeled tracers and applying the results to a compartment model, the specific, displaceable binding of insulin to tissue receptors could be demonstrated. Binding was detected in the liver, muscle, fat, adrenal glands, pancreas, small intestines, and spleen.

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