scholarly journals Population Pharmacokinetic Study of Cefathiamidine in Infants With Augmented Renal Clearance

2021 ◽  
Vol 12 ◽  
Author(s):  
Bin Du ◽  
Yue Zhou ◽  
Bo-Hao Tang ◽  
Yue-E Wu ◽  
Xin-Mei Yang ◽  
...  
Keyword(s):  
Renal Clearance ◽  
Pharmacokinetic Study ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Augmented Renal Clearance ◽  
Population Pharmacokinetic Study ◽  
Dosing Regimens

Objectives: Augmented renal clearance (ARC) of primarily renally eliminated antibacterial agents may result in subtherapeutic antibiotic concentrations and, as a consequence, worse clinical outcomes. Cefathiamidine is frequently used as empirical antimicrobial therapy in children with ARC, but pharmacokinetic studies in infants are lacking. This population pharmacokinetic study in infants with ARC was conducted to determine optimal dosing regimens of cefathiamidine.Methods: The population pharmacokinetics was conducted in 20 infants treated with cefathiamidine. Plasma samples of cefathiamidine were collected using opportunistic sampling, and the concentrations were detected by UPLC-MS/MS. Data analysis was performed to determine pharmacokinetic parameters and to characterize pharmacokinetic variability of cefathiamidine using nonlinear mixed effects modelling (NONMEM) software program.Results: The data (n = 36) from 20 infants (age range, 0.35–1.86 years) with ARC were fitted best with a 1-compartment model. Allometrically scaled weight and age as significant covariates influenced cefathiamidine pharmacokinetics. The median (range) values of estimated clearance and the volume of distribution were 0.22 (0.09–0.29) L/h/kg and 0.34 (0.24–0.41) L/kg, respectively. Monte Carlo simulations showed that the cefathiamidine doses of 100 mg/kg/day q12 h, 50 mg/kg/day q8 h and 75 mg/kg/day q6 h were chosen for bacteria with MIC 0.25, 0.5 and 2 mg/L, respectively.Conclusion: The population pharmacokinetic model of cefathiamidine for infants with ARC was developed. The PTA - based dosing regimens were recommended based on the final model.

scholarly journals Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study

Antibiotics ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1559
Author(s):  
Francisco Beraldi-Magalhaes ◽  
Suzanne L. Parker ◽  
Cristina Sanches ◽  
Leandro Sousa Garcia ◽  
Brenda Karoline Souza Carvalho ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Oral Absorption ◽  
Compartment Model ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Population Pharmacokinetic ◽  
Icu Patients ◽  
Population Pharmacokinetic Study ◽  
Dosing Regimens ◽  
Dose Combination

Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Methods: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. Results: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. Conclusions: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures.

scholarly journals A Population Pharmacokinetic Approach to Describe Cephalexin Disposition in Adult and Aged Dogs

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Ana Paula Prados ◽  
Paula Schaiquevich ◽  
Verónica Kreil ◽  
Agustina Monfrinotti ◽  
Pamela Quaine ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Elimination Rate ◽  
Compartment Model ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Mixed Breed ◽  
Pharmacokinetic Approach

This study was conducted in order to characterize the pharmacokinetics of orally administered cephalexin to healthy adult and aged dogs, using a population pharmacokinetic approach. Two hundred and eighty-six cephalexin plasma concentrations obtained from previous pharmacokinetic studies were used. Sex, age, pharmaceutical formulation, and breed were evaluated as covariates. A one-compartment model with an absorption lag-time (Tlag) best described the data. The final model included age (adult; aged) on apparent volume of distribution (Vd/F), apparent elimination rate (ke/F), and Tlag; sex (female; male) on ke/F, and breed (Beagle; mixed-breed) on Vd/F. Addition of the covariates to the model explained 78% of the interindividal variability (IIV) in Vd/F, 36% in ke/F, and 24% in Tlag, respectively. Formulation did not affect the variability of any of the pharmacokinetic parameters. Tlag was longer, whereas Vd/F and ke/F were lower in aged compared to adult animals; in female aged dogs ke/F was lower than in male aged dogs; however, the differences were of low magnitude. Different disposition of cephalexin may be expected in aged dogs.

Zalcitabine Population Pharmacokinetics: Application of Radioimmunoassay

1998 ◽  
Vol 42 (2) ◽  
pp. 409-413 ◽  
Author(s):  
John M. Adams ◽  
Mark J. Shelton ◽  
Ross G. Hewitt ◽  
Mary DeRemer ◽  
Robin DiFrancesco ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Information Age ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Oral Clearance ◽  
Standard Curve ◽  
Immunodeficiency Virus ◽  
Traditional Approaches

ABSTRACT Zalcitabine population pharmacokinetics were evaluated in 44 human immunodeficiency virus-infected patients (39 males and 5 females) in our immunodeficiency clinic. Eighty-one blood samples were collected during routine clinic visits for the measurement of plasma zalcitabine concentrations by radioimmunoassay (1.84 ± 1.24 samples/patient; range, 1 to 6 samples/patient). These data, along with dosing information, age (38.6 ± 7.13 years), sex, weight (79.1 ± 15.0 kg), and estimated creatinine clearance (89.1 ± 21.5 ml/min), were entered into NONMEM to obtain population estimates for zalcitabine pharmacokinetic parameters (4). The standard curve of the radioimmunoassay ranged from 0.5 to 50.0 ng/ml. The observed concentrations of zalcitabine in plasma ranged from 2.01 to 8.57 ng/ml following the administration of doses of either 0.375 or 0.75 mg. A one-compartment model best fit the data. The addition of patient covariates did not improve the basic fit of the model to the data. Oral clearance was determined to be 14.8 liters/h (0.19 liter/h/kg; coefficient of variation [CV] = 23.8%), while the volume of distribution was estimated to be 87.6 liters (1.18 liters/kg; CV = 54.0%). We were also able to obtain individual estimates of oral clearance (range, 8.05 to 19.8 liters/h; 0.11 to 0.30 liter/h/kg) and volume of distribution (range, 49.2 to 161 liters; 0.43 to 1.92 liters/kg) of zalcitabine in these patients with the POSTHOC option in NONMEM. Our value for oral clearance agrees well with other estimates of oral clearance from traditional pharmacokinetic studies of zalcitabine and suggests that population methods may be a reasonable alternative to these traditional approaches for obtaining information on the disposition of zalcitabine.

scholarly journals Population Pharmacokinetic Study of Ceftriaxone in Elderly Patients, Using Cystatin C-Based Estimates of Renal Function To Account for Frailty

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Shu Jin Tan ◽  
Matthew Cockcroft ◽  
Madhu Page-Sharp ◽  
Glenn Arendts ◽  
Timothy M. E. Davis ◽  
...  
Keyword(s):  
Renal Function ◽  
Elderly Patients ◽  
Cystatin C ◽  
Pharmacokinetic Study ◽  
Severe Renal Impairment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Total Exposure ◽  
Population Pharmacokinetic Study ◽  
Trough Concentrations

ABSTRACT Ceftriaxone is widely used for respiratory and urinary infections in elderly and frail patients, but there are few pharmacokinetic studies. A prospective population pharmacokinetic study of ceftriaxone in adults over 65 years old was undertaken. Dried blood spots collected at baseline (predose) and 0.5, 1, 4, 8, and 24 h after administration of 1 g of ceftriaxone were assayed using a validated liquid chromatography-mass spectroscopy analytical method. Frailty was classified using the Edmonton frailty scale and grip strength via a hand dynamometer. Estimates of glomerular filtration rate were determined using creatinine-based and cystatin C-based equations. Of 26 patients recruited, 23 (88%) were vulnerable or very frail. Estimates of drug clearance improved significantly with a cystatin C-based estimate of renal function that accounted for frailty. Simulations indicate that the combined effects of ranges of size and renal function resulted in a 6-fold range in peak ceftriaxone concentrations and 9-fold range in total exposure (area under the concentration-time curve [AUC]). For elderly patients with moderate or severe renal impairment, 48-h dosing results in greater trough concentrations and total exposure than the trough concentrations and total exposure in patients with normal renal function receiving 24-h dosing. Cystatin C-based measures of renal function improved predictions of ceftriaxone clearance in elderly patients.

scholarly journals 1119. Assessment of Vancomycin Pharmacokinetic Parameters in Pediatric Patients After Liver Transplantation

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S651-S652
Author(s):  
Ronaldo Morales ◽  
Vanessa D Juodinis ◽  
Daniela Carla de Souza ◽  
Silvia Regina C Jorge Santos
Keyword(s):  
Liver Transplantation ◽  
Therapeutic Target ◽  
Bacterial Infections ◽  
Pediatric Patients ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Critical Conditions ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies

Abstract Background Vancomycin is largely prescribed to treat gram-positive bacterial infections in pediatric patients after liver transplantation with the same empirical doses prescribed in other critical conditions due to the absence of pharmacokinetic studies in this population. The objective of this investigation was to describe the vancomycin pharmacokinetic parameters and to assess the vancomycin percentage of target attainment with empirical regimen. Methods Prospective and longitudinal study with pediatric post-liver transplantation patients who received at least 48 hours of vancomycin between January 2020 and May 2021. Patients with acute or chronic renal failure or receiving renal replacement therapy were excluded. Vancomycin therapy started with 40-60mg/kg daily, one-hour infusion. The pharmacokinetic parameters were determined by one-compartment model with first-order kinetics using near steady-state postdistributional peak and trough within the same dosing interval. Therapeutic target was defined as vancomycin 24-hour area under the curve/minimum inhibitory concentration (AUCss0-24/MIC) ≥ 400 and &lt; 600. The study protocol was approved by the local ethics committee. Results We included 18 sets of peak/trough serum concentrations obtained from 12 patients. The patients had median age of 11 (interquartile range [IQ] 8-16) months. The found vancomycin clearance, volume of distribution and half-life values were, respectively, 2.1 (IQ 1.4-2.8) mL/kg/min, 0.6 (IQ 0.5-0.7) L/kg and 3.2 (IQ 2.3-4.0) hours. After the initial dose regimen, 5 (42%) patients reached the therapeutic target. Conclusion Using the one-compartment model, we evaluate the pharmacokinetic parameters of vancomycin in pediatric patients after liver transplantation. Most of patients did not reach the therapeutic target with empirical regimen, so it is prudent to monitor the exposure to vancomycin directly by AUC/MIC ratio to maximize antimicrobial efficacy. Disclosures All Authors: No reported disclosures

Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav

2020 ◽  
Vol 75 (12) ◽  
pp. 3611-3618
Author(s):  
G Mellon ◽  
K Hammas ◽  
C Burdet ◽  
X Duval ◽  
C Carette ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Open Label ◽  
Mixed Effect ◽  
Mean Values ◽  
Two Compartment Model ◽  
Amoxicillin Clavulanate ◽  
Dosing Regimens ◽  
Obese Subjects

Abstract Background Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. Materials and methods Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC–tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. Results Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT&gt;MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). Conclusions Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.

Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment

2021 ◽  
Author(s):  
Sonya Tang Girdwood ◽  
Min Dong ◽  
Peter Tang ◽  
Erin Stoneman ◽  
Rhonda Jones ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Pediatric Intensive Care ◽  
Compartment Model ◽  
The United States ◽  
Volume Of Distribution ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Modeling ◽  
Dosing Regimens

Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most prescribed antibiotics in patients admitted to the pediatric intensive care unit (PICU). We sought to develop population PK models of both total ceftriaxone and free ceftriaxone in children admitted to a single-center PICU using a scavenged opportunistic sampling approach. We tested if the presence of sepsis and phase of illness (before or after 48 hours of antibiotic treatment) altered ceftriaxone PK parameters. We performed Monte Carlo simulations to evaluate whether dosing regimens commonly used in PICUs in the United States (50 mg/kg every 12 hours vs. 24 hours) resulted in adequate antimicrobial coverage. We found that a two-compartment model best described both total and free ceftriaxone concentrations. For free concentrations, the population clearance value is 6.54 L/h/70 kg, central volume is 25.4 L/70 kg and the peripheral volume is 19.6 L/70kg. For both models, we found that allometric weight scaling, post-menstrual age, creatinine clearance and daily highest temperature had significant effects on clearance. Presence of sepsis or phase of illness did not have a significant effect on clearance or volume of distribution. Monte Carlo simulations demonstrated that to achieve free concentrations above 1 μg/mL for 100% of the dosing intervals, a dosing regimen of 50 mg/kg every 12 hours is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the minimum inhibitory concentrations (4 μg/mL).

scholarly journals Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Silke Gastine ◽  
Thomas Lehrnbecher ◽  
Carsten Müller ◽  
Fedja Farowski ◽  
Peter Bader ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Modeling ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Concentration Data ◽  
Days Of Therapy ◽  
Dosing Regimens

ABSTRACT The pharmacokinetic variability of voriconazole (VCZ) in immunocompromised children is high, and adequate exposure, particularly in the first days of therapy, is uncertain. A population pharmacokinetic model was developed to explore VCZ exposure in plasma after alternative dosing regimens. Concentration data were obtained from a pediatric phase II study. Nonlinear mixed effects modeling was used to develop the model. Monte Carlo simulations were performed to test an array of three-times-daily (TID) intravenous dosing regimens in children 2 to 12 years of age. A two-compartment model with first-order absorption, nonlinear Michaelis-Menten elimination, and allometric scaling best described the data (maximal kinetic velocity for nonlinear Michaelis-Menten clearance [V max] = 51.5 mg/h/70 kg, central volume of distribution [V 1] = 228 liters/70 kg, intercompartmental clearance [Q] = 21.9 liters/h/70 kg, peripheral volume of distribution [V 2] = 1,430 liters/70 kg, bioavailability [F] = 59.4%, Km = fixed value of 1.15 mg/liter, absorption rate constant = fixed value of 1.19 h−1). Interindividual variabilities for V max, V 1, Q, and F were 63.6%, 45.4%, 67%, and 1.34% on a logit scale, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/liter (additive error). Monte Carlo simulations of a regimen of 9 mg/kg of body weight TID simulated for 24, 48, and 72 h followed by 8 mg/kg two times daily (BID) resulted in improved early target attainment relative to that with the currently recommended BID dosing regimen but no increased rate of accumulation thereafter. Pharmacokinetic modeling suggests that intravenous TID dosing at 9 mg/kg per dose for up to 3 days may result in a substantially higher percentage of children 2 to 12 years of age with adequate exposure to VCZ early during treatment. Before implementation of this regimen in patients, however, validation of exposure, safety, and tolerability in a carefully designed clinical trial would be needed.

Mixed-effects Modeling of the Influence of Alfentanil on Propofol Pharmacokinetics

2004 ◽  
Vol 100 (4) ◽  
pp. 795-805 ◽  
Author(s):  
Martijn J. Mertens ◽  
Erik Olofsen ◽  
Anton G. L. Burm ◽  
James G. Bovill ◽  
Jaap Vuyk
Keyword(s):  
Heart Rate ◽  
Cardiac Output ◽  
Venous Blood ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Mixed Effects ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Elimination Clearance ◽  
End Tidal

Background The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol. Methods The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed. Results A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model. Conclusions Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.

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