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.

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.

Letters to the Editor

PEDIATRICS ◽  
1981 ◽  
Vol 68 (4) ◽  
pp. 602-603
Author(s):  
Charles H. Feldman ◽  
Vincent E. Hutchinson ◽  
Charles E. Pippenger ◽  
Thomas A. Blumenfeld ◽  
Bernard R. Feldman ◽  
...  
Keyword(s):  
Elimination Rate ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Apparent Volume ◽  
Systemic Circulation ◽  
Volume Of Distribution ◽  
Letters To The Editor ◽  
Correct Formula ◽  
Original Report ◽  
Apparent Volume Of Distribution

We appreciate the comments of Weinberger et al and Spino et al. The equation utilized in our original report to calculate the apparent volume of distribution (V) was in error, as it was based on determinations for drugs that exhibit monoexponential elimination following a single intravenous dose. The correct formula for oral dosing at steady state with a drug obeying one-compartment model kinetics is: V = F.X0/AUCτ. K, where F is the total fraction of dose reaching systemic circulation, X0, is the dose, AUCτ is the area under the curve during a dosing interval; K is the elimination rate constant.1

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 Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

2018 ◽  
Author(s):  
Nilar Lwin ◽  
Zheng Liu ◽  
Mark Loewenthal ◽  
Pauline Dobson ◽  
Ji Woong Yoo ◽  
...  
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Time Course ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Device Removal ◽  
Standard Dosage

Flucloxacillin, a beta-lactam antibiotic of the penicillin class, is considered first line therapy for methicillin sensitive Staphylococcus aureus (MSSA) in Australia. At our tertiary referral hospital in the home (HITH) program, it has been prescribed in a standard dosage of 8 grams per day by continuous infusion for more than 20 years. The aim of this observational study was to characterize the pharmacokinetic profile of flucloxacillin in patients who receive continuous infusion in the HITH setting, and to undertake population pharmacokinetic analysis performed with NONMEM software by comparing various structural models. This study utilised flucloxacillin concentrations from 44 separate specimens obtained from 23 patients. Twenty-five of these were collected immediately after elastomeric device removal, representing steady-state concentrations, and the remaining 19 were each collected at least 45 minutes after device removal to determine clearance of the drug. Plasma concentrations ranged from 13 to 194 mg/L with median steady-state concentration of 51.5 mg/L and inter-quartile range of 24.6 mg/L. The time-course of flucloxacillin was best described by a 1-compartment model. The best three covariates, CrCL (ΔOFV= -11.7), eGFR (ΔOFV= -5.9) and serum albumin (ΔOFV= -5.8) were found to be equivalent in terms of decreasing the OFV. CrCL was superior in explaining inter individual variability. The best model for flucloxacillin clearance was a one compartment model with CrCL as the sole covariate. The estimated population parameters were 9.5 L for volume of distribution and 8.1 L/h for flucloxacillin clearance.

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 < 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 Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis

2021 ◽  
Author(s):  
Tomohiro Sasaki ◽  
Elin M. Svensson ◽  
Xiaofeng Wang ◽  
Yanlin Wang ◽  
Jeffrey Hafkin ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Population Pharmacokinetic Analysis ◽  
Apparent Volume ◽  
Multidrug Resistant ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 to 17 years old, enrolled in 2 clinical trials, were utilized for the analysis. The final dataset contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two compartment models for each component with linear elimination were selected to characterize the disposition of delamanid and DM-6705, respectively. The covariates included in the model were body weight on apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible vs film coated tablet) on mean absorption time; age, formulation, and dose on bioavailability of delamanid; age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB, QT corrected by Bazett’s' formula) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc value were less than 10 ms at the simulated Cmax of DM-6705 following administration of maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive delamanid.

scholarly journals Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

2009 ◽  
Vol 53 (9) ◽  
pp. 3837-3846 ◽  
Author(s):  
Joel Tarning ◽  
Rose McGready ◽  
Niklas Lindegardh ◽  
Elizabeth A. Ashley ◽  
Mupawjay Pimanpanarak ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Pregnant Women ◽  
Population Pharmacokinetics ◽  
Plasma Concentrations ◽  
Plasmodium Falciparum Malaria ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Increased Risk ◽  
Pharmacokinetic Properties

ABSTRACT Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.

Estimation of Pharmacokinetic Parameters at Steady-State in Patients

1978 ◽  
Vol 12 (10) ◽  
pp. 612-616 ◽  
Author(s):  
James W. Crow ◽  
Milo Gibaldi
Keyword(s):  
Steady State ◽  
Rate Constant ◽  
Elimination Rate ◽  
Simulated Data ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Total Clearance ◽  
Dosing Intervals ◽  
Apparent Volume Of Distribution

A method to characterize the pharmacokinetics of a drug in a patient receiving it chronically is proposed. In principle, such characterization may be carried out by obtaining one or more drug concentration in plasma-time values from several different dosing intervals, combining the data to create a composite dosing interval representative of the steady-state situation and fitting the data to an appropriate equation. The method was evaluated using simulated data based on the average pharmacokinetic parameters of theophylline in children. Reasonable estimates of the elimination rate constant and apparent volume of distribution may be obtained, but the estimation of the absorption rate constant presents formidable problems. The method appears to be most useful for obtaining very accurate estimates of total clearance.

scholarly journals Studies on effects of lactose on experimental Trypanosoma vivax infection in Zebu cattle. 1. Plasma kinetics of intravenously administered lactose at onset of infection and pathology

2008 ◽  
Vol 75 (2) ◽  
Author(s):  
M. Y. Fatihu ◽  
S. Adamu ◽  
I. A. Umar ◽  
N. D.G. Ibrahim ◽  
L. O. Eduvie ◽  
...  
Keyword(s):  
Muscular Atrophy ◽  
Elimination Rate ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Zebu Cattle ◽  
Trypanosoma Vivax ◽  
Histopathological Lesions ◽  
The Mean ◽  
Total Body

Lactose in normal saline was administered intravenously to a group of Zebu cattle infected with Trypanosoma vivax to determine the bloodplasma kinetics at onset of an experimental infection and its ability to protect tissues against damage as part of preliminary studies to determine its suitability for use in the treatment of trypanosomosis. Significant (P <0.01) higher lactose concentrations were observed in the T. vivax-intecled bulls at 30 min and 1h (P< 0.05) post-infectio (p.i.) and by 4 h p.i. the plasma lactose remained above the level prior to infusion, after which it fell slightly below the preinfusion level in the uninfected group. Calculated pharmacokinetic parameters revealed delayed excretion of lactose in the T. vivax-intected group soon after infection. The total body clearance (C/B )was significantly (P < 0.05) reduced. The biological half-life (t1/2), elimination rate constant (kel) and apparent volume of distribution (Vd) were relatively decreased (P > 0.05) as a result of the T. vivax infection. Retention of lactose in the plasma was attributed to decreased plasma clearance l.t is suggested that the presence of trypanosomes in circulation rather than organic lesions could have been responsible for the delay observed in the excretion of lactose.At 12 weeks p.i., when the experiment was terminated, the group infected and given lactose infusion (despiteh igherp arasitaemia) had no gross or histopathological lesions in the brain, spleen, lymphnodes, heart, kidneys, liver and testes. However, the group infected but not infused with lactose were emaciated, had pale mucosae, watery blood, general muscular atrophy, serous atrophy of coronary fat and other adiposet issue, hepatomegalys, plenomegalys, wollen and oedematous lymph nodes, all of which are suggestive of trypanosomosis. Histopathological lesions included arrowing of Bowman's space and hypercellularity of glomerular tufts in the kidneys with the mean glomerula truft nucleairn dices (GTNs) in the group significantly higher (P <0.01)than the mean GTNs of the lactoseinfused and control bulls. Degenerative changes occurred in the myocardium, spleen, testes and epididymides. The tesicular and epididymal lesions are indicative of male reproductive dysfunction.

Estimation of Phenytoin Pharmacokinetic Parameters in Saudi Epileptic Patients

Pharmacology ◽  
2019 ◽  
Vol 104 (1-2) ◽  
pp. 60-66 ◽  
Author(s):  
Saeed Alqahtani ◽  
Thuraya Alzaidi ◽  
Mashal Alotaibi ◽  
Abdullah Alsultan
Keyword(s):  
Body Weight ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Total Daily Dose ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Linear Absorption ◽  
Significant Covariates ◽  
Saudi Patients

Objective: This study aimed to assess the population pharmacokinetics of phenytoin in Saudi patients and identify factors affecting therapeutic parameters. Method: A retrospective chart review was performed at King Saud University Medical City on patients treated with oral phenytoin. We used Monolix 4.4. for population pharmacokinetic modeling. A base model was developed to investigate several covariates, including age, gender, weight, total daily dose (TTD), and liver function test results. Results: The analysis included a total of 81 phenytoin plasma concentrations from 43 patients (70% male). Patients’ mean (± SD) age was 41 (±18.7) years and body weight was 65.4 (±17.7) kg. The patients received a phenytoin TDD of 330.5 (±104.5) mg/day, resulting in a trough concentration of 11.2 (±10.3) mg/L. The data were sufficiently described by the one-compartment open model with linear absorption and nonlinear elimination processes. Average parameter estimates for phenytoin volume of distribution (V), maximal elimination rate (Vmax), and Michaelis-Menten constant (Km) were 0.61 L/h/kg, 6.12 mg/kg/day, and 5.33 mg/L, respectively. The most significant covariates on phenytoin Vmax and Km were the age and body weight of the patients, along with valproic acid (VPA) cotherapy. Conclusion: The population pharmacokinetic model of phenytoin in Saudi patients found significant interindividual variability between subjects, which was affected by the patients’ age, body weight, and VPA cotherapy as the most significant covariates on phenytoin Vmax and Km. To provide guidance in drug dosage decisions, further studies are required to evaluate all factors that may potentially influence the pharmacokinetics of phenytoin.

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