Pharmacokinetic study after single oral dose of beta-lactam and fluoroquinolone antimicrobials in Bangladeshi healthy male volunteers

The variability of response to antimicrobial has been inadequately explained because of lack of pharmacokinetic data. The present pharmacokinetic study was designed to provide information beneficial to formulate a population pharmacokinetic model appropriate for Bangladeshi population. Among the beta-lactams, amoxicillin (500 mg), flucloxacillin (250 mg), cefuroxime (500 mg) and among the fluoroquinolones, ciprofloxacin (500 mg), levofloxacin (500 mg), gatifloxacin (400 mg) were studied in 15 healthy Bangladeshi male volunteers. The Cmax, AUC0infinity, Tmax, T1/2 and Ctrough were studied with all antimicrobials. Later, the Cmax and AUC0infinity were adjusted for bodyweight and dose. Among the studied antimicrobials, the Cmax varied to great extent even after adjustment for bodyweight and dose. The Cmax after adjustment was highest in case of flucloxacillin and lowest in case of ciprofloxacin, indicating excellent absorption of flucloxacillin in Bangladeshi population. The information obtained through this study generates necessity of new cut-off value for the antimicrobials.DOI: http://dx.doi.org/10.3329/bjpp.v30i1.20789 Bangladesh J Physiol Pharmacol 2014; 30(1):16-24

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Population Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02387-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 2

Author(s):

Si-Chan Li ◽

Qi Ye ◽

Hua Xu ◽

Long Zhang ◽

Yang Wang

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Pediatric Patients ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Nonparametric Bootstrap ◽

Bootstrap Analysis ◽

Final Model

ABSTRACT Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize the dosing strategy in order to improve therapeutic efficacy. We performed a prospective pharmacokinetic study of pediatric patients aged 0 to 12 years. The population pharmacokinetic model was developed using the NONMEM program. Goodness-of-fit plots, nonparametric bootstrap analysis, normalized prediction distribution errors, and a visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model. The pharmacokinetic data from 112 pediatric patients ages 0.03 to 11.9 years were analyzed. The pharmacokinetics could best be described by a one-compartment model with first-order elimination along with body weight and the estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg of body weight every 8 h (q8h) would lead to a high risk of underdosing for children in the presence of bacteria with MICs of ≥2 mg/liter. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them. The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization.

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Impact of gender, albumin, and CYP2C19 polymorphisms on valproic acid in Chinese patients: a population pharmacokinetic model

Journal of International Medical Research ◽

10.1177/0300060520952281 ◽

2020 ◽

Vol 48 (8) ◽

pp. 030006052095228

Author(s):

Jinlin Guo ◽

Yayu Huo ◽

Fang Li ◽

Yuanping Li ◽

Zhaojun Guo ◽

...

Keyword(s):

Valproic Acid ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Volume Of Distribution ◽

Chinese Patients ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Mixed Effect ◽

First Order ◽

The Impact

Objective This prospective study aimed to establish the valproic acid (VPA) population pharmacokinetic model in Chinese patients and realise personalised medication on the basis of population pharmacokinetics. Methods The patients’ clinical information and VPA plasma concentrations were collected from The General Hospital of Taiyuan Iron & Steel (Group) Corporation (TISCO). Nonlinear mixed-effect modelling was used to build the population pharmacokinetic model. To characterise the pharmacokinetic data, a one-compartment pharmacokinetic model with first-order absorption and elimination was used. The first-order conditional estimation with η-ε interaction was applied throughout the model-developing procedure. The absorption rate constant (Ka) was fixed at 2.38 hour−1, and the impact of covariates on clearance and apparent volume of distribution were also explored. Medical records of 60 inpatients were reviewed prospectively and the objective function value (OFV) of the base model and final model were 851.813 and 817.622, respectively. Results Gender was identified as the covariate that had a significant impact on the volume of distribution, and albumin and CYP2C19 genotypes influenced clearance. Conclusion Bootstrap and VPC indicated that a reliable model had been developed that was based on the simulation results, and a simple-to-use dosage regimen table was created to guide clinicians for VPA drug dosing.

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Reply to Baklouti et al., “Why Is It Desirable To Do the External Evaluation of a Population Pharmacokinetic Model?”

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01908-21 ◽

2021 ◽

Author(s):

Pier Giorgio Cojutti ◽

Matteo Rinaldi ◽

Eleonora Zamparini ◽

Nicolò Rossi ◽

Sara Tedeschi ◽

...

Keyword(s):

Pharmacokinetic Study ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Optimal Treatment ◽

Adult Patients ◽

Population Pharmacokinetic ◽

External Evaluation ◽

Population Pharmacokinetic Study ◽

Osteoarticular Infections ◽

French Group

We thank Baklouti et al. (1) for commenting on our population pharmacokinetic study of dalbavancin for optimal treatment of adult patients with staphylococcal osteoarticular infections (2) and for suggesting that our model tends to underestimate the concentrations observed in a group of French patients (French group).…

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Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00973-15 ◽

2015 ◽

Vol 59 (9) ◽

pp. 5681-5696 ◽

Cited By ~ 32

Author(s):

Ahmad Y. Abuhelwa ◽

David J. R. Foster ◽

Stuart Mudge ◽

David Hayes ◽

Richard N. Upton

Keyword(s):

Single Dose ◽

Healthy Subjects ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Oral Absorption ◽

Compartment Model ◽

Time Dependent ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Size Estimation

ABSTRACTItraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies.

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Development of population and Bayesian models for applied use in patients receiving cefepime

10.1101/19009647 ◽

2019 ◽

Author(s):

Jiajun Liu ◽

Michael Neely ◽

Jeffrey Lipman ◽

Fekade Sime ◽

Jason Roberts ◽

...

Keyword(s):

Clinical Outcomes ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Drug Exposure ◽

Model Performance ◽

Compartment Model ◽

Population Pharmacokinetic ◽

List Type ◽

Beta Lactam ◽

Lactam Antibiotic

AbstractUnderstanding exposures of cefepime, a β-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment. Multiple physiologically relevant models were fit to pediatric and adult subject data. To evaluate the final model performance, a withheld group of twelve pediatric and two separate adult populations were assessed. Seventy subjects with a total of 604 cefepime concentrations were included in this study. All adults (n=34) on average weighed 82.7 kg and displayed a mean creatinine clearance (CrCL) of 106.7 mL/min. All pediatric subjects (n=36) had mean weight and CrCL of 16.0 kg and 195.64 mL/min, respectively. A covariate-adjusted two compartment model described the observed concentrations well (population model R2, 87.0%; Bayesian model R2, 96.5%). In the evaluation subsets, the model performed similarly well (population R2, 84.0%; Bayesian R2, 90.2%). The identified model serves well for population dosing and as a Bayesian prior for precision dosing.Key pointsA unified cefepime population pharmacokinetic model has been developed from adult and pediatric patients and evaluates well in independent populations.When paired with real time beta-lactam assays, precision dosing approach will optimize drug exposure and improve clinical outcomes.

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Suramin: development of a population pharmacokinetic model and its use with intermittent short infusions to control plasma drug concentration in patients with prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.1.166 ◽

1994 ◽

Vol 12 (1) ◽

pp. 166-175 ◽

Cited By ~ 25

Author(s):

D I Jodrell ◽

L M Reyno ◽

R Sridhara ◽

M A Eisenberger ◽

K H Tkaczuk ◽

...

Keyword(s):

Prostate Cancer ◽

Linear Model ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Hormone Refractory Prostate Cancer ◽

Pharmacokinetic Models ◽

Hormone Refractory

PURPOSE This study aimed to (1) develop a population pharmacokinetic model for suramin; (2) use Bayesian methods to assess suramin pharmacokinetics in individual patients; (3) use individual patients' pharmacokinetic parameter estimates to individualize suramin dose and schedule and maintain plasma suramin concentrations within predetermined target ranges; and (4) assess the feasibility of outpatient administration of suramin by intermittent, short infusions. METHODS Plasma suramin concentrations were measured by high-performance liquid chromatography (HPLC), and compartmental pharmacokinetic models were fit using a Bayesian algorithm. Population pharmacokinetic models were developed using an iterative two-stage approach. Estimates of each patient's central-compartment volume were used to calculate suramin dosage. Simulation of that patient's suramin clearance was used to predict the time of his next dose. Using this approach, plasma suramin concentration was maintained at between 200 and 300, 175 and 275, 150 and 250, or 100 and 200 microgram/mL in four sequential patient cohorts. The ability of two- and three-compartment, open, linear models to fit the pharmacokinetic data was compared. Population pharmacokinetic parameters were estimated, using both two- and three-compartment structural models in 69 hormone-refractory prostate cancer patients. RESULTS Target plasma suramin concentrations in individual patients were rapidly achieved. Concentrations were maintained within desired ranges for > or = 85% of treatment duration in all cohorts. A three-compartment, open, linear model described suramin pharmacokinetics better than did a two-compartment, open, linear model. Population pharmacokinetic estimates generated for two- and three-compartment pharmacokinetic models demonstrated modest interpatient pharmacokinetic variability and the long terminal half-life of suramin. CONCLUSION Suramin can be administered by intermittent short infusion. Adaptive-control-with-feedback dosing facilitated precise control of plasma suramin concentrations and allowed a number of different concentration ranges to be studied. This approach is expensive and labor-intensive. Although we have demonstrated the ability to control drug exposure, simpler dosing schedules require critical evaluation. Population pharmacokinetic parameters generated in men with hormone-refractory prostate cancer will facilitate rational design of such schedules.

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Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02401-16 ◽

2017 ◽

Vol 61 (3) ◽

Cited By ~ 4

Author(s):

Ashley M. Hopkins ◽

Jessica Wojciechowski ◽

Ahmad Y. Abuhelwa ◽

Stuart Mudge ◽

Richard N. Upton ◽

...

Keyword(s):

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Phase 1 ◽

Plasma Concentrations ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Delayed Release

ABSTRACT The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.

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