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

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.

Population pharmacokinetics of fondaparinux administered at prophylactic doses after major orthopaedic surgery in everyday practice

2010 ◽  
Vol 104 (08) ◽  
pp. 252-260 ◽  
Author(s):  
Paul Zufferey ◽  
Denis Baylot ◽  
Philippe Nguyen ◽  
Jeanne-Yvonne Borg ◽  
Michaela Fontenay ◽  
...  
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Compartment Model ◽  
Individual Variability ◽  
Everyday Practice ◽  
Population Pharmacokinetic ◽  
Antithrombotic Agent ◽  
Orthopaedic Patients

SummaryFondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. A population pharmacokinetic model of fondaparinux, based on data obtained in patients included in phase II/III trials, has been described. However, the validity of this model in everyday practice needed to be confirmed. This study was a multicenter, prospective cohort study in consecutive orthopaedic patients treated with 2.5 mg of fondaparinux. Anti-Xa activities were recorded in 809 patients. Population parameters and inter-individual variability were estimated using NONMEM VI software. A two-compartment model with first-order absorption best described fondaparinux pharmacokinetics. Covariates partly explaining inter-individual variability were body weight, age and creatinine clearance estimated by the simplified Modification of Diet in Renal Disease formula (MDRD). A body weight less than 50 kg and moderate renal failure increased drug exposure. Although the population pharmacokinetic model of fondaparinux was described, this one requires to be validated in everyday practice.

scholarly journals Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 54 ◽  
Author(s):  
Amaia Soraluce ◽  
Helena Barrasa ◽  
Eduardo Asín-Prieto ◽  
Jose Ángel Sánchez-Izquierdo ◽  
Javier Maynar ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Standard Dose ◽  
Compartment Model ◽  
Antimicrobial Treatment ◽  
Population Pharmacokinetic ◽  
Renal Replacement Therapies ◽  
Continuous Renal Replacement Therapies

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

scholarly journals Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization

2022 ◽  
Vol 12 ◽  
Author(s):  
SiChan Li ◽  
SanLan Wu ◽  
WeiJing Gong ◽  
Peng Cao ◽  
Xin Chen ◽  
...  
Keyword(s):  
Maintenance Dose ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Immunocompromised Patients ◽  
First Order ◽  
Dosing Regimens

Purpose: The aims of this study were to establish a joint population pharmacokinetic model for voriconazole and its N-oxide metabolite in immunocompromised patients, to determine the extent to which the CYP2C19 genetic polymorphisms influenced the pharmacokinetic parameters, and to evaluate and optimize the dosing regimens using a simulating approach.Methods: A population pharmacokinetic analysis was conducted using the Phoenix NLME software based on 427 plasma concentrations from 78 patients receiving multiple oral doses of voriconazole (200 mg twice daily). The final model was assessed by goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to evaluate and optimize the dosing regimens.Results: A one-compartment model with first-order absorption and mixed linear and concentration-dependent-nonlinear elimination fitted well to concentration-time profile of voriconazole, while one-compartment model with first-order elimination well described the disposition of voriconazole N-oxide. Covariate analysis indicated that voriconazole pharmacokinetics was substantially influenced by the CYP2C19 genetic variations. Simulations showed that the recommended maintenance dose regimen would lead to subtherapeutic levels in patients with different CYP2C19 genotypes, and elevated daily doses of voriconazole might be required to attain the therapeutic range.Conclusions: The joint population pharmacokinetic model successfully characterized the pharmacokinetics of voriconazole and its N-oxide metabolite in immunocompromised patients. The proposed maintenance dose regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.

scholarly journals Population Pharmacokinetic Model for Gatifloxacin in Pediatric Patients

2007 ◽  
Vol 51 (4) ◽  
pp. 1246-1252 ◽  
Author(s):  
Christopher M. Rubino ◽  
Edmund V. Capparelli ◽  
John S. Bradley ◽  
Jeffrey L. Blumer ◽  
Gregory L. Kearns ◽  
...  
Keyword(s):  
Body Weight ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Population Pharmacokinetic ◽  
Forward Selection ◽  
Once Daily

ABSTRACT The broad spectrum of antimicrobial activity, oral bioavailability, extensive tissue distribution, and once-daily intravenous or oral dosing of gatifloxacin, an expanded-spectrum 8-methoxy fluoroquinolone, make it a potentially useful agent for the treatment of pediatric infections. A population pharmacokinetic model was developed to describe the pharmacokinetics of gatifloxacin in children. Data for analysis were obtained from a single-dose safety/pharmacokinetic study utilizing intensive blood sampling in patients aged 6 months to 16 years. Each subject received a single oral dose of gatifloxacin as a suspension, at doses of 5, 10, or 15 mg/kg of body weight. A total of 845 samples were obtained from 82 patients. A one-compartment model with first-order absorption and elimination was the most appropriate to describe the gatifloxacin concentrations. Covariate analysis using forward selection and backward elimination found that apparent clearance was related to body surface area, and apparent volume of distribution was related to body weight. No effect of age on drug clearance could be identified once clearance was corrected for body surface area. Based on pharmacokinetic simulations, the 10-mg/kg (maximum, 400 mg) once-daily dose of gatifloxacin is expected to provide drug exposure similar to that in healthy adults. The population pharmacokinetic model described herein will be used for Bayesian analyses of sparse pharmacokinetic sampling in phase II/III clinical trials and for Monte Carlo simulation experiments. The success of this strategy provides a model for future pediatric drug development programs.

scholarly journals Population Pharmacokinetic Model of Oxfendazole and Metabolites in Healthy Adults following Single Ascending Doses

2021 ◽  
Author(s):  
Thanh Bach ◽  
Daryl J. Murry ◽  
Larissa V. Stebounova ◽  
Gregory Deye ◽  
Patricia Winokur ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Dose Range ◽  
Formation Rate ◽  
Human Study ◽  
Compartment Model ◽  
Healthy Adults ◽  
Population Pharmacokinetic ◽  
Mixed Effect ◽  
Clinical Pharmacokinetics

Oxfendazole is a potent veterinary benzimidazole anthelmintic under transition to human for the treatment of multiple parasitic infectious diseases. The first-in-human study evaluating the disposition of oxfendazole and its metabolites in healthy adults following single ascending oral doses from 0.5 to 60 mg/kg shows that oxfendazole pharmacokinetics is substantially nonlinear, which complicates correlating oxfendazole dose to exposure. To quantitatively capture the relation between oxfendazole dose and exposure, a population pharmacokinetic model for oxfendazole and its metabolites, oxfendazole sulfone and fenbendazole, in humans was developed using nonlinear mixed-effect modeling approach. Our final model incorporated mechanistic characterization of dose limited bioavailability as well as different oxfendazole metabolic processes and provided insight to the significance of pre-systemic metabolism in oxfendazole and metabolites disposition. Oxfendazole clinical pharmacokinetics was best described by a one-compartment model with nonlinear absorption and linear elimination. Oxfendazole apparent clearance and apparent volume of distribution were estimated to be 2.57 L/h and 35.2 L, respectively, at the lowest dose (0.5 mg/kg), indicating that oxfendazole is a low extraction drug with moderate distribution. The disposition of both metabolites was adequately characterized by one-compartment model with formation-rate limited elimination. Fenbendazole formation from oxfendazole was primarily through systemic metabolism while both pre-systemic and systemic metabolism were critical to the formation of oxfendazole sulfone. Our model adequately captured the concentration-time profiles of both oxfendazole and its two metabolites in healthy adults over a wide dose range. The model can be used to predict oxfendazole disposition under new dosing regimens to support dose optimization in humans.

scholarly journals Effect of Pregnancy on Unbound Raltegravir Concentrations in the ANRS 160 RalFe Trial

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Yi Zheng ◽  
Déborah Hirt ◽  
Sandrine Delmas ◽  
Gabrielle Lui ◽  
Sihem Benaboud ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Third Trimester ◽  
Open Label ◽  
First Order ◽  
The Third ◽  
Pregnancy And Postpartum

ABSTRACT A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. The RalFe ANRS160 study was a nonrandomized, open-label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing 400 mg raltegravir twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one-compartment model with a transit compartment with first-order absorption, evolving to bound raltegravir (by a linear binding to albumin) or metabolism to RAL-glucuronide or to a first-order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound area under the curve from 0 to 12 h significantly decreased by 36% and 27% during pregnancy. Median total trough concentration (Ctrough) decreased significantly in the evening (28%); however, the median total Ctrough in the morning, unbound Ctrough in the morning, and unbound Ctrough in the evening showed a nonsignificant decrease of 16%, 1%, and 15%, respectively, during pregnancy compared to the postpartum period. This is the first study reporting the pharmacokinetics of unbound raltegravir during pregnancy. As unbound Ctrough did not significantly decrease during the third trimester, the pregnancy effect on raltegravir unbound concentrations was not considered clinically relevant. (This study has been registered at ClinicalTrials.gov under identifier NCT02099474.)

scholarly journals O11 Characterising the pharmacokinetics of phenobarbitone in neonates to facilitate future individualised dosing

2019 ◽  
Vol 104 (6) ◽  
pp. e5.1-e5 ◽  
Author(s):  
A Williams ◽  
T Donovan ◽  
B Charles ◽  
C Staatz
Keyword(s):  
Oral Bioavailability ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Absolute Bioavailability ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Young Infants ◽  
Intravenous And Oral Administration

BackgroundPhenobarbitone is commonly used as a first-line drug in the treatment of neonatal seizures. Previous studies, with small subject numbers, have identified covariates that may influence the pharmacokinetics of phenobarbitone but results have been inconsistent. In particular, oral bioavailability is poorly described with doses reported as being identical for intravenous and oral administration, however, 2 recent studies have reported oral bioavailability of 49% and 59% respectively.1,2MethodsA population pharmacokinetic model was built based on routine therapeutic drug monitoring data from 112 infants at the Royal Brisbane and Women’s Hospital Neonatal Intensive Care Unit. Population modelling was performed using NONMEM 7.3 and PsN 4.7 with assistance from R studio and the packages Xpose and VPC. Body weight with allometric scaling on Clearance (CL) and Volume of Distribution (V) were included a priori in the structural model. Covariates tested included age (post-menstrual, gestational and post-natal), Apgar scores, concomitant phenytoin treatment, infection and method of nutrition.ResultsA one-compartment model provided an adequate fit to the data. Typical clearance increased with patient post-natal age (PNA) and was best modelled using the equation CL = 5.1 *WT0.75 * (PNA/6.25)0.43 (mL/h) were weight is in kg, PNA in days and 6.25 is the median post-natal age. Volume of distribution (V) was best modelled using the equation V = 799 * WT1.0 (mL). Oral bioavailability (F) was 85%. Between-subject variability was 25% and 30% respectively for CL and V.ConclusionThis study describes the largest population pharmacokinetic model of phenobarbitone developed to date with estimates of CL and V similar to previously published models. Estimated F is higher than previously reported but still lower than the implied F of 100% in most recommended dosing regimens. The model could be used to assist with future individualisation of dosing in this cohort.ReferencesMarsot A, et al. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach. Fundam Clin Pharmacol 2014;28(4):465–71.Voller S, et al. Model-based clinical dose optimization for phenobarbital in neonates: An illustration of the importance of data sharing and external validation. Eur J Pharm Sci 2017;109s:S90–S97.Disclosure(s)Nothing to disclose

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

2015 ◽  
Vol 59 (9) ◽  
pp. 5681-5696 ◽  
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.

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

2014 ◽  
Vol 30 (1) ◽  
pp. 16-24
Author(s):  
Reefat Zaman Chowdhury ◽  
Md Saiful Islam ◽  
Md Sayedur Rahman
Keyword(s):  
Pharmacokinetic Study ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Healthy Male ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Male Volunteers ◽  
Bangladeshi Population

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, AUC0–infinity, Tmax, T1/2 and Ctrough were studied with all antimicrobials. Later, the Cmax and AUC0–infinity 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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