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

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.

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 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 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 Development of a Population Pharmacokinetic Model for Cyclosporine from Therapeutic Drug Monitoring Data

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Martín Umpiérrez ◽  
Natalia Guevara ◽  
Manuel Ibarra ◽  
Pietro Fagiolino ◽  
Marta Vázquez ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Interindividual Variability ◽  
Visual Predictive Check ◽  
Lag Time ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Mixed Effect ◽  
Blood Concentrations ◽  
Apparent Clearance

Aim. To develop a population pharmacokinetic model for Uruguayan patients under treatment with cyclosporine (CsA) that can be applied to TDM. Patients and Methods. A total of 53 patients under treatment with CsA were included. 37 patients with at least one pharmacokinetic profile described with four samples were considered for model building, while the remaining 16 were considered for the assessments of predictive performances. Pharmacokinetic parameter estimation was performed using a nonlinear mixed effect modelling implemented in the Monolix® software (version 2019R1, Lixoft, France); meanwhile, simulations were performed in R v.3.6.0 with the mlxR package. Results. A two-compartment model with a first-order disposition model including lag time was used as a structural model. The final model was internally validated using prediction corrected visual predictive check (pcVPC) and other graphical diagnostics. A total of 621 CsA steady-state concentrations were analyzed for model development. Population estimates for the absorption constant (ka) and lag time were 0.523 h-1 and 0.512 h, respectively; apparent clearance (CL/F) was 30.3 L/h ( relative   standard   error   RSE ± 8.25 % ) with an interindividual variability of 39.8% and interoccasion variability of 38.0%; meanwhile, apparent clearance of distribution (Q/F) was 17.0 L/h ( RSE ± 12.1 % ) with and interindividual variability of 53.2%. The covariate analysis identified creatinine clearance (ClCrea) as an individual factor influencing the Cl of CsA. The predictive capacity of the population model was demonstrated to be effective since predictions made for new patients were accurate for C1 and C2 (MPPEs below 50%). Bayesian forecasting improved significantly in the second and third occasions. Conclusion. A population pharmacokinetic model was developed to reasonably estimate the individual cyclosporine clearance for patients. Hence, it can be utilized to individualize CsA doses for prompt and adequate achievement of target blood concentrations of CsA.

scholarly journals Population Pharmacokinetic Analysis of Amikacin for Optimal Pharmacotherapy in Korean Patients with Nontuberculous Mycobacterial Pulmonary Disease

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 784
Author(s):  
Xuanyou Jin ◽  
Jaeseong Oh ◽  
Joo-Youn Cho ◽  
SeungHwan Lee ◽  
Su-jin Rhee
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Pulmonary Disease ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Compartment Model ◽  
The Body ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Properties

Amikacin is used as a therapy for patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) who are resistant to macrolide antibiotics or have severe symptoms. This study aimed to characterize the pharmacokinetic properties of amikacin in patients with NTM-PD by developing a population pharmacokinetic model and to explore the optimal pharmacotherapy in patients with NTM-PD. For this study, all data were retrospectively collected. The amikacin pharmacokinetic properties were best described by a two-compartment model with first-order elimination. The estimated glomerular filtration rate and body weight were identified as significant covariates for clearance and the volume of distribution, respectively. A model-based simulation was conducted to explore the probability of reaching the target therapeutic range when various dose regimens were administered according to the body weight and renal function. The simulation results indicated that the amikacin dosage should be determined based on the body weight, and for patients who weigh over 70 kg, it is necessary to adjust the dose according to renal function. In conclusion, the optimal pharmacotherapy of amikacin for patients with NTM-PD was recommended based on the population pharmacokinetic model, which is expected to enable the personalization of drug therapy and improve the clinical outcomes of amikacin therapy.

scholarly journals A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
C. C. Llanos-Paez ◽  
C. E. Staatz ◽  
R. Lawson ◽  
S. Hennig
Keyword(s):  
Pediatric Oncology ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
External Evaluation ◽  
Oncology Patients ◽  
Mixed Effect ◽  
Final Model

ABSTRACT To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is recommended but is unavailable, as no population model that describes the pharmacokinetics of gentamicin in pediatric oncology patients exists. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalized dosing in pediatric oncology patients. A nonlinear mixed-effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination best described the gentamicin disposition. The final model included renal function (described by fat-free mass and postmenstrual age) and the serum creatinine concentration as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL, 5.77 liters/h/70 kg; central volume of distribution, 21.6 liters/70 kg; peripheral volume of distribution, 13.8 liters/70 kg; and intercompartmental clearance, 0.62 liter/h/70 kg. External evaluation suggested that current models developed in other pediatric cohorts may not be suitable for use in pediatric oncology patients, as they showed a tendency to overpredict the observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean square error, 46.0%; mean relative prediction error, −3.40%) and may therefore be useful for the personalization of gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model.

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