A Population Pharmacokinetic Model Describing the Activity-Time-Course of PEG-Asparaginase in Children.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2746-2746 ◽  
Author(s):  
Georg Hempel ◽  
Claudia Lanvers-Kaminsky ◽  
Hans-Joachim Mueller ◽  
Gudrun Wuerthwein ◽  
Joachim Boos
Keyword(s):  
Time Course ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Activity Time ◽  
Serum Samples ◽  
Limit Of Quantification ◽  
Treatment Protocols ◽  
First Order ◽  
Activity Measurements ◽  
Asparaginase Activity

Abstract PEG-Asparaginase is an important part of many treatment protocols for ALL. In many centres Asparaginase activity is measured after administration of PEG-asparaginase. However, a predictive pharmacokinetic model is lacking. Such a model would be helpful for dose adjustment and decision making when to switch to another preparation due to the development of inactivating antibodies. Previously described models like linear one-compartment [V.I. Avramis et al., Blood 2002, 99: 1986–1994] or a one-compartment Michaelis-Menten model [H.J. Mueller et al., Cancer Chemother. Pharmacol. 2002, 49, 149–154] describe the data sufficiently for one dose alone, but cannot account for the phenomenom that the time to reach a lower activity limit after administration is not increasing with increasing the dose. Therefore, we analysed 1189 serum activity measurements in 185 children from the ALL-BFM 95 study. Patients received 500, 1000 or 2500 U/m2 PEG-Asp on up to 9 occasions. Serum asparaginase activity was measured using a semi-automatic enzymatic assay with a limit of quantification of 2 U/l [C. Lanvers et al. Anal. Biochem. 2002, 309, 117–126]. Data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. V). Different models like Michaelis-Menten, linear first-order, Weibull and gamma models were tested. The best model applicable to all dosing groups was a modified first-order one-compartmental model with clearance increasing with time according to the formula: Cl = Cli*exp(0.0853*t) with Cli=initial clearance, and t=time. Addition of a second compartment did not improve the model. A typical activity-time course of a patient receiving 1000 U/m2 is shown below displaying the typical shape observable in all patients and in all doing groups. The population parameters found were: Volume of distribution (V) 1.05 ± 27.3% l/m2, Cli 60.3 ± 70.8% ml/day/m2 (mean ± interindividual variability). Interoccasion variability was substantial with 0.223 l/m2 for V and 37.7 ml/day/m2 for Cl, respectively. A subgroup of one third of the patients is identifiable showing a high clearance probably due to the development of inactivating antibodies. Drug monitoring of serum PEG-Asparaginase activity is required to identify these patients who do not benefit from PEG-Asp therapy. The pharmacokinetic model presented here should help to reduce the number of required serum samples per patient. Figure Figure

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.

scholarly journals Population Pharmacokinetic Analysis of Yimitasvir in Chinese Healthy Volunteers and Patients With Chronic Hepatitis C Virus Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiao-duo Guan ◽  
Xian-ge Tang ◽  
Ying-jun Zhang ◽  
Hong-ming Xie ◽  
Lin Luo ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Healthy Volunteers ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Oral Clearance ◽  
First Order ◽  
Apparent Oral Clearance ◽  
Significant Covariates

Yimitasvir is a novel, oral hepatitis C virus (HCV) non-structural protein 5A inhibitor for the treatment of chronic HCV genotype 1 infection. The objective of this analysis was to develop a population pharmacokinetic model of yimitasvir in Chinese healthy volunteers and HCV infection patients. The model was performed using data from 219 subjects across six studies. Nonlinear mixed effects models were developed using Phoenix NLME software. The covariates were evaluated using a stepwise forward inclusion (p < 0.01) and then a backward exclusion procedure (p < 0.001). A two-compartment model with sequential zero-first order absorption and first-order elimination reasonably described yimitasvir pharmacokinetics (PK). The apparent oral clearance and central volume of distribution were 13.8 l·h−1 and 188 l, respectively. The bioavailability (F) of yimitasvir decreased 12.9% for each 100 mg dose increase. Food was found to affect absorption rate (Ka) and F. High-fat meal decreased Ka and F by 90.9% and 38.5%, respectively. Gender and alanine aminotransferase were identified as significant covariates on apparent oral clearance. Female subjects had lower clearance than male subjects. Zero-order absorption duration was longer in healthy volunteers (2.17 h) than that in patients (1.43 h). The population pharmacokinetic model described yimitasvir PK profile well. Food decreased Ka and F significantly, so it was recommended to take yimitasvir at least 2 h before or after a meal. Other significant covariates were not clinically important.

scholarly journals Pilot Study of Oral Realgar-Indigo Naturalis Formula in Pediatric Acute Promyelocyticleukemia: Effectiveness and Population Pharmacokinetics

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5084-5084
Author(s):  
Li Zhang ◽  
Xin-mei Yang ◽  
Jing Chen ◽  
Lei Hu ◽  
Fan Yang ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Acute Promyelocytic Leukemia ◽  
Pharmacokinetic Model ◽  
Compartment Model ◽  
Promyelocytic Leukemia ◽  
Population Pharmacokinetic ◽  
Newly Diagnosed ◽  
Dosing Regimen ◽  
First Order ◽  
Indigo Naturalis

# The first two authors contributed equally * The last two authors contributed equally Background: Realgar-Indigo Naturalis Formula (RIF), the only commercially oral arsenic agent, was launched in China from 2009. It has been recommended as consolidation or maintenance therapy in adults with acute promyelocytic leukemia (APL). Recently, RIF had been off-label used in pediatric APL in China. However, the knowledge of efficacy and dosage of RIF in pediatric was limited until now. Objective: The purpose of this pilot study was to evaluate effectiveness and pharmacokinetics of RIF as consolidation or maintenance therapy for newly diagnosed and relapsed APL in pediatric after induction therapy with intravenous arsenic trioxide. Meanwhile, modeling and simulation techniques were used to evaluate and optimize RIF dosing regimen in pediatric population. Patients and Methods: A total of 11 newly diagnosed APL and 1 relapsed patient (4-14years of age) were included from July 2016 to August 2017.The one relapsed and six newly diagnosed patients were treated with RIF (60 mg/kg/day TID) as maintenance therapy. Five newly diagnosed patients were treated with RIF (60 mg/kg/day TID) as consolidation and maintenance therapy. The treatment protocol and MRD results are shown in Figure 1. Event-free survival and overall survival were used to evaluate the efficacy. The plasma concentration of arsenic was quantified by inductively coupled plasma mass spectrometry (ICP-MS). Population pharmacokinetic analysis was carried out using the nonlinear mixed effects modeling program NONMEM V 7.2 (Icon Development Solutions, USA). Results: All newly diagnosed APL patients were alive as of July 1, 2019 and were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%. Of note, all the patients completed the postremission therapy containing RIF on an outpatient basis. A total of 107 arsenic concentrations were used for population pharmacokinetic model building. The arsenic concentrations of the blood samples ranged from 0.1 to 75.0 µg/L. The steady-state trough plasma arsenic concentration during the RIF treatment was 47.43μg/L (range, 25.74 to 62.97μg/L).A one-compartment model with first-order elimination fitted the data. Body weight was the only significant covariate of CL for the final model development. The developmental pharmacokinetic model was evaluated by goodness-of-fit plots and bootstrap analysis. The mean and variance of NPDE were -0.118 and 0.93, respectively. Conclusions: The effectiveness and pharmacokinetics were evaluated for the first time in pediatricAPL.The developmental population pharmacokinetic model for RIF in children revealed that one-compartment model with first-order elimination fitted the data.The current dosing regimen of 60 mg/kg/day TID resulted higher steady-state through concentration than that in adults (24.4μg/L, range:11.5 to 64μg/L). Disclosures:No relevant conflicts of interest to declare. This trial was conducted in accordance with the Declaration of Helsinki. OffLabel Disclosure: The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has become the front-line treatment for patients with acute promyelocytic leukemia (APL). Realgar-Indigo Naturalis Formula (RIF), the only commercially oral arsenic agent, was launched in China from 2009. Since then, RIF had been used for over 5000 adults with acute promyelocytic leukemia (APL). One pill of RIF is 270 mg which contains 30 mg of Realgar, 125 mg of Indigo naturalis, 50 mg of Radix salviae miltiorrhizae, 45 mg of Radix pseudostellariae, and 20mg of garment film. However, the pharmacokinetics of RIF in children has not been studied.

scholarly journals A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Marlou L. P. S. van Iersel ◽  
Stefaan Rossenu ◽  
Rik de Greef ◽  
Hetty Waskin
Keyword(s):  
Body Weight ◽  
High Risk ◽  
Pharmacokinetic Model ◽  
Tablet Formulation ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Clinical Factors ◽  
Oral Tablet ◽  
First Order ◽  
The Impact

ABSTRACT A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one-compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia versus allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (a single dose versus multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/liter) to a broad range of patients at high risk for invasive fungal disease.

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 Pharmacokinetics of Extended-Infusion Piperacillin-Tazobactam in Hospitalized Patients with Nosocomial Infections

2012 ◽  
Vol 56 (8) ◽  
pp. 4087-4094 ◽  
Author(s):  
T. W. Felton ◽  
W. W. Hope ◽  
B. M. Lomaestro ◽  
J. M. Butterfield ◽  
A. L. Kwa ◽  
...  
Keyword(s):  
Nosocomial Infections ◽  
Pharmacokinetic Profile ◽  
Hospitalized Patients ◽  
Population Pharmacokinetic ◽  
Serum Samples ◽  
First Order ◽  
Clearance Mechanism ◽  
Dosing Regimens ◽  
Extended Infusion ◽  
Nonlinear Clearance

ABSTRACTWhile extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50%fT>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50%fT>MIC for MICs of ≥8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximizefT>MIC in certain hospitalized populations.

scholarly journals Population Pharmacokinetic Model for Intravenous ASN100 in Healthy Subjects

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S529-S529
Author(s):  
Scott A Van Wart ◽  
Christopher Stevens ◽  
Zoltan Magyarics ◽  
Steven A Luperchio ◽  
Paul G Ambrose
Keyword(s):  
Healthy Subjects ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic

scholarly journals Ultrasensitive and label free electrochemical immunosensor for detection of ROR1 as an oncofetal biomarker using gold nanoparticles assisted LDH/rGO nanocomposite

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rozita Abolhasan ◽  
Balal Khalilzadeh ◽  
Hadi Yousefi ◽  
Sahar Samemaleki ◽  
Forough Chakari-Khiavi ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Flexible Structures ◽  
Modified Electrodes ◽  
Electrochemical Immunosensor ◽  
Lymphocytic Leukemia ◽  
Orphan Receptor ◽  
Detection Sensitivity ◽  
Label Free ◽  
Serum Samples ◽  
Limit Of Quantification

AbstractIn the present article, we developed a highly sensitive label-free electrochemical immunosensor based on NiFe-layered double hydroxides (LDH)/reduced graphene oxide (rGO)/gold nanoparticles modified glassy carbon electrode for the determination of receptor tyrosine kinase-like orphan receptor (ROR)-1. In this electrochemical immunoassay platform, NiFe-LDH/rGO was used due to great electron mobility, high specific surface area and flexible structures, while Au nanoparticles were prepared and coated on the modified electrodes to improve the detection sensitivity and ROR1 antibody immobilizing (ROR1Ab). The modification procedure was approved by using cyclic voltammetry and differential pulse voltammetry based on the response of peak current to the step by step modifications. Under optimum conditions, the experimental results showed that the immunosensor revealed a sensitive response to ROR1 in the range of 0.01–1 pg mL−1, and with a lower limit of quantification of 10 attogram/mL (10 ag mL−1). Furthermore, the designed immunosensor was applied for the analysis of ROR1 in several serum samples of chronic lymphocytic leukemia suffering patients with acceptable results, and it also exhibited good selectivity, reproducibility and stability.

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