scholarly journals Population Pharmacokinetics And Bayesian Estimation of Mycophenolate Mofetil In Patients With Autoimmune Hepatitis

2021 ◽  
Author(s):  
Tom Nanga ◽  
Jean-Baptiste Woillard ◽  
Annick Rousseau ◽  
Pierre Marquet ◽  
Aurélie Prémaud
Keyword(s):  
Mycophenolate Mofetil ◽  
Maintenance Phase ◽  
Sampling Strategy ◽  
Adverse Outcomes ◽  
Bayesian Estimator ◽  
Erlang Distribution ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Mixed Effect ◽  
Nonlinear Mixed Effect

Background: Mycophenolate mofetil (MMF) is the most widely used second-line agent in auto-immune hepatitis (AIH). It is generally titrated up to patient response and continued for at least two years following complete liver enzyme normalization. However, in this maintenance phase individual dose adjustment to reach mycophenolic acid (MPA) exposure with the best benefit-risk probability may avoid adverse outcomes. The aim of the present study was to develop population pharmacokinetic (popPK) models and Maximum A-Posteriori Bayesian estimators (MAP-BEs) to estimate MPA inter-dose area under the curve (AUC0-12h) in AIH patients administered MMF using nonlinear mixed effect modelling. Methods: We analysed 50 MPA PK profiles from 34 different patients, together with some demographic, clinical, and laboratory test data. The median number of samples per profile, immediately preceding and following the morning MMF dose, was 7 [4 – 10]. PopPK modeling was performed using parametric, top-down, nonlinear mixed effect modelling with NONMEM 7.3. MAP-BEs were developed based on the the best popPK model and the best limited sampling strategy (LSS) selected among several. Results: The pharmacokinetic data were best described by a 2-compartment model, Erlang distribution to describe the absorption phase, and a proportional error. The best MAP-BE relied on the LSS at 0.33, 1 and 3 hours after mycophenolate mofetil dose administration and was very accurate (bias=5.6%) and precise (RMSE<20%). Conclusion: The precise and accurate Bayesian estimator developed in this study for AIH patients on MMF can be used to improve the therapeutic management of these patients.

scholarly journals Population Pharmacokinetics of Ceftizoxime Administered by Continuous Infusion in Clinically Ill Adult Patients

1998 ◽  
Vol 42 (7) ◽  
pp. 1783-1787 ◽  
Author(s):  
Bryan Facca ◽  
Bill Frame ◽  
Steve Triesenberg
Keyword(s):  
Serum Creatinine ◽  
Continuous Infusion ◽  
Population Pharmacokinetics ◽  
Bacterial Infections ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Beta Lactam ◽  
Serum Samples ◽  
Mixed Effect

ABSTRACT Ceftizoxime is a widely used beta-lactam antimicrobial agent, but pharmacokinetic data for use with clinically ill patients are lacking. We studied the population pharmacokinetics of ceftizoxime in 72 clinically ill patients at a community-based, university-affiliated hospital. A population pharmacokinetic model for ceftizoxime was created by using a prospective observational design. Ceftizoxime was administered by continuous infusion to treat patients with proven or suspected bacterial infections. While the patients were receiving infusions of ceftizoxime, serum samples were collected for pharmacokinetic analysis with the nonlinear mixed-effect modeling program NONMEM. In addition to clearance and volume of distribution, various comorbidities were examined for their influence on the kinetics. All 72 subjects completed the study, and 114 serum samples were collected. Several demographic and comorbidity variables, namely, age, weight, serum creatinine levels, congestive heart failure, and long-term ventilator dependency, had a significant impact on the estimate for ceftizoxime clearance. A mixture model, or two populations for estimation of ceftizoxime clearance, was discovered. One population presented with an additive clearance component of 1.6 liters per h. In addition, a maximizer function for serum creatinine levels was found. In summary, two models for ceftizoxime clearance, mixture and nonmixture, were found and are presented. Clearance for ceftizoxime can be estimated with commonly available clinical information and the models presented. From the clearance estimates, the dose of ceftizoxime to maintain the desired concentration in serum can be determined. Work is needed to validate the model for drug clearance and to evaluate its predictive performance.

scholarly journals Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

2011 ◽  
Vol 55 (11) ◽  
pp. 5314-5324 ◽  
Author(s):  
Almudena Sánchez ◽  
Salvador Cabrera ◽  
Dolores Santos ◽  
M. Paz Valverde ◽  
Aurelio Fuertes ◽  
...  
Keyword(s):  
High Performance ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Nucleotide Polymorphisms ◽  
Mixed Effect ◽  
Factors Affecting ◽  
Nonlinear Mixed Effect ◽  
Study Population ◽  
Major Factors

ABSTRACTDespite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C→T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 − 0.00279·GGT)·0.602CYP2B6*6 [G/T]·0.354CYP2B6*6 [T/T]·0.793MRP4 1497C→T, where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C→T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.

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 Pharmacokinetics and Pharmacodynamic Target Attainment of Isavuconazole against Aspergillus fumigatus and Aspergillus flavus in Adult Patients with Invasive Fungal Diseases: Should Therapeutic Drug Monitoring for Isavuconazole Be Considered as Mandatory as for the Other Mold-Active Azoles?

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2099
Author(s):  
Pier Giorgio Cojutti ◽  
Alessia Carnelutti ◽  
Davide Lazzarotto ◽  
Emanuela Sozio ◽  
Anna Candoni ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Invasive Fungal Disease ◽  
The Other ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Time Curve ◽  
Mixed Effect ◽  
Nonlinear Mixed Effect ◽  
Pharmacodynamic Analysis

Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharmacodynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve (AUC24 h)/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (Ctrough) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, provided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of Ctrough < 1.0 mg/L was around 1%, and that of Ctrough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole.

scholarly journals Application of Size and Maturation Functions to Population Pharmacokinetic Modeling of Pediatric Patients

Pharmaceutics ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 259 ◽  
Author(s):  
Hyun-moon Back ◽  
Jong Bong Lee ◽  
Nayoung Han ◽  
Sungwoo Goo ◽  
Eben Jung ◽  
...  
Keyword(s):  
Clinical Data ◽  
Goodness Of Fit ◽  
Pediatric Patients ◽  
Visual Predictive Check ◽  
Modeling Method ◽  
Population Pharmacokinetic ◽  
Mixed Effect ◽  
Population Pharmacokinetic Modeling ◽  
Nonlinear Mixed Effect ◽  
One Year

Traditionally, dosage for pediatric patients has been optimized using simple weight-scaled methods, but these methods do not always meet the requirements of children. To overcome this discrepancy, population pharmacokinetic (PK) modeling of size and maturation functions has been proposed. The main objective of the present study was to evaluate a new modeling method for pediatric patients using clinical data from three different clinical studies. To develop the PK models, a nonlinear mixed effect modeling method was employed, and to explore PK differences in pediatric patients, size with allometric and maturation with Michaelis–Menten type functions were evaluated. Goodness of fit plots, visual predictive check and bootstrap were used for model evaluation. Single application of size scaling to PK parameters was statistically significant for the over one year old group. On the other hand, simultaneous use of size and maturation functions was statistically significant for infants younger than one year old. In conclusion, population PK modeling for pediatric patients was successfully performed using clinical data. Size and maturation functions were applied according to established criteria, and single use of size function was applicable for over one year ages, while size and maturation functions were more effective for PK analysis of neonates and infants.

PHARMACOKINETIC STUDIES IN NEONATES: IS AN OPPORTUNISTIC SAMPLING STRATEGY SUFFICIENT FOR POPULATION PHARMACOKINETIC MODELLING AND DOSE PREDICTION?

2015 ◽  
Vol 101 (1) ◽  
pp. e1.11-e1
Author(s):  
Stéphanie Leroux ◽  
Mark A. Turner ◽  
Chantal Barin-Le Guellec ◽  
Helen Hill ◽  
Johannes N. van den Anker ◽  
...  
Keyword(s):  
Sampling Strategy ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Pharmacokinetic Modelling ◽  
Blood Samples ◽  
Dose Prediction ◽  
Population Pharmacokinetic Modelling ◽  
Opportunistic Sampling

Background and objectiveThe use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation as well as dose prediction, and compare this strategy to a pre-determined pharmacokinetic sampling approach.MethodsThree population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), pre-determined (i.e., scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), respectively, using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients.ResultsPharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at pre-determined times and 165 that were scavenged from those obtained as part of clinical care. All data sets were fit using a two-compartment model with first order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady state volume of distribution) as compared to the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation and showed similar results. Monte Carlo simulation based on AUC0–24/MIC using either the SC or the TR model gave similar dose prediction for ciprofloxacin.ConclusionBlood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements.

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