scholarly journals Advanced pharmacokinetic models based on organ clearance, circulatory, and fractal concepts

2007 ◽  
Vol 9 (2) ◽  
pp. E268-E283 ◽  
Author(s):  
K. Sandy Pang ◽  
Michael Weiss ◽  
Panos Macheras
Keyword(s):  
Pharmacokinetic Models ◽  
Organ Clearance

scholarly journals External Evaluation of Population Pharmacokinetic Models and Bayes-Based Dosing of Infliximab

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1191
Author(s):  
Celine Konecki ◽  
Catherine Feliu ◽  
Yoann Cazaubon ◽  
Delphine Giusti ◽  
Marcelle Tonye-Libyh ◽  
...  
Keyword(s):  
Goodness Of Fit ◽  
Inflammatory Diseases ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
External Evaluation ◽  
Immunomodulatory Treatment ◽  
Weighted Residuals ◽  
Prediction Distribution ◽  
Target Plasma

Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with the recommendations. This study aimed to submit these models to an external evaluation and verify their predictive capabilities. Eight models were selected for external evaluation, carried out on an independent database (409 concentrations from 157 patients). Each model was evaluated based on the following parameters: goodness-of-fit (comparison of predictions to observations), residual error model (population weighted residuals (PWRES), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE)), and predictive performances (prediction-corrected visual predictive checks (pcVPC) and Bayesian simulations). The performances observed during this external evaluation varied greatly from one model to another. The eight evaluated models showed a significant bias in population predictions (from −7.19 to 7.38 mg/L). Individual predictions showed acceptable bias and precision for six of the eight models (mean error of −0.74 to −0.29 mg/L and mean percent error of −16.6 to −0.4%). Analysis of NPDE and pcVPC confirmed these results and revealed a problem with the inclusion of several covariates (weight, concomitant immunomodulatory treatment, presence of anti-drug antibodies). This external evaluation showed satisfactory results for some models, notably models A and B, and highlighted several prospects for improving the pharmacokinetic models of infliximab for clinical-biological application.

External evaluation of published population pharmacokinetic models of polymyxin B

2021 ◽  
Author(s):  
Ya-qian Li ◽  
Kai-feng Chen ◽  
Jun-jie Ding ◽  
Hong-yi Tan ◽  
Nan Yang ◽  
...  
Keyword(s):  
Polymyxin B ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
External Evaluation

Abstract 2238: New Pharmacokinetic Models for Quantitative Molecular Imaging of Plaque Angiogenesis with Intergrin-targeted Nanoparticles

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hoon Sim ◽  
Anne Neubauer ◽  
Shelton Caruthers ◽  
Gregory Lanza ◽  
Samuel Wickline ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Early Detection ◽  
Cross Sections ◽  
Aortic Wall ◽  
Spin Echo ◽  
Vasa Vasorum ◽  
Pharmacokinetic Models ◽  
Descending Thoracic Aorta ◽  
Targeted Nanoparticles ◽  
Simultaneous Fitting

Cardiovascular molecular imaging with targeted nanoparticles has emerged as a promising method for early detection of atherosclerosis and vulnerable plaque. However, traditional pharmacokinetic models for diffusible drugs are inadequate to describe the efficacy of nanoparticle carriers of diagnostic and therapeutic cargos. To quantify blood and MRI tissue signals from gadolinium-loaded nanoparticles (Gd-NP) targeted to avb3 integrins expressed on angiogenic capillaries in the aortas of cholesterol-fed rabbit, a novel 4 compartment open PK model was developed that utilized a unique simultaneous fitting scheme. In 10 rabbits fed 0.25% cholesterol for 3 months, the concentration of nanoparticles was measured serially from blood samples after injection of 1 ml/kg of targeted or nontargeted Gd-NP. The MRI proton signatures emanating from nanoparticles bound to the expanded vasa vasorum of the descending thoracic aorta was computed for all aortic cross sections in 1.5T T1w fa-suppressed spin-echo images. Based on the PK analysis, the concentration of targeted nanoparticles in the aortic wall is double that of non-targeted nanoparticles. Notably, this signal enhancement is achieved with 20x less gadolinium (4.6x10 −3 mmol Gd/kg BW) as compared with the dose of conventional gadolinium agents (0.1 mmol/kg). Further, the PK analysis shows that the targeted nanoparticles are more than three times more effective at reaching the aortic wall. These results should facilitate development and use of nanotechnologies intended for early detection of atherosclerosis and provide enhanced understanding of the kinetics and mechanisms of active targeting of plaque angiogenesis.

scholarly journals Pharmacokinetics-Pharmacodynamics of Gatifloxacin in a Lethal Murine Bacillus anthracis Inhalation Infection Model

2007 ◽  
Vol 51 (12) ◽  
pp. 4351-4355 ◽  
Author(s):  
Paul G. Ambrose ◽  
Alan Forrest ◽  
William A. Craig ◽  
Chistopher M. Rubino ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Survival Data ◽  
Sensitivity Analyses ◽  
Maximum Effect ◽  
Infection Model ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Concentration Time ◽  
Dosing Regimens ◽  
Adults And Children

ABSTRACT We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine Bacillus anthracis inhalation infection model. We then used population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of B. anthracis (Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC of the drug for the organism (AUC0-24/MIC ratio) was the PK-PD measure most predictive of survival (R 2 = 0.96). The 50% effective dose (ED50) and the ED90 and ED99 corresponded to AUC0-24/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED99). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of B. anthracis to levels as high as 0.5 mg/liter.

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