scholarly journals Use of Mixture Dosing and Nonlinear Mixed Effect Modeling of Eight Environmental Contaminants in Rabbits to Improve Extrapolation Value of Toxicokinetic Data

2021 ◽  
Vol 129 (11) ◽  
Author(s):  
Véronique Gayrard ◽  
Jessika Moreau ◽  
Nicole Picard-Hagen ◽  
Virginie Helies ◽  
Philippe Marchand ◽  
...  
2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Claire Pressiat ◽  
Madeleine Amorissani-Folquet ◽  
Caroline Yonaba ◽  
Jean-Marc Treluyer ◽  
Désiré Lucien Dahourou ◽  
...  

ABSTRACT The MONOD ANRS 12206 trial was designated to assess simplification of a successful lopinavir (LPV)-based antiretroviral treatment in HIV-infected children younger than 3 years of age using efavirenz (EFV; 25 mg/kg of body weight/day) to preserve the class of protease inhibitors for children in that age group. In this substudy, EFV concentrations were measured to check the consistency of an EFV dose of 25 mg/kg and to compare it with the 2016 FDA recommended dose. Fifty-two children underwent blood sampling for pharmacokinetic study at 6 months and 12 months after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the nonlinear mixed-effect modeling (NONMEM) program. The proportion of midinterval concentrations 12 h after drug intake (C 12 h) corresponding to the EFV therapeutic pharmacokinetic thresholds (1 to 4 mg/liter) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose). With both the 25 mg/kg/day dose and the 2016 FDA recommended EFV dose, simulations showed that the majority of C 12 h values were within the therapeutic range (62.6% versus 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose (11.6% versus 1.2%). Conversely, there were more concentrations above the threshold of toxicity with the 25 mg/kg dose (36.2% versus 25.6%), with C 12 h values of up to 15 mg/liter. Only 1 of 52 children was switched back to LPV because of persistent sleeping disorders, but his C 12 h value was within therapeutic ranges. A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable safe therapeutic profiles. (This study has been registered at ClinicalTrials.gov under identifier NCT01127204.)


2004 ◽  
Vol 101 (1) ◽  
pp. 34-42 ◽  
Author(s):  
Ann L.G. Vanluchene ◽  
Hugo Vereecke ◽  
Olivier Thas ◽  
Eric P. Mortier ◽  
Steven L. Shafer ◽  
...  

Background The authors compared the behavior of two calculations of electroencephalographic spectral entropy, state entropy (SE) and response entropy (RE), with the A-Line ARX Index (AAI) and the Bispectral Index (BIS) and as measures of anesthetic drug effect. They compared the measures for baseline variability, burst suppression, and prediction probability. They also developed pharmacodynamic models relating SE, RE, AAI, and BIS to the calculated propofol effect-site concentration (Ceprop). Methods With institutional review board approval, the authors studied 10 patients. All patients received 50 mg/min propofol until either burst suppression greater than 80% or mean arterial pressure less than 50 mmHg was observed. SE, RE, AAI, and BIS were continuously recorded. Ceprop was calculated from the propofol infusion profile. Baseline variability, prediction of burst suppression, prediction probability, and Spearman rank correlation were calculated for SE, RE, AAI, and BIS. The relations between Ceprop and the electroencephalographic measures of drug effect were estimated using nonlinear mixed effect modeling. Results Baseline variability was lowest when using SE and RE. Burst suppression was most accurately detected by spectral entropy. Prediction probability and individualized Spearman rank correlation were highest for BIS and lowest for SE. Nonlinear mixed effect modeling generated reasonable models relating all four measures to Ceprop. Conclusions Compared with BIS and AAI, both SE and RE seem to be useful electroencephalographic measures of anesthetic drug effect, with low baseline variability and accurate burst suppression prediction. The ability of the measures to predict Ceprop was best for BIS.


2015 ◽  
Vol 114 (4) ◽  
pp. 564-569 ◽  
Author(s):  
Friedrich Trefz ◽  
Olaf Lichtenberger ◽  
Nenad Blau ◽  
Ania C. Muntau ◽  
Francois Feillet ◽  
...  

Author(s):  
Fabian Fröhlich ◽  
Anita Reiser ◽  
Laura Fink ◽  
Daniel Woschée ◽  
Thomas Ligon ◽  
...  

2019 ◽  
Vol 8 (12) ◽  
pp. 923-930 ◽  
Author(s):  
Rik Schoemaker ◽  
Matthew Fidler ◽  
Christian Laveille ◽  
Justin J. Wilkins ◽  
Richard Hooijmaijers ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document