Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics

Nguyen, Thi Huyen Tram; Mouksassi, M-S; Holford, Nicholas H. G.; Al‐Huniti, Nidal; Freedman, I.; Hooker, Andrew C.; John, Jyothi; Karlsson, Mats O.; Mould, Diane R.; Pérez‐Ruixo, Juan José; Plan, Elodie L.; Savic, Radojka M.; Hasselt, J. G. Coen van; Weber, Benjamin; Zhou, Congya; Comets, Emmanuelle; Mentré, France

doi:10.1002/psp4.12161

Cited by 287 publications

(286 citation statements)

References 28 publications

(80 reference statements)

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“…A total of 1000 simulations were used to estimate confidence intervals. A prediction corrected visual predicted check was used to evaluate how well the model predicted the distribution of observations.…”

Section: Methodsmentioning

confidence: 99%

A manual propofol infusion regimen for neonates and infants

Morse

Hannam

Cortínez

et al. 2019

Pediatric Anesthesia

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Aims Manual propofol infusion regimens for neonates and infants have been determined from clinical observations in children under the age of 3 years undergoing anesthesia. We assessed the performance of these regimens using reported age‐specific pharmacokinetic parameters for propofol. Where performance was poor, we propose alternative dosing regimens. Methods Simulations using a reported general purpose pharmacokinetic propofol model were used to predict propofol blood plasma concentrations during manual infusion regimens recommended for children 0‐3 years. Simulated steady state concentrations were 6‐8 µg.mL−1 in the first 30 minutes that were not sustained during 100 minutes infusions. Pooled clinical data (n = 161, 1902 plasma concentrations) were used to determine an alternative pharmacokinetic parameter set for propofol using nonlinear mixed effects models. A new manual infusion regimen for propofol that achieves a steady‐state concentration of 3 µg.mL−1 was determined using a heuristic approach. Results A manual dosing regimen predicted to achieve steady‐state plasma concentration of 3 µg.mL−1 comprised a loading dose of 2 mg.kg−1 followed by an infusion rate of 9 mg.kg−1.h−1 for the first 15 minutes, 7 mg.kg−1.h−1 from 15 to 30 minutes, 6 mg.kg−1.h−1 from 30 to 60 minutes, 5 mg.kg−1.h−1 from 1 to 2 hours in neonates (38‐44 weeks postmenstrual age). Dose increased with age in those aged 1‐2 years with a loading dose of 2.5 mg.kg−1 followed by an infusion rate of 13 mg.kg−1.h−1 for the first 15 minutes, 12 mg.kg−1.h−1 from 15 to 30 minutes, 11 mg.kg−1.h−1 from 30 to 60 minutes, and 10 mg.kg−1.h−1 from 1 to 2 hours. Conclusion Propofol clearance increases throughout infancy to reach 92% that reported in adults (1.93 L.min.70 kg−1) by 6 months postnatal age and infusion regimens should reflect clearance maturation and be cognizant of adverse effects from concentrations greater than the target plasma concentration. Predicted concentrations using a published general purpose pharmacokinetic propofol model were similar to those determined using a new parameter set using richer neonatal and infant data.

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Section: Methodsmentioning

confidence: 99%

A manual propofol infusion regimen for neonates and infants

Morse

Hannam

Cortínez

et al. 2019

Pediatric Anesthesia

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“…Population PK parameters were estimated using first‐order conditional estimations with interactions. Model selection was based on the objective function value (OFV) calculated by NONMEM, the relative SE of the parameter estimates, and model diagnosis plots …”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Meloxicam in East Asian Populations: The Role of Ethnicity on Drug Response

Aoyama

Ishida

Kaneko

et al. 2017

CPT Pharmacom & Syst Pharma

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We aimed to reanalyze the differences in the pharmacokinetics (PKs) of meloxicam in East Asian populations based on a population approach using previously published data and to investigate the factors found in population PK analysis that affect the pharmacodynamics (PDs) of meloxicam. Population PK analysis was performed in 119 healthy male subjects (30 Japanese, 30 Chinese, 29 Korean, and 30 white) under strictly controlled trial conditions with regulated meals and a single lot of the drug. We found that CYP2C9 genotype and lean body mass were statistically significant predictors of clearance and volume of distribution, respectively. A statistical significant difference in the PK parameters between ethnic groups could not be identified. Simulations using PK/PD models showed that CYP2C9 genotype is the factor that affects the PDs of meloxicam. The genetic polymorphisms highlighted in this study would be beneficial for conducting clinical trials in East Asians with similar genetic backgrounds.

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“…below the quantification limit) data. In agreement with recent guidelines from Nguyen et al (), observations are displayed on a log scale to better evaluate the quality of fit [Colour figure can be viewed at wileyonlinelibrary.com]…”

Section: Resultsmentioning

confidence: 95%

Nonlinear mixed‐effects pharmacokinetic modeling of the novel COX‐2 selective inhibitor vitacoxib in dogs

Wang

Schneider

Sun

et al. 2019

Vet Pharm & Therapeutics

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The objective of this study was to develop a nonlinear mixed‐effects model of vitacoxib disposition kinetics in dogs after intravenous (I.V.), oral (P.O.), and subcutaneous (S.C.) dosing. Data were pooled from four consecutive pharmacokinetic studies in which vitacoxib was administered in various dosing regimens to 14 healthy beagle dogs. Plasma concentration versus time data were fitted simultaneously using the stochastic approximation expectation maximization (SAEM) algorithm for nonlinear mixed‐effects as implemented in Monolix version 2018R2. Correlations between random effects and significance of covariates on population parameter estimates were evaluated using multiple samples from the posterior distribution of the random effects. A two‐compartment mamillary model with first‐order elimination and first‐order absorption after P.O. and S.C. administration, best described the available pharmacokinetic data. Final parameter estimates indicate that vitacoxib has a low‐to‐moderate systemic clearance (0.35 L hr−1 kg−1) associated with a low global extraction ratio, but a large volume of distribution (6.43 L/kg). The absolute bioavailability after P.O. and S.C. administration was estimated at 10.5% (fasted) and 54.6%, respectively. Food intake was found to increase vitacoxib oral bioavailability by a fivefold, while bodyweight (BW) had a significant impact on systemic clearance, thereby confirming the need for BW adjustment with vitacoxib dosing in dogs.

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Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics

Cited by 287 publications

References 28 publications

A manual propofol infusion regimen for neonates and infants

A manual propofol infusion regimen for neonates and infants

Pharmacokinetics and Pharmacodynamics of Meloxicam in East Asian Populations: The Role of Ethnicity on Drug Response

Nonlinear mixed‐effects pharmacokinetic modeling of the novel COX‐2 selective inhibitor vitacoxib in dogs

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