Population pharmacokinetics

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Target-Mediated Drug Disposition Population Pharmacokinetics Model of Alirocumab in Healthy Volunteers and Patients: Pooled Analysis of Randomized Phase I/II/III Studies

Target-Mediated Drug Disposition Population Pharmacokinetics Model of Alirocumab in Healthy Volunteers and Patients: Pooled Analysis of Randomized Phase I/II/III Studies

Background and Objective Proprotein convertase subtil- isin/kexin type 9 inhibition with monoclonal antibodies such as alirocumab significantly reduces low-density lipoprotein-cholesterol levels ± other lipid-lowering ther- apies. We aimed to develop and qualify a population pharmacokinetics (PopPK) model for alirocumab in heal- thy subjects and patients, taking into account the mecha- nistic target-mediated drug disposition (TMDD) process. Methods This TMDD model was developed using a subset of the alirocumab clinical trial database, including nine phase I/II/III studies (n = 527); the model was subse- quently expanded to a larger data set of 13 studies (n = 2870). Potential model parameters and covariate
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Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children

42. Yukawa E, Higuchi S, Aoyama T. Phenobarbitone population pharmacokinetics from routine clinical data: role of patient characteristics for estimating dosing regimens. J Pharm Pharmacol. 1992;44(9):755–60. 43. Banfield CR, Zhu GR, Jen JF, Jensen PK, Schumaker RC, Perhach JL, Affrime MB, Glue P. The effect of age on the apparent clearance of felbamate: a retrospective analysis using nonlinear mixed-effects modeling. Ther Drug Monit. 1996;18(1):19–29.

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Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates.

Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates.

Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Déborah Hirt, Saik Urien, Elisabeth Rey, Elise Arrivé, Didier Ekouévi, Patrick Coffié, Sim Kruy Leang, Sarita Lalsab, Divine Avit, Eric Nerrienet, et al.

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Powers of the likelihood ratio test and the correlation test using empirical bayes estimates for various shrinkages in population pharmacokinetics.

Powers of the likelihood ratio test and the correlation test using empirical bayes estimates for various shrinkages in population pharmacokinetics.

Population pharmacokinetics (PK) is increasingly used in drug development and is based on nonlinear mixed-effect models (NLMEMs). 1 Several software algorithms developed to estimate the parameters of these models have been compared, as by Plan et al. 2 The first and most popular software is NONMEM and, since version 7, several estima- tion algorithms have been available, such as first-order con- ditional estimation with interaction (FOCEI) and stochastic approximation expectation maximization (SAEM). Gibian- sky et al. 3 compared the performance of NONMEM estima- tion methods in simulated examples of a target-mediated drug disposition model using either default options or by designing the options to get the best possible results for each algorithm (“expert” options). They demonstrated the importance of the estimation options in the algorithm per- formance by comparing standard errors of NONMEM esti- mates with those predicted using PFIM 3.2 optimal design software. 4 The SAEM algorithm provided estimates similar to those of FOCEI.
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Population pharmacokinetics of nalbuphine after surgery in children

Population pharmacokinetics of nalbuphine after surgery in children

neonates whose mothers had received nalbuphine during labour. Jacqz-Aigrain and colleagues 8 have reported data of a population pharmacokinetic study carried out in neo- nates. These authors found that birth weight is a major determinant of variability in nalbuphine disposition. Jaillon and colleagues 4 have shown that the elimination half-life of nalbuphine is shorter in infants of 1.5–5 yr of age than in those of 5– 8.5 yr and that systemic clearance per kilogram of body weight decreased with age. However, only seven infants have been included in each group. The present study was designed to provide data on pharmacokinetics of nalbuphine in a paediatric population aged 1 –11 yr old. The purpose of this study was (i) to determine accurate population pharmacokinetic parameters by using a two- compartment open model; this model was parameterized in terms of total clearance, central volume of distribution, inter-compartment clearance, and peripheral volume of dis- tribution, (ii) to accurately estimate both inter- and residual variability in pharmacokinetic parameters, and (iii) to identify which of the patient physiological parameters could have influenced drug disposition. These data provide further valu- able information regarding appropriate paediatric dosing.
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A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects.

A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects.

The goodness-of-fit plots of the best joint model are shown in Figure 3. The plots of observations versus population predictions and observations versus individual predictions indicated that the model adequately described the observations over the dose range. The normalised prediction distribution error plots, NPDE versus time and NPDE versus predictions, show a symmetric distribution around zero, except for the early times and the small concentrations of bound aflibercept. This bias was caused by omitting the NPDE corresponding to below the quantification limit (BQL) observations. For BQL data, the metric NPDE has not yet been developed.
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Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide.

Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide.

biological functions, and the pharmacokinetics in patients may show a number of modifications. All the evaluation methods we presented aim at providing one or a small set of metrics to assess model adequacy. As such they are criteria combining information about various sources of model misspecification and it is not always easy to assert which part of the model should be improved. For instance for evaluation through predicted concentrations, a model with or without covariates should have correct standardized prediction errors if the estimation of inter-individual variability is adequate [28]. Also misspecification of the error model may lead to errors in the model of the random effects, which are not always easy to find when exploring only the post-hoc distribution [33]. We therefore recommend to use several approaches or metrics to evaluate a model in order to provide a more informative overview.
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Evaluation of bootstrap methods for estimating uncertainty of parameters in nonlinear mixed-effects models: a simulation study in population pharmacokinetics

Evaluation of bootstrap methods for estimating uncertainty of parameters in nonlinear mixed-effects models: a simulation study in population pharmacokinetics

Keywords Bootstrap · Nonlinear mixed-effects models · Pharmacokinetics · Uncertainty of parameters · MONOLIX 1 Introduction Nonlinear mixed-effects models (NLMEM) have been widely used in the field of pharmacokinetics (PK) and pharmacodynamics (PD) to characterize the profile of drug concentrations or treatment response over time for a population. NLMEM not only provides the estimates of fixed-effect parameters in the studied population but also describes their variability quantified by the variance of the random effects in a single estimation step. This approach was introduced by Lewis Sheiner and Stuart Beal and has now become an
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Methods and software tools for design evaluation for population pharmacokinetics-pharmacodynamics studies.: Softwares for design evaluation in population PKPD

Methods and software tools for design evaluation for population pharmacokinetics-pharmacodynamics studies.: Softwares for design evaluation in population PKPD

D-criterion predicted by the different software tools for the warfarin PK model compared to simulated D-criterion calculated from the inverse of the empirical covariance matrix. NM FOC[r]

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Pharmacogenetics and population pharmacokinetics: impact of the design on three tests using the SAEM algorithm.

Pharmacogenetics and population pharmacokinetics: impact of the design on three tests using the SAEM algorithm.

* Correspondence should be adressed to: Julie Bertrand <julie.bertrand@inserm.fr > Abstract Pharmacogenetics is now widely investigated and health institutions acknowledge its place in clinical pharmacokinetics. Our objective is to assess through a simulation study, the impact of design on the statistical performances of three different tests used for analysis of pharmacogenetic information with nonlinear mixed effects models: i) an ANOVA to test the relationship between the empirical Bayes estimates of the model parameter of interest and the genetic covariate, ii) a global Wald test to assess whether estimates for the gene effect are significant, and iii) a likelihood ratio test (LRT) between the model with and without the genetic covariate. We use the stochastic EM algorithm (SAEM) implemented in MONOLIX 2.1 software. The simulation setting is inspired from a real
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Population pharmacokinetics and pharmacodynamics of cysteamine in nephropathic cystinosis patients

Population pharmacokinetics and pharmacodynamics of cysteamine in nephropathic cystinosis patients

Modeling strategy and population pharmacokinetic- pharmacodynamic model Data were analysed using the nonlinear mixed effect modelling software program Monolix version 31s http:// wfn.software.monolix.org[9]. Parameters were estimated by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization) using the stochastic approximation expec- tation maximization (SAEM) algorithm combined to a MCMC (Markov Chain) monte Carlo) procedure. The number of MCMC chains was fixed to 5 for all estima- tions. The between-subject variabilities (BSV or h) were ascribed to an exponential model. Parameter shrinkage was calculated as {1-sd(eta)/omega}, where sd(eta) and omega are the standard deviation of individual eta para- meters and the population model estimate of the BSV respectively [10]. The Likelihood Ratio Test (LRT) including the log-likelihood, the Akaike information cri- terion (AIC) and the bayesian information criterion
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Methods and software tools for design evaluation in population pharmacokinetics-pharmacodynamics

Methods and software tools for design evaluation in population pharmacokinetics-pharmacodynamics

Answer to Referees' comments Referee 1 Comments to the Author The authors describe how one experimental design can be evaluated by the set of existing optimal design software tools (that all are based on calculation of the FIM). Two design problems based on population PKPD models are studied, and the design evaluations are compared between the tools and with respect to empirical simulations. Data indicate that all tools give similar output. Evaluation of a single design is a fundamental subroutine in search for an optimal design, and the study therefore functions as a software tool quality check.
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Population pharmacokinetics of levobupivacaine during a transversus abdominis plane block in children

Population pharmacokinetics of levobupivacaine during a transversus abdominis plane block in children

7. Sola C, Menace C, Rochette A, Raux O, Bringuier S, Molinari N, et al. Ultrasound-guided tranversus abdominis plane block for herniorrhaphy in children: what is the optimal dose of levobupivacaine? Eur J Anaesthesiol. 2014;31:327–32. 8. Mathieu O, Hillaire-Buys D, Dadure C, Barnay F, Mathieu-Daudé JC, Bressolle F. Liquid chromatography-electrospray mass spectrometry determination of free and total concentrations of ropivacaine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2006;831:91–8. 9. Parke J, Holford NH, Charles BG. A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Programs Biomed. 1999;59:19–29. 10. Yano Y, Beal SL, Sheiner LB. Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn. 2001;28:171–92.
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Pharmacokinetics of intramuscular alfaxalone and its echocardiographic, cardiopulmonary and sedative effects in healthy dogs.

Pharmacokinetics of intramuscular alfaxalone and its echocardiographic, cardiopulmonary and sedative effects in healthy dogs.

13.8 ± 4.6 minutes; 31.4 ± 6.9 minutes; 75.1 ± 28.9 minutes at 2, 3, 6 and 20 mg kg -1 , respec- tively) [ 4 , 6 ]. Most studies report that the quality of recovery from alfaxalone anaesthesia alone in dogs is “quite smooth” to “excellent” [ 4 , 10 , 24 , 27 ]. However, it was also reported that dogs exhibited transient muscular tremor, staggering gait, paddling of the forelimb, muscular twitching, limb extension or vocalization during the early recovery phase [ 3 , 10 ]. Ferchichi et al. [ 28 ] suggested that the dogs were no longer exposed to alfaxalone during the recovery phase from a 50–90 minutes-anaesthesia produced by 2 mg kg -1 alfaxalone IV associated with methadone and that the excitement observed during recovery could not be considered as a side effect of alfaxalone. We also observed some of these events in our study and it was suggested that they are more common when alfaxalone is administered IM as compared with the IV route because of differ- ences in pharmacokinetics [ 10 ]. In our study, the time needed to clear the plasma from the drug (considering five times the plasma terminal half-life) would be approximatively 2h30, which is longer than the duration of the sedation. Therefore, the dogs were most likely still exposed to alfaxalone during the recovery phase as observed in Fig 3 . Nevertheless, in accor- dance with Ferre´ et al.’s [ 14 ] observations, the agitation occurred only in response to either manipulation or sounds during sedation. Further studies would be required to evaluate the effect of premedication with butorphanol on the quality of sedation and recovery from IM alfaxalone.
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Influence of alpha-1 glycoprotein acid concentrations and variants on atazanavir pharmacokinetics in HIV-infected patients included in the ANRS 107 trial.: alpha 1 glycoprotein acid polymorphism and atazanavir pharmacokinetics

Influence of alpha-1 glycoprotein acid concentrations and variants on atazanavir pharmacokinetics in HIV-infected patients included in the ANRS 107 trial.: alpha 1 glycoprotein acid polymorphism and atazanavir pharmacokinetics

Influence of alpha-1 glycoprotein acid concentrations and variants on atazanavir pharmacokinetics in HIV-infected patients included in the ANRS 107 trial.: alpha 1 glycoprotein acid poly[r]

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Effects of rabeprazole on the antiplatelet effects and pharmacokinetics of clopidogrel in healthy volunteers.

Effects of rabeprazole on the antiplatelet effects and pharmacokinetics of clopidogrel in healthy volunteers.

Subjects were randomized based on a Latin square design to receive clopidogrel, 75 mg o.d. in the morning in the fasting state for 7 days during 3 study periods separated by a drug-free period of 2 to 3 weeks together with placebo, 20 mg of rabeprazole or 20 mg of omeprazole given at the same time as clopidogrel. Platelet function evaluation (pharmacodynamics) was performed on day 1 before dosing and on day 7 before and 4 hrs after the last intake of study drugs. Pharmacokinetics of clopidogrel, its inactive carboxylic acid metabolite as well as the active metabolite was determined from blood samples taken before (H0) and at various times after administration of the last dose of clopidogrel with the concomitant drug (either placebo or PPI). Additional blood samples for determination of omeprazole, 5-hydoxy-omeprazole, rabeprazole and rabeprazole-thioether plasma concentrations were taken 3 and 4 hrs post-dose on Day 7 to confirm proper exposure to PPIs.
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In vivo evaluation of safety, biodistribution and pharmacokinetics of laser-synthesized gold nanoparticles.

In vivo evaluation of safety, biodistribution and pharmacokinetics of laser-synthesized gold nanoparticles.

Anne-Laure Bailly 1,2 , florian correard 1,3 , Anton popov 4,5 , Gleb tselikov 4 , florence chaspoul 6 , Romain Appay 1,7 , Ahmed Al-Kattan 4 , Andrei V. Kabashin 4,5 , Diane Braguer 1,3 & Marie-Anne esteve 1,3 Capable of generating plasmonic and other effects, gold nanostructures can offer a variety of diagnostic and therapy functionalities for biomedical applications, but conventional chemically-synthesized Au nanomaterials cannot always match stringent requirements for toxicity levels and surface conditioning. Laser-synthesized Au nanoparticles (Aunp) present a viable alternative to chemical counterparts and can offer exceptional purity (no trace of contaminants) and unusual surface chemistry making possible direct conjugation with biocompatible polymers (dextran, polyethylene glycol). this work presents the first pharmacokinetics, biodistribution and safety study of laser-ablated dextran-coated Aunp (Aunpd) under intravenous administration in small animal model. our data show that Aunpd are rapidly eliminated from the blood circulation and accumulated preferentially in liver and spleen, without inducing liver or kidney toxicity, as confirmed by the plasmatic ALAT and ASAT activities, and creatininemia values. Despite certain residual accumulation in tissues, we did not detect any sign of histological damage or inflammation in tissues, while IL-6 level confirmed the absence of any chronic inflammation. The safety of AuNPd was confirmed by healthy behavior of animals and the absence of acute and chronic toxicities in liver, spleen and kidneys. our results demonstrate that laser-synthesized Aunp are safe for biological systems, which promises their successful biomedical applications.
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La population autochtone

La population autochtone

Qui plus est, les esti ma tions de popu la tion de l’ère pré sta tis ti que que l’on tro uve dans les sour ces sont notoi re ment impré ci ses et sou vent repri ses d’un auteur[r]

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Population et habitat

Population et habitat

Le résul tat de tout ce pro ces sus est visi ble à la fois dans l’espace et dans la topo ny mie locale (rang des Caron, rang des Matte, etc.), et laisse l’impres sion d’une orga ni[r]

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Population et territoire

Population et territoire

Les regis tres qué bé cois sont d’une grande qua­ lité. D’une part, le calme rela tif de l’his toire qué bé­ coise et le res pect de l’ordon nance de 1678, exi geant que les regis tres[r]

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