Population Pharmacodynamic Modeling and Covariate Detection for Central Neural Blockade

Schnider, Thomas W.; Minto, Charles F.; Bruckert, Heini; Mandema, Jaap W.

doi:10.1097/00000542-199609000-00009

Cited by 56 publications

(56 citation statements)

References 21 publications

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“…In this study, as in previous studies in other therapy areas [30][31][32], height was used as a measure of body size. While height and weight both represent composite measures of body size, and weight is the more practical of the two if dose adjustment is needed, none of the body composition-related covariates appeared to have a clinically relevant effect on vortioxetine PK.…”

Section: Discussionmentioning

confidence: 99%

A Population Pharmacokinetic–Pharmacodynamic Meta‐Analysis of Vortioxetine in Patients with Major Depressive Disorder

Naik

Chan

Vakilynejad

et al. 2015

Basic Clin Pharma Tox

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Vortioxetine is approved for the treatment of major depressive disorder (MDD). This analysis aimed to develop pharmacokinetic (PK) and PK/Efficacy models to evaluate the exposure-response relationship for vortioxetine in patients with MDD. PK data from 10 MDD and two generalized anxiety disorder studies of vortioxetine (3160 patients), and efficacy data [Montgomery-Asberg Depression Rating Scale (MADRS)] from seven MDD studies (2537 patients), were used for the development of PK and PK/Efficacy models. One-and two-compartment models were evaluated as structural PK models, and linear and nonlinear (E max ) models were used to describe the relationship between average vortioxetine concentration at steady-state (C av ) and change in MADRS score from baseline (DMADRS). The impact of selected covariates on the PK and efficacy parameters of vortioxetine was also investigated. PK of vortioxetine was best characterized by a two-compartment model with first-order absorption and elimination. Mean estimates for oral clearance (CL/F) and volume of distribution for the central compartment of vortioxetine were 42 L/hr and 2920 L. Creatinine clearance, height and geographic region had statistically significant effects on vortioxetine CL/F, but the effect of each of these covariates was not considered clinically relevant, as they lead to AE26% change in area under the curve or C max of vortioxetine. An E max model best described the relationship between DMADRS and C av . Half-maximal effective concentration (EC 50 ) and E max estimates were 24.9 ng/mL and 7.0. No identified covariates, except region, had clinically meaningful effects on vortioxetine efficacy. These PK/Efficacy models adequately characterized the vortioxetine exposure-response relationship.A recent systematic review reported a global prevalence of major depressive disorder (MDD) of 4.7% [1], and according to the World Health Organization it is the leading cause of disability globally in middle-to high-income countries [2]. There is significant variability both in types of MDD and severity of symptoms. Most antidepressant therapies act on the serotonergic system, and the most common fall into the categories of selective serotonin reuptake inhibitors, such as fluoxetine; serotonin and norepinephrine reuptake inhibitors, such as venlafaxine; and norepinephrine and dopamine reuptake inhibitors, such as bupropion.Vortioxetine (Lu AA21004) is a new antidepressant extensively studied in the treatment of MDD [3][4][5][6][7][8][9][10][11][12][13] and in generalized anxiety disorder (GAD) [14][15][16][17][18]. Vortioxetine received marketing authorization for use in MDD in the United States of America (USA) in October 2013, and in the European Union (EU) in December 2013 [19,20]. The mechanism of action of vortioxetine is thought to be related to multimodal activity [21], through direct modulation of receptor activity, and modulation of the serotonin transporter (SERT). In vitro and in vivo studies have shown that vortioxetine is a 5-hydroxytryptamine (HT) 3 , ...

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Section: Discussionmentioning

confidence: 99%

A Population Pharmacokinetic–Pharmacodynamic Meta‐Analysis of Vortioxetine in Patients with Major Depressive Disorder

Naik

Chan

Vakilynejad

et al. 2015

Basic Clin Pharma Tox

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“…One measurement may provide more information than all of the relevant covariates available 61 (but exploring covariates of course provides information on the underlying mechanisms). Second, 60 it was found that the coefficient of correlation between the Bayesian predictions and the measurements of the level of bupivacaine analgesia improved from 0.5 (no knowledge) to 0.7 (30 to 60 minutes of information) to 0.9 (all data). Models that can be ÔÔindividualizedÕÕ on-line are useful for target-controlled infusion devices (when the blood concentrations of the administered can be measured on-line) or for more complicated control systems, 2,20,62 possibly without knowing blood concentrations.…”

Section: E386mentioning

confidence: 97%

“…Some anesthesiology articles on population modeling 3,7,16,[58][59][60] discussed the possibilities of Bayesian forecasting based on the article by Sheiner et al 61 When a …”

Section: Bayesian Forecastingmentioning

confidence: 99%

Population pharmacokinetics/pharmacodynamics of anesthetics

Olofsen

Dahan

2005

AAPS J

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In this article we review how population pharmacokinetic/ pharmacodynamic (PD) modeling has evolved in the specialty of anesthesiology, how anesthesiology benefited from the mixed-effects approach, and which features of modeling need careful attention. Key articles from the anesthesiology literature are selected to discuss the modeling of typical anesthesiological PD end points, such as level of consciousness and analgesia, interactions between hypnotics and analgesics, estimation with poor and sometimes rich data sets from populations of various sizes, covariate detection, covariances between random effects, and Bayesian forecasting.

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“…In PK and PD models, the kinetic parameters of each individual are modeled in terms of the fixed effect observed, and other of random nature, while PK-PD poblational models, based on nonlinear mixed effects analysis, characterize the pharmacokinetic parameters and concentration-effect relationship, in poblational terms more than individual. Thus, in PK and PK-PD poblational models, we need to know in advance the average behaviour of pharmacokinetic parameters in target population, to identify and assess demographic, pathophysiological and environmental factors, affecting population under study and, finally, evaluate the inter and intraindivual variability through the variation coefficient of the PK parameters and their residual components (Dominguez-Gil & Lanao 1999;Schnider et al 1996).…”

Section: Pk-pd Modelsmentioning

confidence: 99%

“…Its complex origin, is attributed to a defective transmission of noradrenaline and dopamine associated with dysregulation of the hypothalamic-pituitary-adrenal axis , HPA, which is reflected by the alteration of the cortisol escape from suppression by dexamethasone in the Dexamethasone Suppression test, DEX test, and by the increased response of cortisol in the Dexamethasone-Suppressed Corticotropin-Releasing Hormone Stimulation Test, DEX-CRH test. The decrease in serotonergic transmission in the brain and increased secretion of cortisol in patients with major depression have reached the status of an axiom in textbooks, being the cortisol the biological key mediator through which the brain slows down serotonergic transmission that causes depression in vulnerable people (American Psychiatric Association 2000; Dinan, 1996;Goodwin & Post 1983;Noll 2006;Schnider et al 1996).…”

Section: Escitalopram-ssrimentioning

confidence: 99%

Biomarkers and Therapeutic Drug Monitoring in Psychiatry

Lozano¹,

Marin²,

Pascual³

et al. 2012

Biomarker

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Population Pharmacodynamic Modeling and Covariate Detection for Central Neural Blockade

Abstract: A population model was derived for the description of the time course of central neural blockade. Based on the population model, a continuous effect profile over time was obtained for each person...

Cited by 56 publications

References 21 publications

A Population Pharmacokinetic–Pharmacodynamic Meta‐Analysis of Vortioxetine in Patients with Major Depressive Disorder

A Population Pharmacokinetic–Pharmacodynamic Meta‐Analysis of Vortioxetine in Patients with Major Depressive Disorder

Population pharmacokinetics/pharmacodynamics of anesthetics

Biomarkers and Therapeutic Drug Monitoring in Psychiatry

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