Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin

Gulati, Abhishek; Faed, James M.; Duffull, Stephen B.

doi:10.1007/s11095-015-1715-1

Cited by 3 publications

(5 citation statements)

References 8 publications

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“…used a similar approach to derive an empirical function that approximated the relationship between the concentration of activating agents and a proposed clotting time test based on a QSP model of the coagulation network. The function was used to optimise the design of a pilot study aimed at evaluating the proposed test as a tool for monitoring of enoxaparin therapy 52 . Similarly, Dumont et al 53 .…”

Section: Nonparametric Methodsmentioning

confidence: 99%

“…used logistic and polynomial functions to approximate the relationship between warfarin exposure and response in terms of International Normalised Ratio to predict warfarin dose requirements. Gulati et al 52 . used a similar approach to derive an empirical function that approximated the relationship between the concentration of activating agents and a proposed clotting time test based on a QSP model of the coagulation network.…”

Section: Nonparametric Methodsmentioning

confidence: 99%

“…The function was used to optimise the design of a pilot study aimed at evaluating the proposed test as a tool for monitoring of enoxaparin therapy. 52 Similarly, Dumont et al 53 used PBPK-simulated pseudodata to develop a simplified pharmacokinetic model that was used to design a paediatric clinical trial.…”

Section: Empirical Approximationmentioning

confidence: 99%

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A framework for simplification of quantitative systems pharmacology models in clinical pharmacology

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Section: Nonparametric Methodsmentioning

confidence: 99%

Section: Nonparametric Methodsmentioning

confidence: 99%

See 1 more Smart Citation

A framework for simplification of quantitative systems pharmacology models in clinical pharmacology

Derbalah

Al‐Sallami

Hasegawa

et al. 2020

Brit J Clinical Pharma

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“…The in vitro CT tests were carried out using a STart hemostasis analyzer, which utilizes a viscosity-based detection system. Concentrations of Xa and Actin FS used in this study were based on a previous study 10 and were equal to 20 nM and 0.17%, respectively.…”

Section: In Vitro Ct Test Experimentsmentioning

confidence: 99%

“…Subsequent in vitro evaluation in an adaptive design cohort study of 6 healthy volunteers identified phospholipid Actin FS as a useful stabilizing cofactor for this Xa-based clotting time test (TenaCT test). 10 The TenaCT test accounts for the variability in the coagulation factors and reflects the activity of the coagulation network. Actin FS is a commercially available aPTT reagent consisting of purified soy phosphatides (as the phospholipid component) and ellagic acid activator (as the activating agent in the commercially available aPTT test) and was included in order to determine the net anticoagulant effect of LMWHs.…”

Section: Introductionmentioning

confidence: 99%

An Evaluation of a Factor Xa-Based Clotting Time Test for Enoxaparin: A Proof-of-Concept Study

Duffull

Faed

et al. 2017

Clin Appl Thromb Hemost

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A well-accepted test for monitoring anticoagulation by enoxaparin is not currently available. As inadequate dosing may result in thrombosis or bleeding, a clinical need exists for a suitable test. Previous in silico and in vitro studies have identified factor Xa as an appropriate activating agent, and the phospholipid Actin FS as a cofactor for a Xa clotting time (TenaCT) test. A proof-of-concept study was designed to (1) explore the reproducibility of the TenaCT test and (2) explore factors that could affect the performance of the test. In vitro clotting time tests were carried out using plasma from 20 healthy volunteers. The effect of enoxaparin was determined at concentrations of 0.25, 0.50, and 1.0 IU/mL. Clotting times for the volunteers were significantly prolonged with increasing enoxaparin concentrations. Clotting times were significantly shortened for frozen plasma samples. No significant differences in prolongation of clotting times were observed between male and female volunteers or between the 2 evaluated age groups. The clotting times were consistent between 2 separate occasions. The TenaCT test was able to distinguish between the subtherapeutic and therapeutic concentrations of enoxaparin. Plasma should not be frozen prior to performing the test, without defining a frozen plasma reference range. This study provided proof-of-concept for a Xa-based test that can detect enoxaparin dose effects, but additional studies are needed to further develop the test.

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Reduction of quantitative systems pharmacology models using artificial neural networks

Derbalah

Al‐Sallami

Duffull

2021

J Pharmacokinet Pharmacodyn

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cuyas enseñanzas de vida me han motivado para persistir. IX ResumenFarmacocinética poblacional en el manejo empírico de infecciones en pacientes con neoplasias hematológicas y neutropenia febril pos-quimioterapia Los pacientes con neoplasias hematológicas y neutropenia febril postquimioterapia podrían presentar alteraciones fisiológicas que lleven a cambios en la farmacocinética (PK) de los fármacos comparado a individuos sin cáncer o neutropenia. Estos cambios, en la PK de antibióticos, podrían resultar en fallos terapéuticos y esto a su vez en hospitalizaciones prolongadas, empeoramiento en la severidad de la infección e inclusive en la muerte. En este estudio, se desarrollaron modelos de PK poblacional para cefepime (FEP) y vancomicina (VAN) en el tratamiento empírico de infecciones en pacientes con neutropenia post-quimioterapia. La farmacocinética de FEP fue descrita por un modelo de dos compartimentos con aclaramiento dependiente del nivel de creatinina sérica (S CR ), variabilidad interindividual en todos los parámetros y variabilidad residual con una función aditiva. Por otra parte, la farmacocinética de VAN fue descrita con un modelo de dos compartimentos con aclaramiento dependiente del aclaramiento renal de creatinina (ClCr), variabilidad interindividual en todos los parámetros, correlación entre los parámetros V 1 y V 2 y una variabilidad residual con funciones aditivas dependientes del método de determinación de VAN. Mediante simulaciones de Monte Carlo se encontró que para FEP, el alcance de los objetivos PK/PD (60 % f T >MIC y 100 % f T >MIC ) es muy dependiente de la duración de infusión, así como del efecto de S CR . Para VAN se encuentra que el alcance del indicador AUC/MIC ≥ 400 se ve afectado por cambios en la dosis diaria total y la prolongación de la duración de infusión no afecta el PTA. Se realizó una comparación entre objetivos dependientes de AUC vs C min , y se encuentró que el último no es un predictor adecuado del primero.

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Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin

Abstract: This study shows that parsimonious adaptive DP-optimal designs may provide both precise parameter estimates for response surface modelling as well as clinical confidence in the potential benefits of the study.

Cited by 3 publications

References 8 publications

A framework for simplification of quantitative systems pharmacology models in clinical pharmacology

A framework for simplification of quantitative systems pharmacology models in clinical pharmacology

An Evaluation of a Factor Xa-Based Clotting Time Test for Enoxaparin: A Proof-of-Concept Study

Reduction of quantitative systems pharmacology models using artificial neural networks

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