Exposure-Effect Population Model of Inolimomab, a Monoclonal Antibody Administered in First-Line Treatment for Acute Graft-Versus-Host Disease View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2007-05

AUTHORS

Céline Dartois, Gilles Freyer, Mauricette Michallet, Emilie Hénin, Benoît You, Isabelle Darlavoix, Claudine Vermot-Desroches, Brigitte Tranchand, Pascal Girard

ABSTRACT

Background and objectiveInolimomab, a monoclonal antibody against interleukin (IL)-2Rα (CD25) has shown promising results in the treatment of corticosteroid-resistant acute graft-versus-host disease (GvHD). The objective of the present study was to characterise the pharmacokinetic and pharmacodynamic properties of inolimomab as first-line treatment in this condition.MethodsThe data came from 21 patients with acute GvHD (8 with an International Bone Marrow Transplant Registry [IBMTR] score of B, 11 with a score of C and 2 with a score of D) following haematopoietic stem cell transplantation after a median delay of 26 days (range 10–127 days). Inolimomab was administered at 0.1, 0.2, 0.3 or 0.4 mg/kg daily in association with methylprednisolone (2 mg/kg) for 8 or 16 days depending on the status at day 9. Then, for responder patients, administrations were continued three times weekly until day 28. Inolimomab concentrations and pharmacodynamic data (acute GvHD scores) were recorded during the study. The pharmacodynamic data were assessed in four grades according to the IBMTR and Glucksberg classification in parallel with Karnofsky scores. A population analysis was developed using a nonlinear mixedeffects model to define the pharmacokinetic model, to test covariates and, when apparent, to model the exposure-effect relationship by a proportional odds model. The modelling was finally qualified by a predictive check.ResultsThe best pharmacokinetic model was two-compartmental. For each score, the most demonstrative exposure-effect graphics linked the cumulative area under the concentration-time curve to cumulated probabilities of observing a specific score. This relationship was identified as a maximum effect model for the skin (with two patient subpopulations: sensitive/less sensitive) and a linear model for the intestinal tract and liver. No covariate was identified as influencing any of these parameters.ConclusionInolimomab exposure-effect relationships as first-line treatment for acute GvHD have been identified and modelled. The discovered dose-effect relationship allows confirmation of the treatment response, thereby establishing the first step towards optimising the inolimomab dosage in future trials. More... »

PAGES

417-432

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.2165/00003088-200746050-00004

    DOI

    http://dx.doi.org/10.2165/00003088-200746050-00004

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/17465640


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    31 schema:description Background and objectiveInolimomab, a monoclonal antibody against interleukin (IL)-2Rα (CD25) has shown promising results in the treatment of corticosteroid-resistant acute graft-versus-host disease (GvHD). The objective of the present study was to characterise the pharmacokinetic and pharmacodynamic properties of inolimomab as first-line treatment in this condition.MethodsThe data came from 21 patients with acute GvHD (8 with an International Bone Marrow Transplant Registry [IBMTR] score of B, 11 with a score of C and 2 with a score of D) following haematopoietic stem cell transplantation after a median delay of 26 days (range 10–127 days). Inolimomab was administered at 0.1, 0.2, 0.3 or 0.4 mg/kg daily in association with methylprednisolone (2 mg/kg) for 8 or 16 days depending on the status at day 9. Then, for responder patients, administrations were continued three times weekly until day 28. Inolimomab concentrations and pharmacodynamic data (acute GvHD scores) were recorded during the study. The pharmacodynamic data were assessed in four grades according to the IBMTR and Glucksberg classification in parallel with Karnofsky scores. A population analysis was developed using a nonlinear mixedeffects model to define the pharmacokinetic model, to test covariates and, when apparent, to model the exposure-effect relationship by a proportional odds model. The modelling was finally qualified by a predictive check.ResultsThe best pharmacokinetic model was two-compartmental. For each score, the most demonstrative exposure-effect graphics linked the cumulative area under the concentration-time curve to cumulated probabilities of observing a specific score. This relationship was identified as a maximum effect model for the skin (with two patient subpopulations: sensitive/less sensitive) and a linear model for the intestinal tract and liver. No covariate was identified as influencing any of these parameters.ConclusionInolimomab exposure-effect relationships as first-line treatment for acute GvHD have been identified and modelled. The discovered dose-effect relationship allows confirmation of the treatment response, thereby establishing the first step towards optimising the inolimomab dosage in future trials.
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