title: Exposure-effect population model of inolimomab, a monoclonal antibody administered in first-line treatment for acute graft-versus-host disease.
abstract: OBJECTIVE
  Inolimomab, a monoclonal antibody against interleukin (IL)-2Ralpha (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.
  
  
  METHODS
  The 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 mixed-effects 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Inolimomab 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.
authors.affiliation: Université Lyon 1, EA3738 CTO, Faculté de Médecine Lyon Sud, Oullins, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Dartois
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
authors.forename: Mauricette
authors.initials: M
authors.lastname: Michallet
authors.forename: Emilie
authors.initials: E
authors.lastname: Hénin
authors.forename: Benoît
authors.initials: B
authors.lastname: You
authors.forename: Isabelle
authors.initials: I
authors.lastname: Darlavoix
authors.forename: Claudine
authors.initials: C
authors.lastname: Vermot-Desroches
authors.forename: Brigitte
authors.initials: B
authors.lastname: Tranchand
authors.forename: Pascal
authors.initials: P
authors.lastname: Girard
mesh_terms: D000208:Acute Disease; D000328:Adult; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D017567:Karnofsky Performance Status; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; C079843:inolimomab; D008775:Methylprednisolone