Exposure-Effect Population Model of Inolimomab, a Monoclonal Antibody Administered in First-Line Treatment for Acute Graft-Versus-Host Disease
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Background and objective
Inolimomab, 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.
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 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.
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.
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.
- 3.Storb R, Pepe M, Deeg HJ, et al. Long-term follow-up of a controlled trial comparing a combination of methotrexate plus cyclosporine with cyclosporine alone for prophylaxis of graftversus-host disease in patients administered HLA-identical marrow grafts for leukemia. Blood 1992 Jul 15; 80(2): 560–1PubMedGoogle Scholar
- 5.Ruutu T, Niederwieser D, Gratwohl A, et al. A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow, Transplantation (EBMT). Chronic Leukaemia Working Party of the EBMT. Bone Marrow Transplant 1997 Apr; 19(8): 759–64PubMedCrossRefGoogle Scholar
- 14.Herbelin C, Stephan JL, Donadieu J, et al. Treatment of steroidresistant acute graft-versus-host disease with an anti-IL-2-receptor monoclonal antibody (BT 563) in children who received T cell-depleted, partially matched, related bone marrow transplants. Bone Marrow Transplant 1994 May; 13(5): 563–9PubMedGoogle Scholar
- 21.Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: Macleod CM, editor. Evaluation of chemotherapeutic agents. New York: Columbia University Press, 1949: 199–205Google Scholar
- 22.Boeckmann AJ, Sheiner L, Beal SL. NONMEM Project Group. NONMEM user’s guides. San Francisco (CA): University of California, 1998Google Scholar
- 24.Center for Drug Evaluation and Research, Food and Drug Administration, US Department of Health and Human Services. Guidance for industry: population pharmacokinetics [online]. Rockville (MD): Center for Drug Evaluation and Research, 1999. Available from URL: http://www.fda.gov/cder/guidance/1852fnl.pdf [Accessed 2007 Mar 12]Google Scholar
- 25.Wade JR, Edholm M, Salmonson T. A guide for reporting the results of population pharmacokinetic analyses: a Swedish perspective. AAPS PharmSci 2005 Oct; 7(2): 45Google Scholar
- 32.Bay JO, Dhedin N, Goerner M, et al. Inolimomab in steroidefractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: retrospective analysis and comparison with other interleukin-2 receptor antibodies. Transplantation 2005 Sep 27; 80(6): 782–8PubMedCrossRefGoogle Scholar
- 36.Beal SL, Sheiner LB, NONMEM Project Group. NONMEM user’s guide: part VII. Conditional estimation methods. San Francisco (CA): University of California, 1998Google Scholar