Clinical Pharmacokinetics

, Volume 46, Issue 5, pp 417–432

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

  • Céline Dartois
  • Gilles Freyer
  • Mauricette Michallet
  • Emilie Hénin
  • Benoît You
  • Isabelle Darlavoix
  • Claudine Vermot-Desroches
  • Brigitte Tranchand
  • Pascal Girard
Original Research Article
  • 77 Downloads

Abstract

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.

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 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.

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.

Conclusion

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.

References

  1. 1.
    Storb R. Allogeneic hematopoietic stem cell transplantation — yesterday, today, and tomorrow. Exp Hematol 2003 Jan; 31(1): 1–10PubMedCrossRefGoogle Scholar
  2. 2.
    Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991 Mar 7; 324(10): 667–74PubMedCrossRefGoogle Scholar
  3. 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
  4. 4.
    Keever CA, Small TN, Flomenberg N, et al. Immune reconstitution following bone marrow transplantation: comparison of recipients of T-cell depleted marrow with recipients of conventional marrow grafts. Blood 1989 Apr; 73(5): 1340–50PubMedGoogle Scholar
  5. 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
  6. 6.
    Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment. Blood 1991 Apr 15; 77(8): 1821–8PubMedGoogle Scholar
  7. 7.
    Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/ severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood 1990 Feb 15; 75(4): 1024–30PubMedGoogle Scholar
  8. 8.
    Ross WA. Treatment of gastrointestinal acute graft-versus-host disease. Curr Treat Options Gastroenterol 2005 Jun; 8(3): 249–58PubMedCrossRefGoogle Scholar
  9. 9.
    Akpek G, Lee SM, Anders V, et al. A high-dose pulse steroid regimen for controlling active chronic graft-versus-host disease. Biol Blood Marrow Transplant 2001; 7(9): 495–502PubMedCrossRefGoogle Scholar
  10. 10.
    Mollee P, Morton AJ, Irving I, et al. Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis. Br J Haematol 2001 Apr; 113(1): 217–23PubMedCrossRefGoogle Scholar
  11. 11.
    Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood 1999 Oct 1; 94(7): 2208–16PubMedGoogle Scholar
  12. 12.
    Micallef IN, Chhanabhai M, Gascoyne RD, et al. Lymphoproliferative disorders following allogeneic bone marrow transplantation: the Vancouver experience. Bone Marrow Transplant 1998 Nov; 22(10): 981–7PubMedCrossRefGoogle Scholar
  13. 13.
    Hertenstein B, Stefanic M, Sandherr M, et al. Treatment of steroid-resistant acute graft-vs-host disease after allogeneic marrow transplantation with anti-interleukin-2 receptor antibody (BT563). Transplant Proc 1994 Dec; 26(6): 3114–6PubMedGoogle Scholar
  14. 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
  15. 15.
    Cuthbert RJ, Phillips GL, Barnett MJ, et al. Anti-interleukin-2 receptor monoclonal antibody (BT 563) in the treatment of severe acute GVHD refractory to systemic corticosteroid therapy. Bone Marrow Transplant 1992 Nov; 10(5): 451–5PubMedGoogle Scholar
  16. 16.
    Herve P, Bordigoni P, Cahn JY, et al. Use of monoclonal antibodies in vivo as a therapeutic strategy for acute GvHD in matched and mismatched bone marrow transplantation. Transplant Proc 1991 Feb; 23 (1 Pt 2): 1692–4PubMedGoogle Scholar
  17. 17.
    Herve P, Wijdenes J, Bergerat JP, et al. Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10). Blood 1990 Feb 15; 75(4): 1017–23PubMedGoogle Scholar
  18. 18.
    Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974 Oct; 18(4): 295–304PubMedCrossRefGoogle Scholar
  19. 19.
    Thomas ED, Storb R, Clift RA, et al. Bone-marrow transplantation (second of two parts). N Engl J Med 1975 Apr 24; 292(17): 895–902PubMedCrossRefGoogle Scholar
  20. 20.
    Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR severity index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol 1997 Jun; 97(4): 855–64PubMedCrossRefGoogle Scholar
  21. 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. 22.
    Boeckmann AJ, Sheiner L, Beal SL. NONMEM Project Group. NONMEM user’s guides. San Francisco (CA): University of California, 1998Google Scholar
  23. 23.
    Ette EI, Ludden TM. Population pharmacokinetic modeling: the importance of informative graphics. Pharm Res 1995 Dec; 12(12): 1845–55PubMedCrossRefGoogle Scholar
  24. 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. 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
  26. 26.
    Agresti A. Modelling ordered categorical data: recent advances and future challenges. Stat Med 1999 Sep 15; 18(17–18): 2191–207PubMedCrossRefGoogle Scholar
  27. 27.
    Duffull SB, Chabaud S, Nony P, et al. A pharmacokinetic simulation model for ivabradine in healthy volunteers. Eur J Pharm Sci 2000; 10(4): 285–94PubMedCrossRefGoogle Scholar
  28. 28.
    Yano Y, Beal SL, Sheiner LB. Evaluating pharmacokinetic/ pharmacodynamic models using the posterior predictive check. J Pharmacokinet Pharmacodyn 2001 Apr; 28(2): 171–92PubMedCrossRefGoogle Scholar
  29. 29.
    Rubin DB. Bayesianly justifiable and relevant frequency calculations for the applied statistician. Ann Stat 1984; 12: 1151–72CrossRefGoogle Scholar
  30. 30.
    Shiiki T, Hashimoto Y, Inui K. Simulation for population pharmacodynamic analysis of dose-ranging trials: usefulness of the mixture model analysis for detecting nonresponders. Pharm Res 2002 Jun; 19(6): 909–13PubMedCrossRefGoogle Scholar
  31. 31.
    Cahn JY, Bordigoni P, Tiberghien P, et al. Treatment of acute graft-versus-host disease with methylprednisolone and cyclosporine with or without an anti-interleukin-2 receptor monoclonal antibody: a multicenter phase III study. Transplantation 1995 Nov 15; 60(9): 939–42PubMedCrossRefGoogle Scholar
  32. 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
  33. 33.
    Martin P, Bleyzac N, Souillet G, et al. Relationship between CsA trough blood concentration and severity of acute graftversus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors. Bone Marrow Transplant 2003 Oct; 32(8): 777–84PubMedCrossRefGoogle Scholar
  34. 34.
    Andersson BS, Thall PF, Madden T, et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graftversus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant 2002; 8(9): 477–85PubMedCrossRefGoogle Scholar
  35. 35.
    Jacobson P, Rogosheske J, Barker JN, et al. Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation. Clin Pharmacol Ther 2005 Nov; 78(5): 486–500PubMedCrossRefGoogle Scholar
  36. 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
  37. 37.
    Frey N, Laveille C, Paraire M, et al. Population PKPD modelling of the long-term hypoglycaemic effect of gliclazide given as a once-a-day modified release (MR) formulation. Br J Clin Pharmacol 2003 Feb; 55(2): 147–57PubMedCrossRefGoogle Scholar
  38. 38.
    Zingmark PH, Ekblom M, Odergren T, et al. Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients. Br J Clin Pharmacol 2003 Aug; 56(2): 173–83PubMedCrossRefGoogle Scholar
  39. 39.
    Karlsson MO, Molnar V, Bergh J, et al. A general model for time-dissociated pharmacokinetic-pharmacodynamic relationship exemplified by paclitaxel myelosuppression. Clin Pharmacol Ther 1998 Jan; 63(1): 11–25PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Céline Dartois
    • 1
    • 2
  • Gilles Freyer
    • 1
    • 2
    • 3
  • Mauricette Michallet
    • 4
  • Emilie Hénin
    • 1
    • 2
  • Benoît You
    • 1
    • 2
    • 3
  • Isabelle Darlavoix
    • 5
  • Claudine Vermot-Desroches
    • 5
  • Brigitte Tranchand
    • 1
    • 2
    • 6
  • Pascal Girard
    • 1
    • 2
  1. 1.EA3738 CTO, Faculté de Médecine Lyon SudUniversitéLyon 1OullinsFrance
  2. 2.Université de LyonLyonFrance
  3. 3.Service d’Oncologie MédicaleCentre Hospitalier Lyon Sud, Hospices Civils de LyonPierre-BéniteFrance
  4. 4.Service d’HématologieHôpital Edouard HerriotLyonFrance
  5. 5.OPi SALimonestFrance
  6. 6.Centre Anticancéreux Léon BérardLyonFrance
  7. 7.EA 3738Université de Médecine de Lyon Sud BP 12Oullins CedexFrance

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