M. Vigan(1), J. Stirnemann(2,3), C. Caillaud (2,4), R. Froissart (5), A. Boutten (6), B. Fantin (7), N. Belmatoug (2,7), F. Mentré(1)
(1) INSERM, UMR 738, Univ Paris Diderot, Sorbonne Paris Cité, Paris, France; (2) Referral Center for Lysosomal Diseases, Paris, France; (3) Division of General Internal Medicine, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland; (4) Laboratoire de Biochimie, Hôpital Cochin, Paris, France; (5) Laboratory of Inborn Errors of Metabolism, Hospices Civils de Lyon, Bron, France; (6) Laboratoire de Biochimie A, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, 46 rue Henri Huchard, 75018 Paris, France; (7) Service de Médecine Interne, Hôpital Beaujon, AP–HP, Clichy, France.
Objectives: Gaucher disease (GD) [1] is a rare recessively inherited disorder due to the deficiency of lysosomal enzyme glucocerebrosidase. Several biomarkers are significantly increased during this disease, such as ferritin and chitotriosidase. GD can be treated by enzyme replacement therapy (ERT), imi/al-glucerase, but no physiological model was proposed to analyse the evolution of biomarkers during ERT [2,3]. The aim of this study was to develop a drug-disease model explaining the response of biomarkers to ERT and to analyse the influence of several covariates.
Methods: We analysed patients from the French Registry of GD [4] who were treated by ERT (N=238). The accumulation of glucosylceramide in their macrophages leads to an increased production of ferritin and chitotriosidase. Therefore, we modelled that ERT participates in the decrease of these biomarkers and, neglecting their half-life, the turnover models were simplified to exponential drug-disease models. We analysed separately the evolution of both biomarkers using all measurements since initiation of ERT to stop of ERT (more than 6 months) or end of follow-up. Several covariates were tested including age at initiation of ERT, splenectomy and sex. Estimations were performed with MONOLIX 4.2.0 [5].
Results: Median time of follow-up during ERT was 9 [1-19] years. Median age at the initiation of ERT was 22 [1-67] years (18%<15 years), 51% were males, and 40% had a splenectomy before the initiation of the ERT. Data were available in N=152 and 185 patients for ferritin and chitotriosidase, respectively, with median number of observations per patients of 3. The exponential model fit the data well. Estimated baseline levels were 586 ng/l and 8560 nmol/h.ml and corrected values at steady state of ERT were 178 ng/l and 782 nmol/h.ml, for ferritin and chitotriosidase respectively. Estimated half-lifes were 1 and 0.4 year for ferritin and chitotriosidase. Patients under 15 years at initiation of ERT were found to have significantly lower baseline concentrations of ferritin (p<0.001) and higher baseline concentration of chitotriosidase (p=0.03). We also found that the efficacy of ERT on ferritin was significantly lower in patients with splenectomy (p<0.001) and higher in male patients (p<0.001).
Conclusions: This is the first study of the evolution of biomarkers in GD by a dynamic model. It will be further extended by modelling jointly the two biomarkers and by studying the link with repeated bone events [4].
References:
[1] Beutler E. Gaucher disease. Blood Rev. (1988) 2(1):59-70.
[2] Grabowski GA, Kacena K, Cole JA, Hollak CEM, Zhang L, Yee J, Mistry PK, Zimran A, Charrow J, vom Dahl S. Dose-response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1. Genet. Med. (2009) 11(2):92‑100.
[3] Stirnemann J, Belmatoug N, Vincent C, Fain O, Fantin B, Mentré F. Bone events and evolution of biologic markers in Gaucher disease before and during treatment. Arthritis Res. Ther. (2010) 12(4):R156.
[4] Stirnemann J, Vigan M, Hamroun D, Heraoui D, Rossi-Semerano L, Berger MG, Rose C, Camou F, De Roux-Serratrice C, Grosbois B, Kaminsky P, Robert A, Caillaud C, Froissart R, Levade T, Masseau A, Mignot C, Sedel F, Dobbelaere D, Vanier MT, Valayanopoulos V, Fain O, Fantin B, Billette T, Mentré F, Belmatoug N. The French Gaucher’s disease registry: clinical characteristics, complications and treatment of 562 patients. Orphanet J Rare Dis. (2012) 7(1):77.
[5] http://www.lixoft.net.
Reference: PAGE 22 (2013) Abstr 2837 [www.page-meeting.org/?abstract=2837]
Poster: Other Drug/Disease Modelling