Drug monitoring in IBD: the ultimate goal or are we chasing the wrong Holy Grail?

Transcription

1 Drug monitoring in IBD: the ultimate goal or are we chasing the wrong Holy Grail? Karen van Hoeve 1, Ilse Hoffman 1, Ann Gils 2, Séverine Vermeire 3 1 Department of Paediatric Gastroenterology & Hepatology & Nutrition, University Hospitals Leuven, Leuven, Belgium 2 Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven 3 Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium

2 Inflammatory bowel disease Ulcerative colitis (UC) Crohn s Disease (CD) Affects the colon only Continuous inflammation Mucosal inflammation Affects the entire GI tract Discontinuous inflammation Transmural inflammation Loss of haustra Pseudopolyps Damage to mucosa Fat wrapping Wall thickening Fissure Cobble stones 2

3 Inflammatory bowel disease Peadiatric IBD Adult IBD Disease location CD: more panenteric UC: more pancolitis Disease behavior CD: mostly inflammatory UC: more aggressive Clinical presentation Growth and puberty delay CD: more terminal ileal UC: more left-sided colitis CD: more stricturing, penetrating UC: less aggressive Similar clinical symptoms Sauer et al. Gastroenterol Clin North Am 2009 Van Limbergen et al. Gastroenterology 2008 Vernier-Massouille et al. Gastroenterology

4 IBD management Inducing remission Maintaining remission Preventing/treating complications Osterman MT. Mucosal healing in inflammatory bowel disease. J Clin Gastroenterol. 2013; Restore growth Mucosal healing Osterman et al. J Clin Gastroenterol

5 How can today s goals be achieved? 5

6 Treatment options Coskun et al. Trends Pharmacol Sci

7 Treatment options Coskun et al. Trends Pharmacol Sci

8 Management must be tailored to the individual patient Fibrosis Drug toxicity Fistulas Surgery Inflammation Mucosal healing IM Anti-TNF CS Therapeutic drug monitoring IM= immunomodulators CS= corticosteroid 8

9 Role of therapeutic drug monitoring Presence of anti-drug antibodies (ATI) Use of immunomodulators Disease severity High baseline CRP Low baseline albumin Body size Gender Impact on Pharmacokinetics Increases clearance Decreases clearance Reduces anti-drug antibody formation Increases clearance Increases clearance Increases clearance Low body weight results in lower drug concentration due to non-linear distribution in the peripheral compartment High BMI may increase clearance in adults Males have higher clearance van Hoeve et al. Expert Opin Drug Saf. 2018; 17:

10 Impact on pharmacokinetics Presence of anti-drug antibodies (ATI) Use of immunomodulators Disease severity High baseline CRP Low baseline albumin Body size Gender Impact on Pharmacokinetics Increases clearance Decreases clearance Reduces anti-drug antibody formation Increases clearance Increases clearance Increases clearance Low body weight results in lower drug concentration due to non-linear distribution in the peripheral compartment High BMI may increase clearance in adults Males have higher clearance Drug monitoring: even more important in children? van Hoeve et al. Expert Opin Drug Saf. 2018; 17:

11 Use of therapeutic drug monitoring (TDM) in clinical practice Role of TDM in case of loss of response (LOR)? 11

12 TDM proposed treatment algorithms van Hoeve et al. Expert Opin Drug Saf. 2018; 17:

13 TDM proposed treatment algorithms van Hoeve et al. Expert Opin Drug Saf. 2018; 17:

14 TDM proposed treatment algorithms van Hoeve et al. Expert Opin Drug Saf. 2018; 17:

15 TDM proposed treatment algorithms Ideal therapeutic window? IFX: 3-7 µg/ml Vande Casteele et al. Gastroenterology

16 TDM proposed treatment algorithms Ideal therapeutic window? ADA: 7-12 µg/ml Ungar et al. Clin Gastroenterol Hepatol

17 Use of therapeutic drug monitoring (TDM) in clinical practice Role of pro-active TDM? 17

18 Treat-to-target approach Dose intensification Higher IFX TL Higher effectiveness Clinical remission Pro-active TDM Loss of response Mucosal ulcerations Re-active TDM Elevated biomarkers 18

19 Treat-to-target approach Retrospective study from Boston (n= 264) 1 Better clinical outcome Less surgery or hospitalisation and less antibodies to IFX Retrospective study from Vaughn et al. (n= 48) 2 Greater probability on remaining on IFX (FU 5 years) 1 Papamichael et al. Clin Gastroenterol Hepatol. 2017; ²Vaughn et al. Inflamm Bowel Dis

20 Treat-to-target approach Prospective (TAXIT) study (n= 263) 1 After first optimisation, drug level-based dosing or to clinically based dosing showed identical remission rates in both groups at year 1 However, if under-treated, dose increase normalised CRP Prospective (Tailorix) study (n= 122) 2 LOR vs pro-active TDM: sustained response rate was similar in both groups 1 Vande Casteele et al. Gastroenterology. 2015; 2 D Haens et al. Congress of ECCO

21 Conclusion Uncertain role of pro-active TDM Only adult studies available Retrospective studies + Prospective studies - 21

22 Conclusion Uncertain role of pro-active TDM Only adult studies available Retrospective studies + Prospective studies - 22

23 Conclusions The treatment goals in IBD have been shifted from clinical remission to mucosal healing. However, due to limited treatment options, we need to find other ways to improve our current treatment (anti-tnf therapy). Therapeutic drug monitoring has been proposed as one of the ways to improve outcome. However, these studies in children are still under investigated. There is increasing evidence that re-active TDM can improve outcome, however the role of pro-active TDM is uncertain. Future prospective studies should investigate the benefit of proactive TDM in children exposed to anti-tnf agents and try to find the ideal therapeutic window. tekst 23

24 Acknowledgements Dpt. Gastroenterology & Hepatology Marc Ferrante. MD. PhD Paul Rutgeerts. MD. PhD Gert Van Assche. MD. PhD Séverine Vermeire. MD. PhD Dpt. Paediatric Gastroenterology & Hepatology Ilse Hoffman. MD. PhD. Dpt. Colorectal Surgery André D Hoore. MD. PhD. Albert Wolthuis. MD. PhD. Leuven IBD group Vera Ballet Helene Blevi Peter Bossuyt. MD Clara Caenepeel. MD Sofie Coenen Tamara Coopmans Nooshin Davani Magali de Bruyn. PhD Kathleen Machiels. PhD Annick Moens. MD Manuel Noben. PhD Sophie Organe João Sabino. MD. PhD Maaike Van Camelbeke Wiebe Vanhove. PhD Bram Verstockt. MD Willem-Jan Wollants Laboratory for Therapeutic and Diagnostic Antibodies Sumin Bian Els Brouwers Griet Compernolle Iris Detrez Erwin Dreesen Miet Peeters Nathalie Vandenberghe Debby Thomas Sophie Tops Ann Gils, PharmD, PhD Clinical trials Isolde Aerden Patricia Geens Liese Gijbels Tine Hermans Jolien Lefrère Maja Noman. MD An Outier. MD Karen Rans Ganel Schops Karolien Van Den Broeck Ellen Weyts 24