Xavier Roblin, MD, PhD 1, M. Rinaudo, MD 2, E. Del Tedesco, MD 1, J.M. Phelip, MD, PhD 1, C. Genin, MD, PhD 2, L. Peyrin-Biroulet, MD, PhD 3 and S. Paul, PhD 2 Development of an Algorithm Incorporating Pharmacokinetics of Adalimumab in Inflammatory Bowel Diseases 월요저널 R1. 하효정 / Pf. 김효종 Am J Gastroenterol 2014; 109:1250–1256 published online 10 June 2014

Introduction Adalimumab (ADA) : Treatment of both Crohn ’ s disease & ulcerative colitis refractory to standard medications  Loss of response to these agents … ( production of antidrug antibodies -> development of immunogenicity )  Finally, to treatment failure Recent studies found an association between pharmacokinetics of ADA and clinical remission and mucosal healing rates The aim of this prospective study : Explore the clinical utility of therapeutic drug monitoring of ADA in predicting CR rates

Methods (1) Prospective observational study, (January 2011 and June 2013) Saint-Etienne University Hospital, followed up every 2months ADA maintenance Tx(40 mg every other week ) Disease activity score : CDAI, Mayo clinical score (at each visit ) Clinical relapse (CDAI > 220 for CD & Mayo Clinic > 5 for UC) :elevated fecal calprotectin level > 450 μ g/ g stool for CD or the presence of an endoscopic Mayo score > 1 for UC  ADA therapy was optimized at a dose of 40 mg weekly Before ADA optimization : Drug levels of adalimumab (residual trough levels of adalimumab (TRA )) & Antibodies against ADA (AAA) levels.

Methods (1) CR(clinal remission ) : CD = CDAI < 150 and fecal calprotectin level < 250 μ g/ g in stool : UC = Total Mayo score < 3 Mucosal healing( for UC) : Endoscopic Mayo score of 0 or 1 In case of clinical relapse …switched to IFX Perianal fistulizing CD or UC proctitis : exclusion Negative for Clostridium difficile : inclusion.

Methods (2) Measurement of ADA drug levels and AAA Serum samples are collected just before ADA injection and stored at − 20 ° C TRA and AAA concentrations : Lisa-Tracker Premium ADA ELISA kit Fecal calprotectin :The Quantum Blue Calprotectin assay Statistical analysis Quantitative variables : means, standard deviation (s.d.) P values (P < 0.05 :statistically significant) Fisher’ s exact test, χ 2 test, and log-rank test for discontinuation Logistic regression analysis Statistical analysis was performed using IBM SPSS (IBM, Somers, NY).

RESULTS (1) - characteristics Group A ( N = 41) : TRA > 4.9 μ g / ml 10 patients : AAA > 10 μ g / ml 31 patients : negative Group B (N=24) : TRA < 4.9 μ g / ml & undetectable ( < 10 ng / ml) Group C (N=17) : TRA < 4.9 μ g / ml & AAA > 10 ng / ml CRP : A 25 mg / l B 22 mg / l C 21 mg / l The percentage of CD : A 57 % (95 % CI = 39 – 60; N = 23) B 50 % (95 % CI = 31– 69; N = 13) C 58% (95% CI = 39– 86; N = 10)

RESULTS (2) Clinical response after ADA optimization 36.5 %, N=30 67%, N=16 52%, N=13 N=0 Did not achieved CR after ADA optimization : A 15 patients (37%, 95% CI = 15– 57 ) B 2 patients (8%, 95% CI = 0– 18) C 10 patients (58%; 95% CI = 38– 86) Group B (N= 8) : TRA < 4.9 μ g / ml undetectable ( < 10 ng / ml)

RESULTS (2) Clinical response after ADA optimization These are not predictors... (d/t P >0.05)

RESULTS (3) Clinical response after switching to IFX among patients with ADA failure after 6 months Group A ( N = 29) : TRA > 4.9 μ g / ml 6 patients : AAA > 10 μ g / ml 23 patients : negative Group B (N= 8) : TRA < 4.9 μ g / ml & undetectable ( < 10 ng / ml) Group C (N=15) : TRA < 4.9 μ g / ml & AAA > 10 ng / ml CRP : A 21 mg / l B 22 mg / l C 18 mg / l The percentage of CD : A 62 % (95 % CI = 40 – 75; N = 18) B 50 % (95 % CI = 15 – 84; N = 4) C 52 % (95 % CI = 8 – 78; N = 8)

RESULTS (3) Clinical response after switching to IFX among patients with ADA failure after 6 months 30.6 %, N=16 N=0 55%, N=8 80%, N=12 Did not achieved CR after ADA optimization : A 20 patients (68 %, 95% CI = 34– 80) B 4 patients (50%, 95% CI = 23– 68) C 2 patients (13%, 95% CI = 0– 35) Group C (N=15) : TRA < 4.9 μ g / ml AAA > 10 ng / ml

RESULTS (3) Clinical response after switching to IFX among patients with ADA failure after 6 months These are predictors !!

RESULTS (4) Biomarker and endoscopic remission after ADA optimization and switch to IFX Switching to IFX Def. of Biomarker remission : Fecal calprotectin level < 250 μ g/ g stool for CD Def. of Endoscopic remission : Endoscopic Mayo score < 2. ADA optimization 36%, N= %, N=30

CONCLUSION High trough levels of adalimumab : clinical response and mucosal healing Antibodies against ADA : clinical failure Favorable Failure to ADA Failure to ADA & IFX

Thank you !