Volume 147, Issue 6, Pages 1296-1307.e5 (December 2014) Association Between Serum Concentration of Infliximab and Efficacy in Adult Patients With Ulcerative Colitis  Omoniyi J. Adedokun, William J. Sandborn, Brian G. Feagan, Paul Rutgeerts, Zhenhua Xu, Colleen W. Marano, Jewel Johanns, Honghui Zhou, Hugh M. Davis, Freddy Cornillie, Walter Reinisch  Gastroenterology  Volume 147, Issue 6, Pages 1296-1307.e5 (December 2014) DOI: 10.1053/j.gastro.2014.08.035 Copyright © 2014 AGA Institute Terms and Conditions

Figure 1 Patient disposition through the PK analytic time points of interest in the ACT-1 and ACT-2 trials. Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions

Figure 2 Serum infliximab concentrations over time by clinical response status at week 8 in patients randomized to infliximab (A) 5 mg/kg or (B) 10 mg/kg in ACT-1 and ACT-2. The pharmacokinetic profile shown is according to the sampling times in ACT-1 and ACT-2. Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions

Figure 3 Distribution of infliximab concentrations by efficacy outcome status at (A) induction week 8, (B) maintenance week 30, and (C) maintenance week 54 (ACT-1 only) among patients treated with infliximab 5 or 10 mg/kg. Box plots show the median (solid line within box), interquartile range (upper and lower box boundaries), and standard deviation (whiskers). Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions

Figure 4 ROC curves for the relationship between serum infliximab concentrations and clinical response in ACT-1 and ACT-2 at (A) induction week 8, (B) maintenance week 30, and (C) maintenance week 54 (ACT-1 only) among patients treated with infliximab 5 or 10 mg/kg. (A) CPW2, CPW6, CW8, (B and C) CPW14, CPW30, or (C) CPW54 (ACT-1 only) represent the ROC curves for clinical response and serum infliximab concentrations at weeks 2, 6, 8, 14, 30, and 54, respectively, all preinfusion except week 8. A, area under the ROC curve. Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 1 Infliximab dosing and pharmacokinetic sampling scheme for ACT-1 and ACT-2. Open circles and squares indicate treatment with infliximab 5 mg/kg or 10 mg/kg, respectively. Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 2 Distribution of infliximab concentrations among patients treated with infliximab 5 or 10 mg/kg in ACT-1 and ACT-2. CPW2, CPW6, CW8, CPW14, CPW30, and CPW54 (ACT 1 only) represent serum infliximab concentrations at weeks 2, 6, 8, 14, 30, and 54, respectively; all preinfusion with the exception of week 8. Box plots below show median (solid line in box), interquartile range (upper and lower boundaries of box), mean (dotted line), and distribution of individual patient concentrations (circles). Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 3 Proportion of patients achieving efficacy outcomes by serum infliximab concentration quartiles in ACT-1 and ACT-2 for the 5-mg/kg treatment group at induction week 8 (A), maintenance week 30 (B), and maintenance week 54 (C; ACT-1 only). The trend of the proportion of patients achieving clinical outcomes across the quartiles was evaluated using the 1-sided Cochrane-Armitage trend test. Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 4 Proportion of patients achieving clinical response by serum infliximab concentration quartiles in ACT-1 and ACT-2 stratified by dose regimen at induction week 8 (A) and maintenance week 30 (B). The trend of the proportion of patients achieving clinical outcomes across the quartiles was evaluated using the 1-sided Cochrane-Armitage trend test. Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 5 The influence of serum infliximab concentration on subsequent efficacy outcome for the combined 5- and 10-mg/kg infliximab doses. Median serum infliximab concentrations at weeks 30, 14, and 8 are shown for patients who did and did not achieve clinical remission at weeks 54 (ACT-1 only), 30, and 30, respectively (A -C) and proportions of patients in clinical remission at weeks 54 (ACT-1 only), 30, and 30 by serum infliximab concentration quartiles at weeks 30, 14, and 8, respectively, among patients in remission at weeks 30, 8, and 8, respectively (D-F). For all panels, the 5- and 10-mg/kg doses of infliximab are combined. Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions

Supplementary Figure 6 The influence of serum infliximab concentration on subsequent efficacy outcome by infliximab dose. Median serum infliximab concentrations at week 30 are shown for patients who did and did not achieve clinical remission at week 54 (ACT-1 only) for patients receiving infliximab 5 mg/kg (A) and 10 mg/kg (B) and proportions of patients in clinical remission at week 54 (ACT-1 only) by serum infliximab concentration quartiles at week 30 among patients in remission at week 30 for patients receiving infliximab 5 mg/kg (C) and 10 mg/kg (D). Gastroenterology 2014 147, 1296-1307.e5DOI: (10.1053/j.gastro.2014.08.035) Copyright © 2014 AGA Institute Terms and Conditions