Background: Prior pharmacokinetic (PK) investigations have identified an association between anti-TNF trough concentrations (cTrough) and clinical or biochemical remission for children with Crohn’s Disease (CD). This study aimed to identify early and late PK parameters associated with endoscopic healing (EH), transmural healing (TH) and deep remission (DR).
Methods: CD patients were enrolled from 10/2019-12/2022 at four pediatric centers with longitudinal blood specimens collected prior to the start of anti-TNF and throughout the observational study. Infliximab (IFX) cTrough was quantified prior to dose2, 3, 4, 6 and month12 (m12) while adalimumab (ADAL) cTrough were collected prior to injection3 (inj3) and at m3, m6 and m12. IFX/ADAL cTrough were quantified with ECLIA (Esoterix, LabCorp specialty lab, Calabasas, CA). At m12, a research-only/mucosal healing ileocolonoscopy and MRE was recommended. EH was defined as a Simple Endoscopic Score-CD (SES-CD) <3. TH was defined as a total (small bowel/colon) simplified MaRIA<3 (and sMaRIA<2 from all segments) and SES-CD<3 with DR defined by SES-CD<3 and wPCDAI<12.5. IFX exposure (area under the curve, AUC) and clearance (CL) were estimated by Bayesian estimation using the Xiong et al. population PK model with NONMEM.
Results: We enrolled 80 anti-TNF naïve CD patients with 58 patients completing a m12 ileocolonoscopy. Ten patients declined an endoscopy while 7 had surgery, and 5 stopped anti-TNF therapy before m12. EH was achieved by 37/58 (64%, Table1), 65% on IFX and 60% on ADAL. DR and TH were achieved by 36/58 (62.1%) and 24/44 (54.5%), respectively. We found IFX cTrough were higher in patients with EH at dose2 (30[12.6] vs 21.6[7.6] µg/mL, p=.02), dose3 (21.8[10] vs 12.5[7] µg/mL, p=.002) and dose4 (8.4[6.2-12]vs 3.4[0.5-4.5] µg/mL, p<.001) with no difference at m12. Similar results were seen for DR as EH. The IFX cTrough cut-points at dose3 and dose4 for m12 EH were 15 µg/mL (AUC .8 [.66-0.93]) and 4.7 µg/mL (AUC .81 [0.65-0.97]), respectively. IFX cTrough at dose2 (p=.02) and dose4 (p=.0012) were higher for TH vs no-TH. The ADAL cTrough were higher at inj3 (27[6] vs 16[4] µg/mL, p=.01) and month3 (17.7[2] vs 11.2[4] µg/mL, p=.008) for EH and DR. Too few patients receiving ADAL had an MRE to analyze TH. Importantly, we found both higher IFX exposure and lower IFX CL were associated with favorable outcomes (Fig.1). The IFX dose4 exposure cut-point associated with EH was 85,043 µg*h/mL (AUC .75 [.6-.9]). Patients achieving this IFX dose4 target were significantly more likely to achieve EH (OR 8.2 [2.3-34]) and EH+TH (OR 27 [13.6-597]) at m12.
Conclusions: Achieving anti-TNF exposure targets during induction and early maintenance positively influences CD outcomes. Incorporation of these PK parameter thresholds into precision dosing platforms will allow clinicians to personalize anti-TNF dosing regimens.

<b>Figure1</b>. Infliximab exposure (area under the curve, µg*h/mL; A, C) and clearance (L/h; B, D) was assessed for patients (A, B) with endoscopic healing (EH) and endoscopic activity (EA) and for patients (C, D) with transmural healing (TH) and transmural activity (TA). EH was defined by a simple endoscopic score-Crohn’s disease (SES-CD)<3 and TH was defined by SES-CD<3 and a total small bowel/colon sMaRIA<3 (including sMaRIA<2 at all bowel segments). *, p<0.05; **, p<0.01; ***, p<0.001; NS, non-significant; W, week; BL, baseline; D, dose.

Figure1. Infliximab exposure (area under the curve, µg*h/mL; A, C) and clearance (L/h; B, D) was assessed for patients (A, B) with endoscopic healing (EH) and endoscopic activity (EA) and for patients (C, D) with transmural healing (TH) and transmural activity (TA). EH was defined by a simple endoscopic score-Crohn’s disease (SES-CD)<3 and TH was defined by SES-CD<3 and a total small bowel/colon sMaRIA<3 (including sMaRIA<2 at all bowel segments). *, p<0.05; **, p<0.01; ***, p<0.001; NS, non-significant; W, week; BL, baseline; D, dose.

<b>Table1.</b> Baseline demographics of all patients and those who had ileocolonoscopy after 12 months of anti-TNF therapy. Endoscopic healing was defined as a Simple Endoscopic Score-Crohn’s disease <3. Data shown as mean (standard deviation).

Table1. Baseline demographics of all patients and those who had ileocolonoscopy after 12 months of anti-TNF therapy. Endoscopic healing was defined as a Simple Endoscopic Score-Crohn’s disease <3. Data shown as mean (standard deviation).

Kei Irie

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