Effect of vedolizumab dose intensification on serum drug concentrations and regain of response in inflammatory bowel disease patients with secondary loss of response

Abstract

Background and Aims Dose intensification of vedolizumab (VDZ) for moderate‐to‐severe ulcerative colitis (UC) and Crohn's disease (CD) may be effective in patients losing response. We aimed to assess the clinical and pharmacokinetic effect of VDZ dose intensification. Methods We performed a multicentre open‐label prospective study from June 2017 through December 2018 in patients on VDZ losing response, defined as total Mayo score >6 (UC) or Harvey‐Bradshaw Index >4 with inflammation (CD). Blood samples and clinical scores were collected at baseline and after VDZ infusion at Weeks 4 and 8. Clinical response was defined as a decrease of partial Mayo score ≥2 points or Harvey‐Bradshaw Index ≥3 points. Biological response was defined as a decrease of C‐reactive protein to ≤5 mg/L or of >50%. Results A total of 59 patients (31 UC and 28 CD) were included. Median (IQR) trough levels (TLs) increased from 8.7 (5.1‐12.7) µg/mL (baseline) to 19.1 (12.4‐22.4) µg/mL (Week 4) and 23.1 (16.7‐28.4) µg/mL (Week 8) (all P < 0.0001). Partial Mayo score decreased with 3 points from baseline to Week 4 (P = 0.001) but stabilised to Week 8 (P = 0.16). Harvey‐Bradshaw Index decreased with 4 points from baseline to Week 4 (P = 0.001) and 1 point to Week 8 (P = 0.04). Recapture of clinical and biological response was achieved in 49% and 27% at Week 4, and 54% and 37% at Week 8 respectively. Conclusion Dose escalation to VDZ every 4 weeks after loss of response resulted in higher TLs with regain of clinical response in half of the patients.

Vedolizumab: what is the benefit from increasing the dose frequency?

“…A literature review (box 1) identified seven studies (four observational studies and three single arm open-label studies), with 411 patients with IBD, that examined the effect of dose escalation for patients experiencing a LOR (table 1). 10–16 The criteria for dose escalation for LOR varied between studies, particularly in patients with UC. The definition for response and remission were also heterogeneous with different scoring systems being used and some using a physician’s assessment (table 1).…”

“…The results from six studies of dose escalation for LOR in people with CD show an overall response rate of 47%–61% and remission rate of 14%–34% reported for various time-points from 8 to 52 weeks 10 12–16. In UC, the response rate was 32%–63% and remission rate was 11%–34% reported for timepoints between 4 and 52 weeks 11 13–16.…”

“…These findings suggest that some patients who experience LOR during maintenance treatment, benefited from dose escalation. It should be noted that 53%–100% of participants had prior TNFα inhibitor use 10–15…”

“…However, there is no consensus about the utility of trough levels to guide treatment escalation 15 19 21. Outtier et al found baseline vedolizumab levels, in patients with LOR did not predict who would respond to dose escalation 15.…”

“…However, there is no consensus about the utility of trough levels to guide treatment escalation 15 19 21. Outtier et al found baseline vedolizumab levels, in patients with LOR did not predict who would respond to dose escalation 15. Vaughn et al examined 58 patients whose dose was escalated to see if vedolizumab trough levels could predict who would subsequently respond to dose escalation; 74% of those with a trough levels <7.4 µg/mL prior to escalation responded compared with only 52% of those with a vedolizumab trough concentration ≥7.4 µg/mL (p=0.08) 21.…”