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P488. Exposure–response relationship of vedolizumab after 6 weeks of treatment in adults with Crohn's disease

M. Rosario1, J. French2, N. Dirks2, A. Milton1, I. Fox1, M. Gastonguay2, 1Takeda Pharmaceuticals International Company, Clinical Pharmacology, Cambridge, United States, 2Metrum Research Group LLC, Biotechnology, Tariffville, United States

Background

Vedolizumab (VDZ) 300 mg has recently demonstrated an apparent exposure–response relationship (ERR) in patients with Crohn's disease (CD) in the GEMINI 2 study (NCT00783692). Covariates, however, may impact VDZ pharmacokinetics (PK) and/or efficacy, thus confounding the ERR. In the current analyses, the VDZ ERR and the potential for covariates to confound the ERR were evaluated.

Methods

Exploratory plots of clinical response (≥70-point decrease in Crohn's Disease Activity Index [CDAI] score from baseline) and clinical remission (total CDAI score of ≤150 points) versus individual predicted average VDZ concentration (Caverage), derived from the VDZ population PK model, were generated from data obtained at week 6 in GEMINI 2. The ERRs were also assessed using a logistic regression model, which adjusted for potentially confounding baseline covariates (ie, prior anti-tumor necrosis factor alpha [TNF-alpha] use, albumin, C-reactive protein [CRP], fecal calprotectin), and an interaction model, which included evaluation of 2-way interactions between exposure and baseline covariates, and assessed the dependence of the ERR on covariates. Adjusted and interaction models were compared using a likelihood ratio test.

Results

Results from the exploratory plots suggest that increasing VDZ Caverage increased the probability of clinical response and clinical remission, with a less-steep ERR slope estimate observed for clinical remission than for clinical response. Also, ERRs for both end points appeared to plateau at high Caverage values. While VDZ ERRs estimated from the adjusted model for both end points were positive, these ERR slope estimates were less steep than those in the exploratory plots. Within groups, defined by quartiles of baseline covariates between Caverage values of 32 to 85 µg/mL (5th and 95th percentiles), the average probability of clinical response and clinical remission increased by 15% and 10%, respectively. Patients with lower baseline CRP levels and no prior anti-TNF-alpha use had a higher probability of clinical remission. The likelihood ratio statistic of the 2-way interaction analysis was not significantly different for either clinical response (2.49; P = 0.647) or remission (5.47; P = 0.243), indicating no dependence of the VDZ ERRs on baseline covariates.

Conclusion

A positive ERR exists for both clinical response and clinical remission in patients with CD after 6 weeks of induction therapy with VDZ 300 mg; however, any ERR derived from plots or tables of observed data may provide an overestimation of the true VDZ ERR. Furthermore, the VDZ ERR was not found to be dependent on any of the covariates tested.