DOP042. Clinical response and remission with vedolizumab across a range of baseline fecal calprotectin levels in ulcerative colitis: Results from GEMINI 1

of this Pop PK analysis was to characterize covariate effects on the PK profile of etrolizumab.Methods: This analysis included data from 145 etrolizumab-treated patients from 3 studies: a Phase 1 dose-escalation study (single doses at 0.3, 1, 3 or 10 mg/kg intravenously [IV], 3 mg/kg subcutaneously [SC] or 3 monthly doses at 0.5, 1.5 or 3 mg/kg SC or 4 mg/kg IV); a Phase 2 efficacy and safety study (2 SC dose cohorts of 100 mg at weeks 0, 4 and 8 or 420 mg at week 0 followed by 300 mg at weeks 2, 4 and 8); and a Phase 2 open-label extension study (300 mg SC monthly).A stepwise forward addition and backward elimination approach was used to evaluate the impact of the following baseline covariates on etrolizumab PK: age, sex, body weight (BW), Mayo Clinic Score, albumin, C-reactive protein, faecal calprotectin, prior use and response to anti-tumour necrosis factor alpha biologics and concomitant treatment with steroids or immunosuppressants.The Pop PK analysis was performed using NONMEM 7.1.2.Results: A 2-compartmental model with first-order absorption and elimination kinetics described etrolizumab PK well.BW and baseline serum albumin were identified as significant covariates for clearance (CL; P < 0.001); each explained 16% and 30% of the interindividual variability (IIV) of CL, respectively.Simulation showed similar exposure variability for a BW-based or fixed dose.No other covariates were found to have a significant impact on etrolizumab PK.The final model estimated the typical population CL value and central volume of distribution to be 0.245 L/day and 3.2 L, respectively.The elimination half-life and SC bioavailability were estimated to be 11 days and 53%, respectively.The IIV of evaluated PK parameters ranged from 19% to 67%.Pop PK simulation estimated that 105 mg every 4 weeks, the proposed Phase 3 dose regimen, can maintain a steady-state trough concentration of >1.7 µg/mL in 85% of patients (1.7 µg/mL is the observed minimum drug level associated with full β7 receptor occupancy in peripheral blood and colonic tissue).Conclusions: Etrolizumab exhibited linear PK at the target therapeutic dose.Based on the available data, BW and baseline serum albumin were identified as statistically significant covariates for CL.However, given the favourable safety and efficacy profiles for etrolizumab, the impact of these covariates on the therapeutic outcome is expected to be minimal and not clinically relevant.

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