Population Pharmacokinetic Analysis of Etrolizumab in Patients with Moderately-to-Severely Active Ulcerative Colitis
BACKGROUND: Etrolizumab is an IgG1-humanised monoclonal antibody that specifically targets the β7 subunit of α4β7 and αEβ7 integrins, and has been evaluated for the treatment of moderately-to-severely active ulcerative colitis (UC). Population pharmacokinetic (PK) analysis was conducted to characterize etrolizumab PK in Phase I, II and III patient population and evaluate covariate impacts on exposure.
METHODS: The population PK model was developed based on etrolizumab serum concentrations from UC patients enrolled in 6 studies (1 Phase I, 1 Phase II, and 4 Phase III) [1]. Phase I PK samples were collected following intravenous and subcutaneous (SC) administration; Phase II and III samples were collected following SC administration. The duration of Phase III studies ranged from 10 to 64 weeks, and included an induction phase and in some studies a maintenance phase, in responders. Stepwise covariate modeling was used to evaluate the impact of 23 pre-specified covariates on one or multiple PK parameters. External model evaluation was based on PK data from one Phase III study [2], available after model finalization.
RESULTS: Etrolizumab PK was best described by a two-compartment model with first-order absorption, and clearance decreasing with time. Population typical values were estimated as 0.260 L/day for clearance (CL) during the first dosing interval, 2.61 L for central volume (Vc), 71.2% for bioavailability (F), and 0.193 day-1 for absorption rate of the SC formulation (Inter-subject variability: CL 24.3%, Vc 25.2%, F 21.1%). CL reduced over study duration, maximum reduction 26% with onset half-life of 4.8 weeks. The estimated mean terminal half-lives after a single dose and at steady-state were 13.0 and 17.1 days, respectively. Baseline body weight and albumin were the most impactful covariates for etrolizumab exposure. Model diagnostics and the external validation exhibited satisfactory predictive performance of the final model.
CONCLUSIONS: Final population PK model well characterized the PK properties of etrolizumab in moderately-to-severely active UC patients and identified influential covariate effects. This model was used to derive etrolizumab individual exposure metrics for exposure-response analysis [3].
CITATIONS:
[1] ClinicalTrials.gov (NCT00694980, NCT01336465, NCT02163759, NCT02171429, NCT02100696, and NCT02165215)
[2] ClinicalTrials.gov (NCT02136069)
[3] Kassir N, Zhu R, et al., Exposure-Response Analysis of Etrolizumab in Patients with Moderately-to-severely Active Ulcerative Colitis, ACoP 2021
Author(s)
- Anita Moein, Genentech (Presenting Author)
- Tong Lu , Genentech (CoAuthor)
- Siv Jönsson , Pharmetheus AB (CoAuthor)
- Jakob Ribbing , Pharmetheus AB (CoAuthor)
- Nastya Kassir, Genentech (CoAuthor)
- Wenhui Zhang, Genentech (CoAuthor)
- Rong Zhang, Genentech (CoAuthor)
- Meina Tang , Retired from Genentech (CoAuthor)
- Young S. Oh , Genentech (CoAuthor)
- Rene Bruno , Roche (CoAuthor)
- Rui Zhu , Genentech (CoAuthor)