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Pharmacokinetic and Pharmacodynamic Modeling of Serum Etrolizumab and Circulating ?7 Receptor Occupancy in Patients With Ulcerative Colitis.

ABSTRACT: Etrolizumab, a humanized monoclonal antibody, specifically binds to the ?7 subunit of the heterodimeric integrins ?4?7 and ?E?7. Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected from an etrolizumab phase 1 trial in patients with moderate to severe ulcerative colitis (UC). We developed a mechanism-based model to simultaneously describe the kinetics of serum etrolizumab concentration and free ?7 receptors on circulating intestinal-homing CD4+ T lymphocytes. Included in the analysis were 38 phase 1 UC patients who received single or 3 monthly doses of etrolizumab intravenously or subcutaneously across a dose range of 0.3 to 10 mg/kg. A quasi-steady-state target-mediated drug disposition model was developed to describe the dynamic interaction between serum etrolizumab concentration and free ?7 receptors on intestinal-homing CD4+ T lymphocytes in UC patients. The time profiles of serum etrolizumab and absolute counts of ?7+ lymphocytes (expressed as percentage of baseline level) were well described by the quasi-steady-state target-mediated drug disposition model. The model was able to characterize the maximum drug occupancy of ?7 receptors on intestinal-homing CD4+ T lymphocytes and the concentration-dependent duration of occupancy. The 90% effective concentration for etrolizumab to saturate the ?7 receptors on intestinal homing CD4+ T cells was 1.3 ?g/mL. PK and PD profiles predicted by the model were consistent with observations from a subsequent phase 2 study. In conclusion, an integrated PK/PD model developed in this analysis reasonably described serum etrolizumab PK profiles and the relationship between PK and PD (free ?7 receptors on circulating intestinal-homing CD4+ T lymphocytes) in UC patients.

SUBMITTER: Wei X

PROVIDER: S-EPMC5836964 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Pharmacokinetic and Pharmacodynamic Modeling of Serum Etrolizumab and Circulating β7 Receptor Occupancy in Patients With Ulcerative Colitis.

Wei Xiaohui X Gibiansky Leonid L Wang Yehong Y Fuh Franklin F Erickson Rich R O'Byrne Sharon S Tang Meina T MT

Journal of clinical pharmacology 20171126 3

Etrolizumab, a humanized monoclonal antibody, specifically binds to the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected from an etrolizumab phase 1 trial in patients with moderate to severe ulcerative colitis (UC). We developed a mechanism-based model to simultaneously describe the kinetics of serum etrolizumab concentration and free β7 receptors on circulating intestinal-homing CD4<sup>+</sup> T lymphocytes. Included in ...[more]

PMID: 29178491

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Project description:IntroductionEtrolizumab is a next-generation anti-integrin with dual action that targets two pathways of inflammation in the gut. A robust phase 3 clinical program in ulcerative colitis (UC) and Crohn's disease is ongoing and will evaluate the efficacy and safety of etrolizumab in well-defined patient populations in rigorous trials that include direct head-to-head comparisons against approved anti-tumor necrosis factor alpha agents (anti-TNF). The etrolizumab phase 3 clinical program consists of six randomized controlled trials (RCTs; UC: HIBISCUS I and II, GARDENIA, LAUREL, HICKORY; Crohn's disease: BERGAMOT) and two open-label extension trials (OLEs; UC: COTTONWOOD; Crohn's disease: JUNIPER) evaluating patients with moderately to severely active UC or Crohn's disease.MethodsIn the UC RCTs, patients are randomly assigned according to each protocol to receive etrolizumab, adalimumab, infliximab, or placebo. In BERGAMOT, patients are randomly assigned to receive etrolizumab 105 mg, etrolizumab 210 mg, or placebo. The primary outcomes for the UC RCTs are Mayo Clinic score-based clinical response, remission, and clinical remission; for BERGAMOT, the co-primary outcomes are clinical remission (based on abdominal pain and stool frequency) and endoscopic improvement (based on the Simple Endoscopic Score for Crohn's disease). The OLEs will primarily assess long-term efficacy and safety. Secondary and exploratory endpoints include endoscopy, histology, quality of life, and biomarkers at various timepoints.DiscussionThe etrolizumab phase 3 clinical program is the largest and most comprehensive in inflammatory bowel disease, enrolling more than 3000 patients. The program explores both induction and maintenance regimens. HIBISCUS I and II and GARDENIA are among the first head-to-head trials in UC against an anti-TNF and are the first registrational trials making that comparison. This program will also help address unanswered clinical questions on evaluation of treatment effects and treatment selection across a range of patients with varying treatment histories using an extensive repository of patient samples and data.Trial registrationClinicalTrials.gov: HIBISCUS I (NCT02163759), HIBISCUS II (NCT02171429), GARDENIA (NCT02136069), LAUREL (NCT02165215), HICKORY (NCT02100696), COTTONWOOD (NCT02118584), BERGAMOT (NCT02394028), JUNIPER (NCT02403323).

Dataset Information

Pharmacokinetic and Pharmacodynamic Modeling of Serum Etrolizumab and Circulating ?7 Receptor Occupancy in Patients With Ulcerative Colitis.

Publications

Pharmacokinetic and Pharmacodynamic Modeling of Serum Etrolizumab and Circulating β7 Receptor Occupancy in Patients With Ulcerative Colitis.

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