Clinical Correlates and Pharmacokinetic Parameters of Certolizumab Pegol Predicted by Modeling in Patients With Crohn’s Disease

Abstract

Introduction: To characterize clinical correlates relevant for pharmacokinetics (PK) of certolizumab pegol (CZP) in patients with Crohn’s disease (CD) via a population PK analysis. Methods: Plasma CZP concentration time data were pooled from 9 clinical studies investigating subcutaneously administered CZP in patients with moderate to severe CD, and were subject to a population PK analysis using nonlinear mixed effects modeling (NONMEM). A co-variate analysis was performed to identify factors that impact the PK parameters. Results: Plasma concentration-time data were available from 2,157 patients with 13,561 quantifiable CZP plasma concentrations. The data were adequately described by a one-compartment, first-order absorption disposition model. CZP anti-drug antibodies were found to influence clearance (CL) of CZP as well as between-subject variability. The estimate of baseline concentrations was also influenced. The results of the co-variate analysis showed that body surface area (BSA), albumin concentrations, and Creactive protein (CRP) at baseline were the most clinically relevant co-variates. Furthermore, BSA influenced both CL and volume of distribution (Vd) in a linear fashion; these parameters increased by over 53% and 49% across the range of BSA measurements. Albumin was found to influence the CL of CZP in a nonlinear fashion, with a steep change in CL with increasing albumin concentrations below 41 g/L (Figure 1). Ethnicity was found to influence Vd, but not all the race categories were statistically significant or met relevant clinical criteria.Figure 1: The impact of albumin concentrations at baseline on the clearance of certolizumab pegol.Conclusion: The clinically and statistically relevant co-variates affecting CL of CZP were anti-CZP antibodies, BSA, albumin, and CRP at baseline. Vd was influenced by BSA and ethnicity. Disclosure - Janet Wade is an employee SGS Exprimo and a consultant to UCB Pharma. Ruth Oliver, Gerry Parker, and Gordana Kosutic are employees of UCB Pharma and have stocks and stock options. Brian Feagan is a Speakers Bureau Member for: Abbott/AbbVie, JnJ/Janssen, Takeda, Warner-Chilcott, UCB Pharma, Consulting Fee/Advisory Board: Abbott/AbbVie, Actogenix, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Axcan, Baxter Healthcare Corp., Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Merck, Millennium, Nektar, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, Tillotts, UCB Pharma, Vertex Pharma, Warner-Chilcott, Wyeth, Zealand, Zyngenia. Contracted Research: Abbott/AbbVie, Amgen, Astra Zeneca, Bristol-Myers Squibb (BMS), Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, UCB Pharma.