Evaluation of pharmacokinetics and pharmacodynamics and clinical efficacy of certolizumab pegol for Crohn’s disease

Abstract

As a Fab' fragment, CZP is effective in binding TNF-α, but does not cause Fc-mediated effects. PEGylation has improved its pharmacokinetic profile and allowed for an increased half-life of 2 weeks. Benefit for inducing response (an improvement in symptoms) and maintenance of remission has been shown. However, the benefit is less clear for the more stringent end-points of inducing remission and mucosal healing. There may be an advantage from the PEGylated formulation of CZP in terms of reduced injection-site reactions, reduced placental transfer in pregnancy and as a treatment option in patients who are unable to tolerate infliximab.

Formation and clearance of TNF–TNF inhibitor complexes during TNF inhibitor treatment

“… b Total TNF production in a 14‐day period, based on steady‐state levels during certolizumab treatment: d[TNF] eq /d t = 0, hence k production = k elimination × [TNF] eq , with k elimination = ln(2)/ t 1/2 ; TNF production in 2 weeks = ; parameters used were t 1/2 = 11 days and V = 8 L (Tun & Lobo, 2015). …”

“…[TNF] eq , with k elimination = ln(2)/t 1/2 ; TNF production in 2 weeks = Ð 14 0 k production Vdt; parameters used were t 1/2 = 11 days and V = 8 L (Tun & Lobo, 2015). c Molar ratio of 40 mg/2 weeks of adalimumab versus the total TNF production during 14 days.…”

“…Because certolizumab is a PEGylated Fab fragment, it has a long half‐life, similar to that of adalimumab, but lacking an Fc tail. Fc‐mediated clearance of TNF–certolizumab is therefore absent, and lacking cross‐linking activity, it also does not signal via membrane‐bound TNF (Baker & Stephens, 2006; Tun & Lobo, 2015). We addressed the possible effects of Fc‐mediated clearance of TNF–TNFi immune complexes and the effect of the TNFi on in vitro TNF production, two factors that might affect steady‐state TNF concentrations.…”

“…Because certolizumab is a PEGylated Fab fragment, it has a long halflife, similar to that of adalimumab, but lacking an Fc tail. Fc-mediated clearance of TNF-certolizumab is therefore absent, and lacking crosslinking activity, it also does not signal via membrane-bound TNF (Baker & Stephens, 2006;Tun & Lobo, 2015). We addressed the…”

Biologic agents and small-molecule inhibitors in systemic autoimmune conditions: an update

“…It is also licensed for the management of CD by the FDA. CZP differs from other anti-TNF-α agents in the absence of Fc-region which confers advantageous properties [22], such as, a lower antibody-dependent cell-mediated cytotoxicity and lack of transport through the placenta in pregnant women since CZP cannot bind the placental neonatal Fc receptors [23]. Another distinctive feature of CZP it that it is PEGylated, which is used to improve drug pharmacokinetics and bioavailability [22].…”