The 40 kDa PEG moiety in Cimzia® represents approximately 44% of its total molecular weight. Attachment of PEG to the Fab’ moiety increases the elimination half-life of Cimzia® to approximately 2 weeks, allowing every 2 or 4 weeks dosing. Toxicology studies included two chronic toxicity studies in cynomolgus monkeys (duration 26 and 52 weeks), which were conducted to provide
safety information for long-term (chronic) dosing in humans (Table 2) [17, 18]. The duration of these chronic studies was sufficiently long to reliably predict effects of life-long treatment in humans . In the cynomolgus monkey studies, PEG-related changes were observed mainly in the reticulo-endothelial system (RES) by histology. Macrophage vacuolation (foamy macrophages) in several organs (lymph nodes, injections sites, red
pulp of spleen, adrenal, Selumetinib manufacturer uterus, cervix and choroid plexus of the brain) were seen check details after 26 weeks at 100 mg kg−1 and after 52 weeks at 50 and 100 mg kg−1 Cimzia® dosed once weekly. The No-Effect-Level for these changes was 10 mg kg−1 Cimzia® (which contains approximately 4.4 mg kg−1 PEG), dosed weekly for 26 weeks. These changes did not lead to functional deficits and were reversible within 13 weeks, except at the high dose of 100 mg kg−1 in the longer 52 week study. Similar macrophage changes were seen in the rat, where Cimzia® is not pharmacologically active. Therefore, it is likely that medchemexpress the macrophage changes are caused by PEG and not by exaggerated pharmacological action of the drug. Cimzia® was cleared
from the circulation via de-conjugation, proteolysis (of the protein component Fab’) and renal excretion of PEG polymers . Clinical studies with Cimzia® included sc and iv dosing up to 104 weeks (Cimzia® EMA EPAR) with doses up to 400 mg once per month after a loading dose. The bioavailability observed in humans after sc administration was between 76% and 88% and the PEG component was renally excreted to an unknown extent in humans (EMA, EPAR). There were a higher number of adverse events in the Cimzia® groups when compared with placebo, but the most frequent adverse events were infections as expected with an anti-TNF treatment and unrelated to PEG. A recent publication summarized the safety of different drugs in clinical trials used for rheumatoid arthritis . The review found that the safety profile of Cimzia® appeared similar with those of other TNF-inhibiting agents, although long-term observational data are still being collected for anti-TNF therapies. Another recent review, found Cimzia® generally well tolerated when used either as monotherapy or when added to MTX (methotrexate) in adult patients with rheumatoid arthritis, given over 24 weeks sc as part of a phase III trial. Most adverse events were mild or moderate and related to the protein activity .