Investigation of the Distribution and Elimination of the PEG Component of Certolizumab Pegol in Rats

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Purpose: Certolizumab pegol is the first PEGylated Fc-free anti-tumour necrosis factor alpha (TNF-α) agent. The purpose of this investigation was to develop a method by which the tissue distribution and excretion of PEG in rats can be readily determined. Methods: PEG was measured in tissues, urine and faeces by proton nuclear magnetic resonance (1H NMR) spectroscopy. First, female Lewis rats were dosed at 100 mg/kg subcutaneously (sc) with either certolizumab pegol or an anti-rat TNF PEGylated Fab' (TN3). At six timepoints up to 84 days, various tissues (brain, mandibular and mesenteric lymph nodes, liver, spleen, kidneys, lungs, heart) were removed and assessed for the amount of PEG they contained. In a second 84-day study, urine and faeces were collected daily from rats in metabolism cages after one 400 mg/kg sc dose of certolizumab pegol. Results: PEG was found in all sampled tissues apart from brain and was cleared within the time frame of the experiment. The distribution of the TN3 PEGylated Fab' was similar to certolizumab pegol, suggesting that TNF binding is not a major mediator of PEG distribution in tissues. Urine analyses showed the excretion was maximal on Day 6 and then declined in a first-order manner; by Day 84 the mean cumulative amount excreted was 65%. Using a first-order increase/decrease model, the total urinary excretion was 73% and the half-life was 23 days. PEG was also detected in faeces up to Day 42, with 18% of total excretion by this route. The total mean recovery was thus 91% of the administered dose. The molecular weight of the excreted PEG was estimated by SDS PAGE to be 40 kDa. Conclusion: The novel method of using 1H NMR for the quantitative measurement of PEG described here enabled extensive distribution and excretion studies to be performed. Comparison of the tissue distributions of certolizumab pegol and the anti-rat TNF reagent TN3 suggested that there was no target-mediated distribution of PEG. In addition, the molecular weight of the excreted PEG (40 kDa) suggests that it is excreted as the intact PEG moiety, cleaved from the Fab' portion. The near-quantitative excretion of PEG, mainly in urine, in a first-order manner, suggests that on repeat dosing a steady state will be reached for the elimination of PEG.

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