Natalizumab is a selective adhesion-molecule inhibitor and binds to the α4-subunit of human integrins, which is highly expressed on the surface of all leukocytes, with the exception of neutrophils. Specifically, natalizumab binds to the α4β1 integrin, blocking the interaction with its cognate receptor, vascular cell adhesion molecule-1 (VCAM-1), and ligands osteopontin, and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). Natalizumab blocks the interaction of α4β7 integrin with the mucosal addressin cell adhesion molecule-1 (MadCAM-1). Disruption of these molecular interactions prevents transmigration of mononuclear leukocytes across the endothelium into inflamed parenchymal tissue.
A further mechanism of action of natalizumab may be to suppress ongoing inflammatory reactions in diseased tissues by inhibiting the interaction of α4-expressing leukocytes with their ligands in the extracellular matrix and on parenchymal cells. As such, natalizumab may act to suppress inflammatory activity present at the disease site, and inhibit further recruitment of immune cells into inflamed tissues.
In MS, lesions are believed to occur when activated T-lymphocytes cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and endothelial cells of the vessel wall. The interaction between α4β1 and its targets is an important component of pathological inflammation in the brain and disruption of these interactions leads to reduced inflammation. Under normal conditions, VCAM-1 is not expressed in the brain parenchyma. However, in the presence of pro-inflammatory cytokines, VCAM-1 is upregulated on endothelial cells and possibly on glial cells near the sites of inflammation.
In the setting of central nervous system (CNS) inflammation in MS, it is the interaction of α4β1 with VCAM-1, CS-1 and osteopontin that mediates the firm adhesion and transmigration of leukocytes into the brain parenchyma and may perpetuate the inflammatory cascade in CNS tissue. Blockade of the molecular interactions of α4β1 with its targets reduces inflammatory activity present in the brain in MS and inhibits further recruitment of immune cells into inflamed tissue, thus reducing the formation or enlargement of MS lesions.
Following the repeat intravenous administration of a 300 mg dose of natalizumab to MS patients, the mean maximum observed serum concentration was 110 ± 52 μg/ml. Mean average steady-state trough natalizumab concentrations over the dosing period ranged from 23 μg/ml to 29 μg/ml. The predicted time to steady-state was approximately 36 weeks.
A population pharmacokinetics analysis was conducted on samples from over 1,100 MS patients receiving doses ranging from 3 to 6 mg/kg natalizumab. Of these, 581 patients received a fixed 300 mg dose as monotherapy. The mean ± SD steady-state clearance was 13.1 ± 5.0 ml/h, with a mean ± SD half-life of 16 ± 4 days. The analysis explored the effects of selected covariates including body weight, age, gender, hepatic and renal function, and presence of anti-natalizumab antibodies upon pharmacokinetics. Only body weight and the presence of anti-natalizumab antibodies were found to influence natalizumab disposition. Body weight was found to influence clearance in a less-than-proportional manner, such that a 43% change in body weight resulted in a 31% to 34% change in clearance. The change in clearance was not clinically significant. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold, consistent with reduced serum natalizumab concentrations observed in persistently antibody-positive patients.
The pharmacokinetics of natalizumab in paediatric MS patients has not been established. The pharmacokinetics of natalizumab in patients with renal or hepatic insufficiency has not been studied.
The effect of plasma exchange on natalizumab clearance and pharmacodynamics was evaluated in a study of 12 MS patients. Estimates of the total natalizumab removal after 3 plasma exchanges (over a 5-8 day interval) was approximately 70-80%. This compares to approximately 40% seen in earlier studies in which measurements occurred after natalizumab discontinuation over a similar period of observation. The impact of plasma exchange on the restitution of lymphocyte migration and ultimately its clinical usefulness is unknown.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Consistent with the pharmacological activity of natalizumab, altered trafficking of lymphocytes was seen as white blood cell increases as well as increased spleen weights in most in vivo studies. These changes were reversible and did not appear to have any adverse toxicological consequences.
In studies conducted in mice, growth and metastasis of melanoma and lymphoblastic leukaemia tumour cells was not increased by the administration of natalizumab.
No clastogenic or mutagenic effects of natalizumab were observed in the Ames or human chromosomal aberration assays. Natalizumab showed no effects on in vitro assays of α4-integrin-positive tumour line proliferation or cytotoxicity.
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human dose; natalizumab did not affect male fertility.
The effect of natalizumab on reproduction was evaluated in 5 studies, 3 in guinea pigs and 2 in cynomolgus monkeys. These studies showed no evidence of teratogenic effects or effects on growth of offspring. In one study in guinea pigs, a small reduction in pup survival was noted. In a study in monkeys, the number of abortions was doubled in the natalizumab 30 mg/kg treatment groups versus matching control groups. This was the result of a high incidence of abortions in treated groups in the first cohort that was not observed in the second cohort. No effects on abortion rates were noted in any other study. A study in pregnant cynomolgus monkeys demonstrated natalizumab-related changes in the foetus that included mild anaemia, reduced platelet counts, increased spleen weights and reduced liver and thymus weights. These changes were associated with increased splenic extramedullary haematopoiesis, thymic atrophy and decreased hepatic haematopoiesis. Platelet counts were also reduced in offspring born to mothers treated with natalizumab until parturition, however there was no evidence of anaemia in these offspring. All changes were observed at doses in excess of the human dose and were reversed upon clearance of natalizumab.
In cynomolgus monkeys treated with natalizumab until parturition, low levels of natalizumab were detected in the breast milk of some animals.
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