Review: Natalizumab in the treatment of multiple sclerosis

Yaldizli, Özgür; Putzki, Norman

doi:10.1177/1756285608101861

Cited by 42 publications

(27 citation statements)

References 86 publications

(114 reference statements)

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“…It is generally well-tolerated, but due to rare and potentially fatal side-effects, it was approved with a restricted-distribution format in 2006. Expert statements and the European Medical Agency recommend the use of natalizumab after failure of first-line disease-modifying therapies in patients with relapsing forms of MS (Yaldizli & Putzki, 2009). Natalizumab may cause a serious viral infection of the brain that can lead to disability and patients should not receive NTZ if they are allergic to it, or if they have ever had a brain infection called progressive multifocal leukoencephalopathy (PML).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

Ramroodi

Khani

Ganjali

et al. 2015

Immunological Investigations

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Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

Ramroodi

Khani

Ganjali

et al. 2015

Immunological Investigations

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“…It has been suggested that natalizumab may inhibit the interaction of α4β1-expressing leukocytes with ligands in the extracellular matrix in the CNS, such as osteopontin and fibronectin, inhibiting further leukocyte recruitment and thereby contributing to the suppression of intrathecal inflammation [Yaldizli and Putzki, 2009].…”

Section: Other Effects Of Natalizumab In Rrmsmentioning

confidence: 99%

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

Sellebjerg

Cadavid

Steiner

et al. 2015

Ther Adv Neurol Disord

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Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing-remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood-brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial.

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“…The interaction between natalizumab and the alpha‐4 receptor can be assessed using a pharmacodynamic (PD) assay that measures alpha‐4 integrin saturation, which thus serves as a PD marker . Natalizumab treatment is also associated with a risk of progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection that is caused by the JC virus, which is likely a result of sustained reduced CNS trafficking of mononuclear leukocytes …”

mentioning

confidence: 99%

Population Pharmacokinetics and Target Engagement of Natalizumab in Patients With Multiple Sclerosis

Muralidharan

Kuesters

Plavina

et al. 2017

The Journal of Clinical Pharma

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Natalizumab (humanized immunoglobulin G4 antibody targeting alpha-4 integrins) is a highly efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) that has been in clinical use since 2006. However, natalizumab pharmacokinetic (PK) characteristics and concentration alpha-4 integrin saturation relationships have not been well described in the scientific literature. Therefore, clinical data from 11 studies were pooled and analyzed to characterize the PK and pharmacodynamic (PD) properties of natalizumab in RRMS subjects. Natalizumab PK was best described using a 2-compartment model with linear first-order and Michaelis-Menten elimination. Subcutaneous absorption of natalizumab was characterized using first-order absorption with lag time. The relationship between natalizumab concentration and alpha-4 integrin saturation (PD) was best described by a direct response model with a sigmoidal effect on alpha-4 integrin saturation mediated by a maximum effect relationship with natalizumab concentrations. Covariate analysis showed that body weight, product formulations, and the presence of antinatalizumab antibodies were the main covariates affecting natalizumab PK, whereas age and formulations affected PD. The use of simulations based on a pharmacokinetic-pharmacodynamic model showed that covariates, although statistically significant, are not expected to have any clinical impact at the approved clinical dosing regimen of natalizumab (300 mg once every 4 weeks).

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Review: Natalizumab in the treatment of multiple sclerosis

Cited by 42 publications

References 86 publications

RETRACTED ARTICLE: Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

RETRACTED ARTICLE: Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

Population Pharmacokinetics and Target Engagement of Natalizumab in Patients With Multiple Sclerosis

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