Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies

Scagnolari, Carolina; Duda, Petra W.; Bagnato, Francesca; Vito, Giuseppe De; Alberelli, Alessia; Lavolpe, Vito; Girardi, Enrico; Durastanti, Valentina; Trojano, María; Kappos, Ludwig; Antonelli, Guido

doi:10.1007/s00415-006-0332-7

Cited by 25 publications

(13 citation statements)

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“…[4][5][6] Myxovirus resistance protein A (MxA) has been used as a biomarker of IFN␤ response in patients with MS. [7][8][9] Viperin and interferoninduced protein with tetratricopeptide repeats 1 (IFIT-1) are, like MxA, specifically and highly induced by IFN␤. 1-3 IFN␤ binds to the IFN␣/␤ receptor (IFNAR) to exert its biologic effects, including induction of antiviral proteins and up-and down-regulation of immune-regulatory genes.…”

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confidence: 99%

Effect of neutralizing antibodies on biomarker responses to interferon beta

Pachner¹,

Warth²,

Pace³

et al. 2009

Neurology

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confidence: 99%

Effect of neutralizing antibodies on biomarker responses to interferon beta

Pachner¹,

Warth²,

Pace³

et al. 2009

Neurology

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“…Other studies reported a fall in serum neopterin levels or in the levels of other IFN biologic response markers, including matrix metalloproteinases (MMPs), beta2 microglobulin, MxA, viperin, TNF-related apoptosis-inducing ligand (TRAIL) and X-linked inhibitor apoptosis factor-1 (XAF-1), when NAb titers were elevated in patients with MS [6,20,38-41]. Data clearly support the hypothesis that neopterin is a sensitive measure of biological response to IFNβ and is reduced by the presence of NAbs.…”

Section: Discussionmentioning

confidence: 99%

“…Binding of IFNβ to its cell-surface receptor stimulates several immunological processes, including neopterin [D- erythro -6-(1',2',3'-trihydroxypropyl)-pterin] production [6] and trp degradation [7,8]. In vitro evidence demonstrated that both IFNβ and IFNγ induce neopterin production [9] and activate the enzyme indoleamine (2,3)-dioxygenase (IDO).…”

Section: Introductionmentioning

confidence: 99%

Neopterin production and tryptophan degradation during 24-months therapy with interferon beta-1a in multiple sclerosis patients

et al. 2011

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BackgroundIncreased synthesis of neopterin and degradation of tryptophan to kynurenine, measured as kynurenine/tryptophan ratio (kyn/trp ratio), are considered in vitro markers of interferon beta-1a (IFNβ-1a) activity. The aim of the study was to investigate the dynamic profile of neopterin and kyn/trp ratio in patients with relapsing remitting multiple sclerosis (RRMS) treated with two different doses of IFNβ-1a over a period of 24 months.MethodsRRMS patients (n = 101) received open-label IFNβ-1a 22 mcg (low dose, LD) or 44 mcg (high dose, HD) subcutaneously (sc), three times weekly for 24 months. Serum measurements of neopterin, kyn/trp ratio and neutralizing antibodies (NAbs) were obtained before treatment (i.e., at baseline) and 48 hours post-injection every 3 months thereafter. Clinical assessments were performed at baseline and every 6 months. Changes in biomarkers over time were compared between LD- and HD-group as well as between patients with/without relapses and with/without NAbs using Analysis of Variance and Mann-Whitney tests.ResultsNeopterin (p < 0.001) and kyn/trp ratio (p = 0.0013) values increased over time vs baseline in both treatment groups. Neopterin values were higher (p = 0.046) in the HD-compared to the LD-group at every time point with the exclusion of months 21 and 24 of therapy. Conversely, there were no differences between the two doses groups in the kyn/trp ratio with the exclusion of month 6 of therapy (p < 0.05). Neopterin levels were significantly reduced in NAb-positive patients starting from month 9 of therapy (p < 0.05); the same result was observed for kyn/trp ratio but only at month 9 (p = 0.02). Clinical status did not significantly affect neopterin production and tryptophan degradation.ConclusionsAlthough differences in serum markers concentration were found following IFNβ administration the clinical relevance of these findings needs to be confirmed with more detailed studies.

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“…After binding of IFNb to the type I IFN receptor, a signaling cascade is induced resulting in the expression of various genes [75]. Some of these gene products are 2¢,5¢-oligoadenylate (2-5A) synthetase [76,77], neopterin [78][79][80][81], b2-microglobulin [78,79,81] and myxovirus protein A (MxA) [76,77,[81][82][83], the latter is well established as IFNb bioactivity marker [84].…”

Section: Correlation Between Pharmacokinetic and Pharmacodynamic Markersmentioning

confidence: 99%

Pharmacokinetic considerations in the treatment of multiple sclerosis with interferon-β

Hegen

Auer

Deisenhammer

2015

Expert Opinion on Drug Metabolism & Toxicology

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IFNβ has a bioavailability of ∼ 30% after subcutaneous or intramuscular administration, shows peak serum concentrations within several hours, has a half-life of < 1 day and is eliminated by a renal and hepatic pathway. PK parameters do not substantially differ between the types of IFNβ and routes of administration; only pegylation of IFNβ results in substantially increased and prolonged PK. Although no clinical dose-effect relationship could be established, there is an association of IFNβ dose with magnetic resonance imaging outcome parameters. Furthermore, there is an association of IFNβ serum levels with the occurrence of adverse events and anti-drug antibodies.

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Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies

Cited by 25 publications

References 50 publications

Effect of neutralizing antibodies on biomarker responses to interferon beta

Effect of neutralizing antibodies on biomarker responses to interferon beta

Neopterin production and tryptophan degradation during 24-months therapy with interferon beta-1a in multiple sclerosis patients

Pharmacokinetic considerations in the treatment of multiple sclerosis with interferon-β

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