Plasma and Cerebrospinal Fluid Pharmacokinetics of Recombinant Interferon Alpha A in Monkeys: Comparison of Intravenous, Intramuscular, and Intraventricular Delivery

Collins, Jerry M.; Riccardi, Riccardo; Trown, P. W.; O'Neill, Dondra; Poplack, David G.

doi:10.1089/cdd.1985.2.247

Cited by 42 publications

(23 citation statements)

References 11 publications

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“…The 93-h half-life is 18 times greater than the 5-h half-life determined for IFN-␣ in cynomolgus monkeys, and 3 times greater than the 30-to 34-h half-life for PEG Intron. Clearance prior to antibody development was 190-fold lower than published pharmacokinetic studies for IFN-␣ in monkeys (Wills et al, 1984;Collins et al, 1985). Although the advantages of Albuferon are as yet unproven, predicted human half-lives of Albuferon, based on allometric scaling, exceed the published human values for PEG Intron or Pegasys.…”

Section: Discussionmentioning

confidence: 73%

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Osborn¹,

Olsen²,

Nardelli³

et al. 2002

J Pharmacol Exp Ther

192

105

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Interferon-␣ (IFN-␣) is indicated for the treatment of certain viral infections including hepatitis B and C, and cancers such as melanoma. The short circulating half-life of unmodified IFN-␣ makes frequent dosing (daily or three times weekly) over an extended period (6 -12 months or more) necessary. To improve the pharmacokinetics of IFN-␣ and decrease dosing frequency, IFN-␣ was fused to human serum albumin producing a new protein, Albuferon. In vitro comparisons of Albuferon and IFN-␣ showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than IFN-␣. Pharmacokinetic and pharmacodynamic properties of the fusion protein were enhanced in monkeys. After a single intravenous injection (30 g/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 g/kg subcutaneous injection, apparent clearance (clearance divided by bioavailability) was 1.4 ml/h/kg, the terminal half-life was 93 h, and bioavailability was 64%. The rate of clearance of Albuferon was approximately 140-fold slower, and the half-life 18-fold longer, than for IFN-␣ given by the subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated doserelated antiviral activity for Ն8 days based on an in vitro bioassay, whereas antiviral activity from IFN-␣-treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2Ј,5Ј-oligoadenylate synthetase mRNA relative to IFN-␣-or vehicle-treated animals were maintained for Ն10 days after subcutaneous dosing. The improved pharmacokinetics of Albuferon are accompanied by an improved pharmacodynamic response suggesting that Albuferon may offer the benefits of less frequent dosing and a potentially improved efficacy profile compared with IFN-␣.

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Section: Discussionmentioning

confidence: 73%

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Osborn¹,

Olsen²,

Nardelli³

et al. 2002

J Pharmacol Exp Ther

192

105

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show abstract

“…This issue has been argued for years, and earlier pharmacokinetic studies estimated that only a small fraction (less than 0.2%) of peripherally administered molecules gain access to the CNS. 16,17 Nevertheless, over the last two decades there have been studies suggesting that systemic cytokines may access the brain and affect brain function by either overcoming the blood-brain barrier through limited diffusion or saturable transport systems 18 or via direct sensory nerve connections from the periphery. 19 Other than its effectiveness for neuroregulatory actions after the intra-cerebral administration of cytokines, 20,21 there was, however, no specific marker to demonstrate and confirm a direct CNS action for IFN-a following systemic peripheral administration.…”

Section: Introductionmentioning

confidence: 99%

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

2007

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The prime anti-viral cytokine interferon-a (IFN-a) has been implicated in several central nervous system (CNS) disorders in addition to its beneficial effects. Systemic IFN-a treatment causes severe neuropsychiatric complications in humans, including depression, anxiety and cognitive impairments. While numerous neuromodulatory effects by IFN-a have been described, it remains unresolved whether or not systemic IFN-a acts directly on the brain to execute its CNS actions. In the present study, we have analyzed the genes directly regulated in post-IFN-a receptor signaling and found that intraperitoneal administration of mouse IFN-a, but not human IFN-a, activated expression of several prototypic IFN-stimulated genes (ISGs), in particular signal transducers and activators of transcription (STAT1), IFN-induced 15 kDa protein (ISG15), ubiquitin-specific proteinase 18 (USP18) and guanylate-binding protein 3 (GBP3) in the brain. A similar temporal profile for the regulated expression of these IFN-aactivated ISG genes was observed in the brain compared with the peripheral organs. Dual labeling in situ hybridization combined with immunocytochemical staining demonstrated a wide distribution of the key IFN-regulated gene STAT1 transcripts in the different parenchyma cells of the brain, particularly neurons. The overall response to IFN-a challenge was abolished in STAT1 knockout mice. Together, our results indicate a direct, STAT1-dependent action of systemic IFN-a in the CNS, which may provide the basis for a mechanism in humans for neurological/neuropsychiatric illnesses associated with IFN-a therapy.

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“…Firstly, pharmacokinetic studies estimated that <0.2% of peripherally administered interferon-α gains access to the central nervous system [5]. The consistent low direct toxicity to the brain may explain the infrequency of seizures.…”

Section: Discussionmentioning

confidence: 99%

Seizures in Patients with Chronic Hepatitis C Treated with NS3/4A Protease Inhibitors: Does Pharmacological Interaction Play a Role?

Milazzo

Falvella²,

Magni

et al. 2013

Pharmacology

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The addition of NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (Peg-IFN)-α and ribavirin for the treatment of hepatitis C virus (HCV) genotype 1-infected patients has led to higher rates of virological response and adverse events. Among the several side effects of interferon, neuropsychiatric symptoms have been described, particularly depression and anxiety, occurring in about 25% of patients. Although seizures have been reported in interferon-treated patients with multiple sclerosis and in a variety of malignancies, the epileptogenic potential of interferon-α in the treatment of HCV infection is considered minimal. In this report we present a new onset of seizures occurring in 2 patients during anti-HCV therapy in association with Peg-IFN, ribavirin and HCV protease inhibitors.

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Plasma and Cerebrospinal Fluid Pharmacokinetics of Recombinant Interferon Alpha A in Monkeys: Comparison of Intravenous, Intramuscular, and Intraventricular Delivery

Cited by 42 publications

References 11 publications

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

Seizures in Patients with Chronic Hepatitis C Treated with NS3/4A Protease Inhibitors: Does Pharmacological Interaction Play a Role?

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