Ziconotide: Use in the treatment of pain

2018-08-18

Introduction 

Ziconotide (previously called SNX-111), currently marketed under the brand name of Prialt, is the synthetic form of the hydrophilic conopeptide (also called conotoxins) ω-MVIIA from the venom of the Pacific fish-hunting snail, C magus. Conotoxins are small disulfide-rich peptides, usually 20-30 amino acids in length, making synthetic derivatives easy to manufacture. Different types of conotoxins act on different kinds of receptors. Ziconotide is a non-opioid, twenty-five amino acid polybasic peptide analogue, and the first clinical trials using it to patients with severe pain began in 1995.

Pharmacologic action

Zinconotide is a non-opioid analgesic that selectively and reversibly blocks N-type voltage-sensitive calcium channels concentrated in the superficial layers in the dorsal horn (Reced laminae I and II) of the spinal cord. These N-type calcium channels are found throughout the central and peripheral nervous systems. By binding to N-type calcium channels, ziconotide appears to block nerve transmission from primary nociceptive afferents by inhibiting the release of neurotransmitters and thus blocking signal transmission. Ziconotide also acts on calcium channels in the cerebral cortex, the neurohypophysis and the spinal cord but not calcium channels in the neuromuscular junction. It shows no affinity for other ion channels or for cholinergic, monoaminergic, mu and kappa opioid receptors.

Function

Zinconotide is a neuroactive venom peptide currently in the final stages of clinical development as a non-opioid treatment for severe chronic pain. In a broad array of animal models of pain, intrathecal ziconotide produced strong antinociceptive effects that produce at least ten times more potent than intrathecal morphine. In Phase III clinical studies ziconotide provided significant pain relief in 57% of patients (n=256) with neuropathic pain who were unresponsive to opioid therapy. Pain was relieved in 98% of patients suffering from chronic neuropathic pain>1 year. This demonstrates ziconotide effectiveness for blocking neuropathic pain in humans as it did in animal models.

Pharmacokinetics and metabolism

Zinconotide is water soluble and highly polar, it has limited tissue penetration secondary to being highly hydrophilic and of large molecular size, and it is 100% bioavailable in the cerebral spinal fluid (CSF) and is not metabolized by the CSF. Intrathecally administered ziconotide has a median elimination half-life in human CSF of 4.5 h. Based on this half-life, ziconotide may reach a CSF steady-state level in ~24h. Intrathecally administered ziconotide is eventually absorbed into the systemic circulation where it is bound to plasma proteins and degraded by ubiquitous proteolytic enzymes (endopeptidases and exopeptidases) found in multiple organs, namely liver, lung, kidney and muscle tissue. Less than 1% of ziconotide is excreted via the kidney following intravenous administration.

References

1. Achim Schmidtko, Jörn Lötsch, Rainer Freynhagen, Gerd Geisslinger. Ziconotide for treatment of severe chronic pain. Lancet, 2010, 375 (9725), 1569-1577.

2. G.P. Miljanich. Ziconotide: Neuronal Calcium Channel Blocker for Treating Severe Chronic Pain. Current Medicinal Chemistry, 2004, 11, 3029-3040.

3. Jason A Williams, Miles Day, James E Heavner. Ziconotide: an update and review. Expert Opin. Pharmacother. 2008, 9(9), 1575-1582.

4. Joseph G McGivern. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatric Disease and Treatment, 2007, 3(1), 69-85.

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