Nonclinical Safety of Ziconotide: An Intrathecal Analgesic of a New Pharmaceutical Class

Abstract

Ziconotide, a potent, selective, reversible blocker of neuronal N-type voltage-sensitive calcium channels, is approved in the United States for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. In the European Union, ziconotide is indicated for the treatment of severe chronic pain in patients who require intrathecal analgesia. Nonclinical investigations of ziconotide included a comprehensive characterization of its toxicology, incorporating acute and subchronic toxicity studies in rats, dogs, and monkeys; reproductive toxicity assessments in rats and rabbits; and mutagenic, carcinogenic evaluations performed in vivo and in vitro. Additional investigations assessed the potential for cardiotoxicity (rats) and immunogenicity (mice, rats, and guinea pigs), and the presence or absence of intraspinal granuloma formation and local cell proliferation and apoptosis (dogs). The resulting nonclinical toxicology profile was predictive of human adverse events reported in clinical trials and consistent with ziconotide's pharmacological activity. Frequently observed nonclinical behavioral effects included tremoring, shaking, ataxia, and hyperreactivity. Occurrences were generally transient and reversible upon cessation of treatment, and intolerable effects occurred at doses more than 45 times the maximum recommended clinical dose. Ziconotide was not associated with target organ toxicity, teratogenicity, or treatment-related gross or histopathological changes; it displayed no mutagenic or carcinogenic potential and no propensity to induce local cell proliferation or apoptosis. Although guinea pigs developed systemic anaphylaxis, antibodies to ziconotide were not detected in mice, rats, or guinea pigs, indicating low immunogenic potential. No evidence of granuloma formation was observed with intrathecal ziconotide treatment. In summary, the results from these nonclinical safety assessments revealed no significant toxicological risk to humans treated with ziconotide as recommended.

(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology

“…Furthermore, the CaV2.2-selective blocker Ziconotide (Prialt®) [44] and the α2δ subunit-targeted antiepileptic drug gabapentin (GBP; Neurontin®) are clinically effective and have been developed to target different components of the CaV2.2 channel complex [1; 27; 72]. Both drugs, however, are encumbered with problematic side effects as well as difficult dosing regimens [53; 54; 57; 67]. The development of novel CaV2.2-targeted drugs with improved efficacy and therapeutic index is highly desirable [50].…”

Screening for antibacterial and antifungal activities in marine benthic invertebrates from northern Norway

“…Ziconotide (Prialt) is the synthetic equivalent of a peptide first purified in 1984 from the venom of a marine mollusk Conus geographus (Olivera et al, 1984). The drug was approved in the United States in 2004 and in the European Union in 2005 for the management of severe chronic pain (Skov et al, 2007).…”

A sleep-inducing peptide from the venom of the Indian cone snail Conus araneosus

“…Preceding three decades of greatly accelerated Conus peptide discovery has revealed several groups of conotoxins. To date, the conotoxin drug approved by the United States Food and Drug Administration for public use is Prialt™, derived from Conus magus to treat chronic pain, which is one of the most potent analgesics available (Atanassoff et al, 2000;Alonso et al, 2003;Skov et al, 2007). Prialt™ is the trade name for u-conotoxin MVIIA, a calcium channel blocker that provides a non-addictive means to block pain in subject patients by preventing the source of pain transmission in nerve cells of the spinal cord (Du et al, 2007;Jacob and McDougal, 2010).…”