Pharmacodynamics

Mechanism of Action

Ziconotide binds to N-type calcium channels located on the primary nociceptive (A-γ and C) afferent nerves in the superficial layers (Rexed laminae I and II) of the dorsal horn in the spinal cord. Although the mechanism of action of ziconotide has not been established in humans, results in animals suggest that its binding blocks N-type calcium channels, which leads to a blockade of excitatory neurotransmitter release from the primary afferent nerve terminals and antinociception.

Interaction with opioids

Ziconotide does not bind to opioid receptors and its pharmacological effects are not blocked by opioid antagonists. In animal models, IT ziconotide potentiated opioid-induced reduction in gastrointestinal (GI) motility, but did not potentiate morphine-induced respiratory depression. In rats receiving IT ziconotide, additive analgesic effects were observed with concurrent administration of morphine, baclofen, or clonidine. Concurrent administration of IT ziconotide and morphine did not prevent the development of morphine tolerance in rats.

Pharmacokinetics

The cerebrospinal fluid (CSF) pharmacokinetics (PK) of ziconotide have been studied after one-hour IT infusions of 1-10 mcg of PRIALT to patients with chronic pain. The plasma PK following intravenous (IV) infusion (0.3- 10 mcg/kg/day) have also been studied. Both IT and IV data are shown below (Table 1).

Table 1: PRIALT PK Parameters (Mean ± SD)

Following one-hour IT administration of 1-10 mcg of PRIALT, both total exposure (AUC; range: 83.6-608 ng·h/mL) and peak exposure (Cmax; range: 16.4-132 ng/mL) values in the CSF were variable and dose-dependent, but appeared approximately dose-proportional. During 5 or 6 days of continuous IT infusions of PRIALT at infusion rates ranging from 0.1 to 7.0 mcg/hr in patients with chronic pain, plasma ziconotide levels could not be quantified in 56% of patients using an assay with a lower limit of detection of approximately 0.04 ng/mL. Predictably, patients requiring higher IT infusion dose rates were more likely to have quantifiable ziconotide levels in plasma. Plasma ziconotide levels, when detectable, remain constant after many months of IT PRIALT infusion in patients followed for up to 9 months.

Distribution

Ziconotide is about 50% bound to human plasma proteins. The mean CSF volume of distribution (Vd) of ziconotide following IT administration approximates the estimated total CSF volume (140 mL).

Metabolism

Ziconotide is cleaved by endopeptidases and exopeptidases at multiple sites on the peptide. Following passage from the CSF into the systemic circulation during continuous IT administration, ziconotide is expected to be susceptible to proteolytic cleavage by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle, etc.), and thus readily degraded to peptide fragments and their individual constituent free amino acids. Human and animal CSF and blood exhibit minimal hydrolytic activity toward ziconotide in vitro. The biological activity of the various expected proteolytic degradation products of ziconotide has not been assessed.

Elimination

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