Pharmacokinetics and Pharmacodynamics of Intrathecal Ziconotide in Chronic Pain Patients

Abstract

The pharmacokinetics and pharmacodynamics of ziconotide were assessed over a 48-hour period following intrathecal (i.t.) administration (1, 5, 7.5, or 10 micrograms) to 22 patients with chronic, nonmalignant pain. Plasma and cerebrospinal fluid (CSF) samples were obtained over a 24-hour period. Analgesic efficacy was monitored using Visual Analog Scale of Pain Intensity (VASPI) and Category Pain Relief Scores (CPRS) measurements. Pharmacokinetic (PK) parameters were calculated by noncompartmental methods. Plasma ziconotide data were insufficient for PK calculations. In CSF, the median half-life of ziconotide was 4.5 hours. The median CSF clearance and volume of distribution were 0.26 mL/min and 99 mL, respectively. CSF pharmacokinetics of ziconotide were linear, based on cumulative exposure and peak CSF concentrations. A dose-related analgesia was observed. Pharmacokinetic-pharmacodynamic efficacy and safety analyses showed that higher CSF ziconotide concentrations were generally associated with analgesia and increased incidence of nervous system adverse events following a 1-hour i.t. infusion.

Pharmacokinetic Analysis of Ziconotide (SNX-111), an Intrathecal N-Type Calcium Channel Blocking Analgesic, Delivered by Bolus and Infusion in the Dog

“…These results compare favorably with a report on LCSF PK in humans after an acute (one‐hour infusion) of ziconotide in humans (16). In that work, after one‐hour IT bolus administration of ziconotide in doses of 1–10 µg, an exponential CL was noted more than 24 hours.…”

“…Studies in humans also have shown that IT bolus injection or continuous infusion of ziconotide is efficacious in a variety of acute and chronic pain states (13–18) and in ameliorating spasticity secondary to spinal injury (19). Initial studies reported significant adverse effects with dose incrementation (15,20), which may have reflected an incomplete appreciation of the kinetics of redistribution of the intrathecally delivered drug.…”

Ziconotide: a review of its pharmacology and use in the treatment of pain

“…This patient was given ziconotide by continuous, constant rate, intrathecal infusion and complete pain relief was achieved, even after the dose was lowered to 2 ng/kg hourly to alleviate the patient’s side-effects of dizziness, blurred vision, and nystagmus. Another trial evaluated the analgesic efficacy, safety, and pharmacokinetic properties of intrathecal ziconotide in patients with chronic neuropathic pain (Wermeling et al 2003). Ziconotide was infused over a 1-hour period at doses of 1, 5, 7.5, or 10 μg.…”

Antinociceptive effects of the marine snail peptides conantokin-G and conotoxin MVIIA alone and in combination in rat models of pain

“…Ziconotide (Prialt®) has been recently approved by the FDA for use in severe pain. However, the therapeutic index of intrathecal MVIIA is narrow and the severity of adverse side-effects appears dose-dependent (Horvath et al, 2002; Scott et al, 2002; Wermeling et al, 2003). …”