Ziconotide

Ziconotide is a synthetic analogue of a ω-conopeptide, MVIIA, found in the venom of the Conus magus marine snail. It is an N-type calcium channel blocker (NCCB). NCCs regulate neurotransmitter release in specific neuronal populations responsible for the spinal processing of pain. In binding to these neuronal NCCs ziconotide inhibits the voltage sensitive calcium current into primary nociceptive afferents terminating in the superficial layers of the dorsal horn of the spinal cord. In turn, this inhibits their release of neurotransmitters (including Substance P) and therefore, the spinal signalling of pain.

Pharmacodynamic effects

Though statistically significant relationships and reasonable correlation between cerebrospinal fluid (CSF) exposure (AUC, C_max) and clinical response measures have been observed following 1 hour IT administration, no well-defined dose-concentration-response relationships have yet been identified. Many responsive patients obtain near-maximal analgesia within a few hours of delivery of an appropriate dose. However, maximal effects may be delayed for approximately 24 hours in some patients. Given the occurrence of analgesia and adverse reactions at similar doses, the recommended interval between dose increases is 48 hours or more. If necessary the dose can be decreased by any amount (including stopping the infusion) for the management of adverse reactions.

Nervous system adverse reactions, particularly dizziness, nausea and abnormal gait appear to be correlated with CSF exposure, though a definitive relationship has not been established.

Low plasma exposure occurs during IT infusion due to the low recommended IT infusion rates and relatively rapid plasma clearance. Therefore, pharmacological effects related to systemic exposure should be minimal.

The median dose at response is approximately 6.0 μg/day and approximately 75% of responsive patients require ≤ 9.6 μg/day. To limit the occurrence of serious adverse reactions, a maximum dose of 21.6 μg/day is recommended. However, in clinical trials it has been observed that patients who tolerate doses of 21.6 μg/day following slow titration over a 3 to 4-week period, generally tolerate higher doses up to 48.0 μg/day.

There is no evidence of the development of pharmacological tolerance to ziconotide in patients. However, in view of limited data, the development of tolerance cannot be excluded. Examination of the patency of the intrathecal catheter should be considered if the required ziconotide dose continually increases and there is no benefit or increase in adverse reactions.

Alternative dosing regimens including initiation of dosing with lower doses of ziconotide and bolus administration have been explored in a limited number of studies available in the literature.

The use of lower doses through continuous administration was demonstrated to achieve efficacy with fewer adverse reactions.

Bolus administration studies suggest that bolus dosing may be useful in identifying patients who may benefit from long term use of ziconotide, however, may result in more adverse reactions than administration by continuous infusion.

These studies suggest that these alternative methods of administration of ziconotide may be possible however, due to the limited numbers of patients, these results are inconclusive and there is currently insufficient evidence available to make definitive recommendations for such alternative dosing regimens.

The CSF pharmacokinetics of ziconotide have been studied following one-hour IT infusions of 1-10 μg of ziconotide in patients with chronic pain. The plasma pharmacokinetics following intravenous doses (0.3–10 μg/kg/24 hr) were also studied. IT and intravenous pharmacokinetics data are summarised below.

CSF and Plasma Pharmacokinetics of Ziconotide [mean ± SD (median)]:

CL = clearance; Vd = distribution volume; t_½ = half life

Absorption

Following one-hour IT administration (1–10 μg), both cumulative exposure (AUC; range: 83.6–608 ng/h/ml) and peak exposure (C_max; range: 16.4–132 ng/ml) values were variable and dose-dependent, but appeared only approximately dose-proportional. Plasma concentrations following continuous (≥48 h) IT infusion (≤21.6 μg/day) appear to be relatively low and typically undetectable (i.e., about 80% of plasma samples collected from pain patients contain no quantifiable medicinal product; <0.04 ng/ml). No accumulation of ziconotide in plasma following long-term IT administration (up to 9 months) has been observed.

Distribution

Median ziconotide CSF volume of distribution (Vd: 99 ml) is between the spinal cord CSF volume (approximately 75 ml) and total CSF volume (approximately 130 ml). Ziconotide appears to distribute mainly within the CSF until transferred to the systemic circulation. Upon reaching the systemic circulation, ziconotide appears to be more extensively distributed, based on a plasma distribution volume of approximately 30 l and is only about 53% bound (non-specifically) to human plasma proteins.

Biotransformation

Ziconotide is a peptide consisting of 25 naturally-occurring amino acids of the L-configuration, and does not appear to be appreciably metabolised in the CSF. Following passage into the systemic circulation, ziconotide is expected to be primarily susceptible to proteolytic cleavage by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle, etc.), and thus degraded to peptide fragments and its individual constituent free amino acids. The generated free amino acids are expected to be taken up by cellular carrier systems and either subjected to normal intermediary metabolism or used as substrates for constitutive biosynthetic processes. Due to the wide distribution of these peptidases it is not expected that hepatic or renal impairment would affect the systemic clearance of ziconotide. The biological activity of the various expected proteolytic degradation products has not been assessed. It is unlikely that the degradation products of ziconotide will have significant biological activity, as peptides consisting of the individual peptide loop structures have been found to have binding affinities for N-type voltage sensitive calcium channels that are several orders of magnitude lower than that of the parent (ziconotide) compound.

Elimination

Mean ziconotide CL (0.38 ml/min) approximates adult human CSF turnover rate (0.3-0.4 ml/min). Hence, ziconotide appears to be mainly eliminated from the CSF (mean t_½ = 4.6 hr) by bulk flow of CSF out of the CNS through the arachnoid villi with subsequent transfer into the systemic circulation. Very low circulating plasma concentrations of ziconotide may be observed following IT administration due to both the low IT infusion rate and relatively rapid plasma clearance. The mean plasma elimination half-life (t_½) is 1.3 hr. Ziconotide is a relatively small molecular weight peptide (MW = 2,639) and is filtered by the kidney glomerulus, but only minimal amounts of ziconotide (<1%) are recovered in human urine following intravenous infusion. This is because almost all of the filtered active substance is rapidly endocytosed and ultimately transported back to the systemic circulation.

Renal and hepatic impairment

No formal studies assessing the impact of renal or hepatic dysfunction have been conducted; however, given that peptidases are present in various body organs, it is not anticipated that renal or hepatic dysfunction will significantly impact systemic exposure of ziconotide.

Other special populations

Although only limited data are available, there is no obvious effect of race, height, weight, gender or age on CSF ziconotide exposure after IT administration.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

In subchronic continuous intrathecal infusion studies in rats and dogs, behavioural effects were seen at doses ≥8-fold the maximum recommended clinical intrathecal infusion dose of 21.6 μg/day (on a mg/kg basis). These effects were defined by exaggerated pharmacological actions of ziconotide and not by neurotoxic lesions or target organ toxicity. Observations included transient and reversible neurological effects consisting of tremors, uncoordinated movements and hyper- and hypoactivity.

The long-term consequences to neuronal function of continuous N-type calcium-channel block have not been demonstrated in experimental animals. Changes in neurological signalling have not been studied in experimental animals. Ziconotide did not induce bacterial gene mutation and was not genotoxic. Chronic animal studies have not been performed to assess the carcinogenic potential of ziconotide. However, ziconotide did not induce cell transformation in the in vitro Syrian hamster embryo (SHE) assay and did not increase cell proliferation (pre-neoplastic lesion formation) or apoptosis after subchronic intrathecal exposure in dogs.

In rat fertility studies, there were no effects in males while reductions in corpora lutea; implantation sites and number of live embryos were observed in females. No adverse effects on female reproduction and post-natal development in rats were seen at systemic exposures up to 2,300 times human exposures at the maximum recommended intrathecal dose.

Ziconotide was not teratogenic in rats and rabbits at exposures <100 times human plasma levels.

These results do not indicate a significant risk to humans due to the relatively high systemic exposures needed to elicit these effects in rats and rabbits.