Pharmacokinetic Analysis of Ziconotide (SNX-111), an Intrathecal N-type Calcium Channel Blocking Analgesic, Delivered by Bolus and Infusion in the Dog
Published Date:2012 Nov-Dec
Area Under Curve
Calcium Channel Blockers
Dose-Response Relationship, Drug
Pubmed Central ID:PMC3514653
Funding:ND-15353/ND/ONDIEH CDC HHS/United States
R01 DA015353/DA/NIDA NIH HHS/United States
Description:Background and purpose
Ziconotide is a peptide that blocks N-type calcium channels and is anti-hyperalgesic after intrathecal delivery. We here characterize the spinal kinetics of intrathecal bolus and infused ziconotide in dog.
Male beagle dogs (N = 5) were prepared with chronic intrathecal (IT) lumbar injection and cerebrospinal fluid (LCSF) sampling catheters connected to vest-mounted pumps. Each dog received: i) IT bolus ziconotide (10 µg + 1 µCi 3H-inulin), ii) IT infusion for 48 hr of ziconotide (1 µg/100 µL/hr), iii) IT infusion for 48 hr of ziconotide (5 µg/100 µL/hr), and iv) intravenous injection of ziconotide (0.1 mg/kg). After IT bolus, LCSF ziconotide and inulin showed an initial peak and biphasic (distribtution/elimination) clearance (ziconotide T1/2 α / ß = 0.14 and 1.77 hr, and inulin T1/2 α / ß = 0.16 and 3.88 hr, respectively). The LCSF: plasma ziconotide concentration ratio was 20,000: 1 at 30 min, and 30: 1 at 8 hr. IT infusion of 1 and then 5 µg/hr resulted in LCSF concentrations that peaked by 8 hr and remained stable at 343 and 1380 ng/mL, respectively, to the end of the 48-hr infusions. Terminal elimination T1/2 after termination of continuous infusion was 2.47 hr. Ziconotide LCSF: cisternal CSF: plasma concentration ratios after infusion of 1 µg/hr and 5 µg/hr were 1: 0.017: 0.001 and 1: 0.015: 0.003, respectively. IT infusion of ziconotide at 1 µg/hr inhibited thermal skin twitch by 24 hr, and produced modest trembling, ataxia, and decreased arousal. Effects continued through the 48-hr infusion period, increased in magnitude during the subsequent 5 µg/hr infusion periods, and disappeared after drug clearance.
Conclusions and Implications
After intrathecal bolus or infusion, ziconotide displays linear kinetics that are consistent with a hydrophilic molecule of approximately 2500 Da that is cleared slightly more rapidly than inulin from the LCSF. Behavioral effects were dose dependent and reversible.
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