Open AccessPharmacokinetic Analysis of Ziconotide (SNX‐111), an Intrathecal N‐Type Calcium Channel Blocking Analgesic, Delivered by Bolus and Infusion in the Dog
Author(s) -
Yaksh Tony L.,
de Kater Annelies,
Dean Robin,
Best Brookie M.,
Miljanich George P.
Publication year - 2012
Publication title -
neuromodulation: technology at the neural interface
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.296
H-Index - 60
eISSN - 1525-1403
pISSN - 1094-7159
DOI - 10.1111/j.1525-1403.2012.00479.x
Subject(s) - bolus (digestion) , medicine , anesthesia , pharmacokinetics , analgesic , beagle , intrathecal , pharmacology , surgery
Background and Purpose: Ziconotide is a peptide that blocks N‐type calcium channels and is antihyperalgesic after intrathecal (IT) delivery. We here characterize the spinal kinetics of IT bolus and infused ziconotide in dog. Experimental Approach: Male beagle dogs ( N = 5) were prepared with chronic IT lumbar injection and cerebrospinal fluid (LCSF) sampling catheters connected to vest‐mounted pumps. Each dog received the following: 1) IT bolus ziconotide (10 µg + 1 µCi 3 H‐inulin); 2) IT infusion for 48 hours of ziconotide (1 µg/100 µL/hour); 3) IT infusion for 48 hours of ziconotide (5 µg/100 µL/hour); and 4) intravenous injection of ziconotide (0.1 mg/kg). After IT bolus, LCSF ziconotide and inulin showed an initial peak and biphasic (distribution/elimination) clearance (ziconotide T 1/2‐α/β = 0.14 and 1.77 hours, and inulin T 1/2‐α/β = 0.16 and 3.88 hours, respectively). The LCSF : plasma ziconotide concentration ratio was 20,000:1 at 30 min and 30:1 at eight hours. IT infusion of 1 and then 5 µg/hour resulted in LCSF concentrations that peaked by eight hours and remained stable at 343 and 1380 ng/mL, respectively, to the end of the 48‐hour infusions. Terminal elimination T 1/2 after termination of continuous infusion was 2.47 hours. Ziconotide LCSF : cisternal CSF : plasma concentration ratios after infusion of 1 and 5 µg/hour were 1:0.017:0.001 and 1:0.015:0.003, respectively. IT infusion of ziconotide at 1 µg/hour inhibited thermal skin twitch by 24 hours and produced modest trembling, ataxia, and decreased arousal. Effects continued through the 48‐hour infusion period, increased in magnitude during the subsequent 5 µg/hour infusion periods, and disappeared after drug clearance. Conclusions and Implications: After IT 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.