title: Pharmacokinetic analysis of ziconotide (SNX-111), an intrathecal N-type calcium channel blocking analgesic, delivered by bolus and infusion in the dog.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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
  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.
authors: Department of Anesthesiology, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. tyaksh@ucsd.edu
authors: Tony L
authors: TL
authors: Yaksh
authors: Annelies
authors: A
authors: de Kater
authors: Robin
authors: R
authors: Dean
authors: Brookie M
authors: BM
authors: Best
authors: George P
authors: GP
authors: Miljanich
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001143:Arousal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007263:Infusions, Parenteral / Q000379:methods*; D007278:Injections, Spinal / Q000379:methods*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D059225:Nociception / Q000187:drug effects; D010599:Pharmacokinetics; D012867:Skin / Q000294:innervation; D013997:Time Factors; D020960:omega-Conotoxins / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
chemical_list: D002121:Calcium Channel Blockers; D020960:omega-Conotoxins; C078452:ziconotide