Pharmacokinetic analysis of ziconotide (SNX-111), an intrathecal N-type calcium channel blocking analgesic, delivered by bolus and infusion in the dog

Abstract

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.

Figure 1

The concentrations of ziconotide (ng/mL) and inulin (DPM/mL) in the lumbar CSF (top) as a function of time after the bolus intrathecal injection of ziconotide (10µg) and inulin (1µCi) in 1 mL. The bottom panel presents the ratio of ziconotide to inulin as a function of time after intrathecal delivery. Each point represents the mean and SEM of data from 5 dogs. Calculated kinetics are presented in Table 1.

Figure 2

The concentrations of ziconotide (ng/mL) in the plasma and lumbar CSF, and the ratio of CSF: plasma levels after the bolus intravenous delivery of ziconotide (0.1 mg/kg). Results presented represent the mean and SEM of data from 5 dogs. Calculated kinetics are presented in Table 2.

Figure 3

The concentrations of ziconotide (ng/ml) in the plasma, lumbar CSF, and the cisternal CSF, and the ratio of CSF: plasma levels at intervals before, during, and after continuous infusion of ziconotide. From 0 to 48 hr, ziconotide was infused at 1µg/hr. From 48 to 96 hr ziconotide was delivered at the rate of 5µg/hr. Cisternal CSF was sampled immediately prior to the initiation of infusion just before changing the infusion rate to 5 µg/hr and just before terminating the infusion of 5µg/hr. Results presented represent the mean and SEM of data from 5 dogs. Calculated kinetics for the two infusion rates and for the clearance of ziconotide after termination of 5 µg/hr infusion in Table 3.

Figure 4

The skin twitch response latency during the continuous intrathecal infusion of ziconotide. From 0 to 48 hr, ziconotide was infused at 1 µg/hr. From 48 to 96 hr, ziconotide was delivered at the rate of 5 µg/hr. Results presented represent the mean and SEM of data from 5 dogs.

Figure 5

The rectal temperature assessed during the continuous intrathecal infusion of ziconotide. From 0 to 48 hr, ziconotide was infused at 1µg/hr. From 48 to 96 hr, ziconotide was delivered at the rate of 5µg/hr. Results presented represent the mean and SEM of data from 5 dogs.

Figure 6

The blood pressure and heart rate responses observed after the intravenous delivery of a bolus of ziconotide (0.1 mg/kg) at t = 0. Results presented represent the mean and SEM of data from 5 dogs.

Figure 7

The blood pressure and heart rate responses observed during the continuous intrathecal infusion of ziconotide. From 0 to 48 hr, ziconotide was infused at 1 µg/hr. From 48 to 96 hr, ziconotide was delivered at the rate of 5 µg/hr. Results presented represent the mean and SEM of data from 5 dogs.