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    Figure 1

    Mean plasma cytarabine concentrations in dogs when administered as a 400 mg/m2 SC infusion over 8 hours using the Omnipod system. Error bars represent SD.

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Novel subcutaneous cytarabine infusion with the Omnipod system in dogs with meningoencephalomyelitis of unknown etiology

Shelby L. ManciniVeterinary Specialty Services-Neurology, Manchester, MO
Department of Clinical Sciences, North Carolina State University Veterinary Hospital, Raleigh, NC

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Peter J. EarlyDepartment of Clinical Sciences, North Carolina State University Veterinary Hospital, Raleigh, NC

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Bailey M. SlaterCornell University Hospital for Animals Pharmacy, Ithaca, NY

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Natasha J. OlbyDepartment of Clinical Sciences, North Carolina State University Veterinary Hospital, Raleigh, NC

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Christopher L. MarianiDepartment of Clinical Sciences, North Carolina State University Veterinary Hospital, Raleigh, NC

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Karen R. MunanaDepartment of Clinical Sciences, North Carolina State University Veterinary Hospital, Raleigh, NC

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Christian W. WoelfelDepartment of Clinical Sciences, North Carolina State University Veterinary Hospital, Raleigh, NC

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Jordan A. SchacherDepartment of Clinical Sciences, North Carolina State University Veterinary Hospital, Raleigh, NC

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Li ZhongRoy J. Carver Biotechnology Center, University of Illinois, Urbana, IL

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Kristen M. MessengerDepartment of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Abstract

OBJECTIVE

To investigate the feasibility and pharmacokinetics of cytarabine delivery as a subcutaneous continuous-rate infusion with the Omnipod system.

ANIMALS

6 client-owned dogs diagnosed with meningoencephalomyelitis of unknown etiology were enrolled through the North Carolina State University Veterinary Hospital.

PROCEDURES

Cytarabine was delivered at a rate of 50 mg/m2/hour as an SC continuous-rate infusion over 8 hours using the Omnipod system. Plasma samples were collected at 0, 4, 6, 8, 10, 12, and 14 hours after initiation of the infusion. Plasma cytarabine concentrations were measured by high-pressure liquid chromatography. A nonlinear mixed-effects approach generated population pharmacokinetic parameter estimates.

RESULTS

The mean peak plasma concentration (Cmax) was 7,510 ng/mL (range, 5,040 to 9,690 ng/mL; SD, 1,912.41 ng/mL), average time to Cmax was 7 hours (range, 4 to 8 hours; SD, 1.67 hours), terminal half-life was 1.13 hours (SD, 0.29 hour), and the mean area under the curve was 52,996.82 hours X μg/mL (range, 35,963.67 to 71,848.37 hours X μg/mL; SD, 12,960.90 hours X μg/mL). Cmax concentrations for all dogs were more than 1,000 ng/mL (1.0 μg/mL) at the 4-, 6-, 8-, and 10-hour time points.

CLINICAL RELEVANCE

An SC continuous-rate infusion of cytarabine via the Omnipod system is feasible in dogs and was able to achieve a steady-state concentration of more than 1 μg/mL 4 to 10 hours postinitiation of cytarabine and a Cmax of 7,510 ng/mL (range, 5,040 to 9,690 ng/mL; SD, 1,912.41 ng/mL). These are comparable to values reported previously with IV continuous-rate infusion administration in healthy research Beagles and dogs with meningoencephalomyelitis of unknown etiology.

Abstract

OBJECTIVE

To investigate the feasibility and pharmacokinetics of cytarabine delivery as a subcutaneous continuous-rate infusion with the Omnipod system.

ANIMALS

6 client-owned dogs diagnosed with meningoencephalomyelitis of unknown etiology were enrolled through the North Carolina State University Veterinary Hospital.

PROCEDURES

Cytarabine was delivered at a rate of 50 mg/m2/hour as an SC continuous-rate infusion over 8 hours using the Omnipod system. Plasma samples were collected at 0, 4, 6, 8, 10, 12, and 14 hours after initiation of the infusion. Plasma cytarabine concentrations were measured by high-pressure liquid chromatography. A nonlinear mixed-effects approach generated population pharmacokinetic parameter estimates.

RESULTS

The mean peak plasma concentration (Cmax) was 7,510 ng/mL (range, 5,040 to 9,690 ng/mL; SD, 1,912.41 ng/mL), average time to Cmax was 7 hours (range, 4 to 8 hours; SD, 1.67 hours), terminal half-life was 1.13 hours (SD, 0.29 hour), and the mean area under the curve was 52,996.82 hours X μg/mL (range, 35,963.67 to 71,848.37 hours X μg/mL; SD, 12,960.90 hours X μg/mL). Cmax concentrations for all dogs were more than 1,000 ng/mL (1.0 μg/mL) at the 4-, 6-, 8-, and 10-hour time points.

CLINICAL RELEVANCE

An SC continuous-rate infusion of cytarabine via the Omnipod system is feasible in dogs and was able to achieve a steady-state concentration of more than 1 μg/mL 4 to 10 hours postinitiation of cytarabine and a Cmax of 7,510 ng/mL (range, 5,040 to 9,690 ng/mL; SD, 1,912.41 ng/mL). These are comparable to values reported previously with IV continuous-rate infusion administration in healthy research Beagles and dogs with meningoencephalomyelitis of unknown etiology.

Meningoencephalomyelitis of unknown etiology (MUE) is one of the most common diseases treated in veterinary neurology. The term MUE refers to a variety of noninfectious, inflammatory diseases of the CNS of dogs that are generally considered immune mediated and are typically treated with immunosuppressive drugs. Cytarabine (CA) is a pyrimidine analog that acts as an antimetabolite and is frequently used in the treatment of MUE.13 CA is the preferred secondary immunosuppressive agent among many veterinary neurologists, given its low incidence of adverse effects and apparent efficacy.15 It has a low plasma protein binding capacity, a high volume of distribution, and easily crosses the blood–brain barrier.4 It also exhibits moderate cytotoxicity of lymphoma cells at a concentration of 1 µg/mL, which suggests moderate cytotoxicity of the lymphocytes present in MUE patients.6

Pharmacokinetic studies have demonstrated clinical utility with values greater than 1 µg/mL after administration of CA as a series of SC boluses or as an IV constant-rate infusion (CRI).79 Although the administration of CA as an SC bolus can achieve similar mean peak blood concentrations and displays a similar terminal half-life when compared with IV CRI administration, it does not achieve steady-state concentrations.9 In addition, 3-month survival rates in MUE patients treated with CA and prednisone were determined to be significantly greater in dogs that received an IV CRI (100 mg/m2 over 24 h) compared to dogs receiving SC administration (50 mg/m2 SC q 12 h for 2 doses) as their initial CA treatment.10

Although IV CRI administration is frequently considered by many clinicians to be the favorable route of delivery, it is more expensive and requires repeated IV catheterization, often leading to progressively difficult venous access. It also generally requires a more extended hospital visit for administration, which can add strain to an owner’s schedule and finances, and is undesirable for aggressive or anxious patients. Alternative routes of administration have been studied in attempts to find an equally effective mechanism of delivery without these disadvantages. However, oral, rectal, and transdermal administration of CA are associated with poor bioavailability.1113

The Omnipod system is an SC insulin delivery system used for the management of diabetes mellitus in humans (Insulet Corp). The Omnipod is a wireless, self-powered, tubeless, disposable, waterproof, continuous insulin management system that consists of a “pod” (insulin pump) and a smartphone-like device (Personal Diabetes Manager [PDM]) that communicates with the pod using Bluetooth technology. The pod has a volume capacity of 2.00 mL and adheres to the skin by adhesive padding. The pod is then activated using the PDM and inserts a cannula into the SC tissue for the administration of insulin. The Omnipod can deliver a continuous infusion of medication for as long as 72 hours. The Omnipod provides a potential alternative for CA delivery that would require only a short visit for placement, and drug administration could continue at home. This modification may improve owner compliance and the utility of CA in patients that may have only been able to receive alternative immunosuppressants previously.

The purpose of this study was to investigate the feasibility of CA delivery as an SC CRI with the Omnipod system and to assess the pharmacokinetics of this delivery method by measuring plasma CA concentrations during and after an 8-hour infusion. We hypothesized that the mean peak plasma concentration (Cmax) of CA and the length of time the CA was at a steady state in MUE patients receiving this drug as an SC CRI would be similar to the reported Cmax and steady state of an IV CRI of CA.

Materials and Methods

Animals

Six client-owned dogs diagnosed with MUE were enrolled through North Carolina State University Veterinary Hospital (NCSU). A diagnosis of MUE was based on characteristic signalment and clinical signs as well as CSF analysis and MRI results. Specifically, these patients had an increased CSF nucleated cell count (> 5 cell/µL) and MRI findings consistent with multifocal to diffuse T2-weighted and fluid-attenuated inversion recovery hyperintensities within the brain, meninges, and/or spinal cord, along with variable contrast enhancement.14,15 Enrollment in this study was performed in place of one of the patients’ routinely scheduled CA administrations as part of their treatment of MUE. Dogs were excluded if they weighed more than 11 kg because the pump was limited to a 2.00-mL maximum capacity. In addition, a vest, typically used for remote cardiac monitoring, was placed on the patient over the Omnipod during the study to prevent dislodging the pod, and these were only available in small sizes, which limited enrollment to small dogs. This study was approved by the NCSU Institutional Care and Use Committee (Protocol No. 20-140).

Preparation and drug administration

A peripherally inserted central catheter (PICC) was placed in the lateral saphenous vein on admission to the hospital. Dexmedetomidine (3 μg/kg) and butorphanol (0.2 to 0.4 mg/kg) were used as needed to aid in catheter placement (dexmedetomidine [Dexdomitor], Zoetis; butorphanol [Torbugesic], Zoetis). Blood was collected through the catheter for a CBC, and an additional 2.4-mL blood sample was collected in a lithium heparin tube for CA plasma concentration pharmacokinetics as a 0-hour time point sample. The CA dose was prepared following the standard operating procedures of the institution in a clean, negative-pressure room with a containment hood and in compliance with US Pharmacopeia (USP) guidelines for sterile and hazardous drugs (USP <797> and <800>). The CA was drawn up by a pharmacist wearing chemotherapy-rated personal protective equipment and using closed-system transfer devices (CSTDs) from Equi-Shield. These syringe systems allow for safer preparation and administration of antineoplastic drugs by lacking exposed sharps and preventing the escape of hazardous drug vapors. The evening before each patient’s trial, the required dose was drawn up aseptically in a 3-mL CSTD and dispensed to the investigators, along with an adapter that allowed the attachment of a standard needle. Nitrile gloves and a face shield were worn by the investigator responsible for loading the CA into the pod. An ∼7- X 10-cm area on the patient’s dorsum, just caudal to the scapulae, was clipped and wiped with isopropyl alcohol and allowed to dry for a minimum of 15 minutes. Immediately before applying the device to the patient, the protective adapter and 5-mm 27-g needle were attached to the CSTD, and the CA was loaded slowly into the Omnipod while the Omnipod remained in a provided plastic tray over a chemotherapy absorbent mat to minimize the risk of spills or leakage. All syringes, gloves, mats, and other materials were disposed of as hazardous chemotherapy waste. This took place in an empty standard room as this remained a closed system on a disposable pad. There was no obvious leakage noted, and the process was performed easily. The Omnipod’s adhesive area (∼4 X 5 cm) was applied directly to the patient’s skin. A PodPal, an extra adhesive bandage designed for use with the Omnipod, was applied around the pod. Last, a vest, typically used for remote cardiac monitoring, was placed on the patient over the Omnipod. A PDM was programed and used to deliver CA at a rate of 50 mg/m2/hour as an SC CRI over 8 hours (400 mg/m2 total). This dose, which is greater than most reported studies of CA in the treatment of MUE, was chosen to compensate for possible inadequate delivery as the efficacy of CA administration by using the Omnipod device was not studied previously in species beyond humans. After completion of the infusion, the PodPal and Omnipod device were removed using Medi-Sol (Orange-Sol), a skin adhesive remover with aloe vera.

Sample collection

All blood samples (2.4 mL) were collected from the PICC into lithium heparin tubes and centrifuged immediately at a relative centrifugal force of 1,380 X g for 10 minutes. Plasma was harvested and frozen at –80°C until analyzed to determine CA concentrations. Blood samples were collected before drug infusion (time 0); at 4, 6, and 8 hours after the start of the infusion; and at 2, 4, and 6 hours after termination of the infusion, providing concentrations for time points at 0, 4, 6, 8, 10, 12, and 14 hours. After collection of the 14-hour blood sample, each dog was administered SC boluses of 50 mg/m2 CA every 2 hours for 3 doses (150 mg/m2 total dose) to ensure adequate CA doses were administered, because the degree of drug absorption through the pod was unknown. A CBC was performed 7 to 10 days after the infusion to evaluate the nadir period in the various blood cell lines.

Pharmacokinetic and statistical analysis

Samples were analyzed via high-pressure liquid chromatography–tandem mass spectrometry using the 5500 QTRAP LC/MS/MS system in a fashion similar to previously described CA pharmacokinetic studies8,9 (5500 QTRAP LC/MS/MS system, Sciex; operated by Metabolomics Lab of Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign). Pharmacokinetic modeling was conducted using commercially available software (Phoenix NLME version 7.0, Certara). A nonlinear mixed-effects approach was used to generate population pharmacokinetics parameter estimates. Different base models were assessed for fit based on visual inspection of the plasma concentration versus time data, residual plots, and Akaike’s information criteria.16,17 The final model was a 1-compartment extravascular model with first-order absorption and elimination, and was parameterized by the microrate constants (first-order absorption rate constant [Ka] and elimination rate constant [Ke]). Random effects for Ka and volume of distribution/fraction of drug absorbed (V/F) were removed from the model because of the high shrinkage (> 0.8) associated with these values. A multiplicative error term was used to describe the residual variability. Covariate testing on the parameters was not performed. Final model validation was performed using a bootstrap method on 1,000 replicate data sets, and visual predictive checks were used to evaluate the final model further. Secondary pharmacokinetics parameters (absorption and elimination half-lives, area under the concentration-vs-time curve [AUC]) were determined using estimates from individual dogs and standard pharmacokinetic equations.18 Noncompartmental pharmacokinetic analysis of CA in plasma was performed using commercially available software (Phoenix WinNonlin, version 8.3; Certara). The pharmacokinetic parameters estimated included the elimination rate constant (Lambda_z), the terminal half-life (HL_Lambda_z), the time to maximum concentration (Tmax), the Cmax, and the AUC from time zero to infinity, which was calculated using the linear log trapezoidal method. All data are reported using descriptive statistics.

Results

Six dogs diagnosed with MUE were enrolled in the study. Dogs ranged in age from 2 to 12 years (median, 4 years), and weight ranged from 3.40 to 8.10 kg (median, 5.21 kg). There were 4 neutered females, 1 intact female, and 1 neutered male. The following breeds were represented in this population: Pomeranian (n = 2), and 1 each of the breeds Miniature Dachshund, Shih Tzu, French Bulldog, and Terrier mix. Any previous dosing of CA was administered at least 21 days before the initiation of our study. All dogs were administered prednisone concurrently at a dose ranging from 0.27 to 1.1 mg/kg/day.

A total of 42 plasma samples from 6 dogs were used in the pharmacokinetic analysis. Plasma drug concentrations ranged from 57 to 9,690 ng/mL. Cmax was 7,510 ng/mL (range, 5,040 to 9,690 ng/mL; SD, 1,912.41 ng/mL) with a Tmax mean and mode of 7 hours and 8 hours, respectively (range, 4 to 8 hours; SD, 1.67 hours). The terminal half-life was 1.13 hours (SD, 0.29 hour). The mean AUC was 52,996.82 hours X μg/mL (range, 35,963.67 to 71,848.37 hours X μg/mL; SD, 12,960.90 hours X μg/mL). The percentage of the AUC from dosing time due to extrapolation from the last dosing time to infinity was 0.83% (range, 0.12 to 2.1%; SD, 0.76%) and mean residence time was 2.48 hours (range, 2.05 to 3.16 hours; SD, 0.38 hour; Figure 1, Table 1). Cmax for all dogs were more than 1,000 ng/mL (1.0 μg/mL) at the 4-, 6-, 8-, and 10-hour time points. One of the 6 dogs maintained a plasma concentration greater than 1.0 μg/mL at the 12-hour time point, but none of the dogs maintained a plasma concentration greater than 1.0 μg/mL at the 14-hour time point.

Figure 1
Figure 1

Mean plasma cytarabine concentrations in dogs when administered as a 400 mg/m2 SC infusion over 8 hours using the Omnipod system. Error bars represent SD.

Citation: American Journal of Veterinary Research 83, 9; 10.2460/ajvr.22.03.0046

Table 1

Pharmacokinetic summary of plasma cytarabine concentrations in dogs when administered via SC infusion using the Omnipod system.

Parameter Units Mean SD
Tmax h 7.00 1.67
Cmax ng/mL 7,510.00 1,912.41
AUCINF_obs h X ng/mL 52,996.82 12,960.90
AUC%extrap_obs % 0.83 0.76
AUClast h X ng/mL 52,587.71 13,031.57
MRTINF_obs h 2.48 0.38
HL_Lamda_z h 1.13 0.29
Lamda_z 1/h 0.65 0.17

AUC = Area under the curve. AUCINF_obs = Area under the curve from dosing time extrapolated to infinity, based on the last observed concentration. AUC%extrap_obs = The percentage of the AUC from dosing time due to extrapolation from the last dosing time to infinity. AUClast = Area under the curve from the time of dosing to the last measurable positive concentration. Cmax = Mean peak plasma concentration. HL_Lamda_z = Terminal half-life. Lamda_z = elimination rate constant. MRTINF_obs = Mean residence time. Tmax = Time to mean peak plasma concentration.

CA administration was well tolerated, with mild adverse effects reported in 2 dogs. One dog developed diarrhea during the study period, which resolved with metronidazole (62.5 mg q 12 h for 3 days) and a bland diet. Ten days after CA administration, another dog showed a mild neutropenia 1.75 X 103/μL (normal range, 2.57 to 8.23 X 103/μL) without associated clinical signs and was prescribed cephalexin (80 mg q 12 h for 7 days). The neutrophil count was within the normal range when rechecked within 30 days after CA administration. There were no adverse skin reactions noted in association with the pod.

Discussion

The Omnipod system was adapted easily for use in dogs in our study. The pod was applied easily to canine skin, and the system delivered subcutaneous infusions of CA successfully to all dogs over an 8-hour period. This resulted in a CA Cmax of 7,510 ng/mL (range, 5,040 to 9,690 ng/mL; SD, 1,912.41 ng/mL). Plasma concentrations were maintained at more than 1 μg/mL during the 8-hour SC CRI administration period and for at least 2 hours afterward. The pods were well tolerated in all dogs, with minimal adverse effects. Thus, the Omnipod system is feasible for the administration of CA as part of the management of MUE in dogs.

Crook et al7 studied the pharmacokinetics of CA administered via IV CRI in healthy dogs and determined that when administered as an IV CRI at a rate of 25 mg/m2/hour for 8 hours (total dose, 200 mg/m2), the Cmax was 2.8 μg/mL (SD, 0.39 μg/mL) and the Tmax was 4 hours. Furthermore, in that study, the mean total AUC from IV CRI was 22.58 μg X hour/mL (SD, 3.19 μg X h/mL). Levitin et al19 administered CA as an IV CRI in dogs with MUE at a rate of 8.33 mg/m2/hour over 24 hours (total dose, 200 mg/m2), which produced a Cmax and AUC of 1.09 μg/mL and 15.74 μg X hour/mL, respectively. They did not calculate Tmax in their study. Our study achieved a greater Cmax and AUC than either of these studies, which may reflect the greater dose administered (400 mg/m2), but nonetheless confirms effective delivery. The later Tmax of 7 hours in our study compared to Tmax of 4 hours by Crook et al7 may reflect the SC route compared to the IV route. Furthermore, our mean concentration at 4 hours, which was Crook’s Tmax, was 6358 ng/mL (range, 4440 to 8960 ug/mL; SD, 1757 ng/mL), which was greater than their Cmax value of 2.80 ug/mL at that time, indicating comparable delivery.

Regarding clinical efficacy, the plasma concentration of CA necessary to produce a therapeutic response in dogs with MUE is unknown. Within the cell, CA is converted to a triphosphate and inhibits DNA replication by competing with cytidine.4 DNA replication then ceases, specifically during the S phase of the cell cycle.4 DNA polymerase is also inhibited by the process, and in turn DNA replication and repair stops.4 Pawlack et al6 found that a concentration of 1 μg/mL showed moderate cytotoxicity against canine lymphoma cells during an in vitro study. In our study, an SC CRI administered at 50 mg/m2/hour maintained a plasma concentration of more than 1 g/mL throughout the duration of the 8-hour administration and 2 hours after completion of the infusion in all dogs.

In addition to the Cmax, the duration of plasma steady-state concentrations is an important measure when considering delivery to the CNS. One limiting factor in drug delivery to the central nervous system is that the transit time is estimated to be very short (approximately 5 seconds).20 Therefore, sustained concentrations in the blood, such as those produced by an IV CRI or the Omnipod’s SC CRI, encourage uptake into the brain and may provide optimal delivery to and effects upon the CNS.

Jones et al21 determined that SC boluses of CA at doses of 50 mg/m2, 100 mg/m2, and 200 mg/m2 could all achieve CA plasma concentrations greater than 1 μg/mL, although the concentration declined quickly after Cmax, and then for 6 to 10 hours it was maintained only at more than 0.1 μg/mL, depending on the dose. Repeat dosing of 50 mg/m2 and 100 mg/m2, for 2 doses or 1 dose, respectively, increased the overall time the plasma concentration of CA was more than 1 μg/mL over the course of treatment.21 This yielded approximately the same AUC for each dosing protocol.21 CA plasma concentrations greater than 1 μg/mL were attained intermittently with SC bolus dosing, but steady-state concentrations in this range were not achieved. However, in our study, steady-state concentrations were achieved with the SC CRI using the Omnipod.

Lowrie et al10 determined that IV CRI administration of CA (100 mg/m2 over 24 h) showed significantly greater 3-month survival rates in MUE patients compared to dogs receiving SC bolus administration of CA (50 mg/m2 SC q 12 h for 2 doses), which may represent the advantage of the IV CRI effects on the CNS resulting from sustained concentrations in the blood. In addition, Levitin et al19 compared CA administration in 2 groups of dogs with MUE using either 4 SC boluses of 50 mg/m2 every 2 hours or a 24-hour IV CRI of 200 mg/m2. When plasma concentrations of CA were compared between groups, the Cmax was greater in the SC group for the initial 8 hours of drug administration, but greater in the IV CRI group from 12 to 24 hours after treatment initiation.19 Although the SC administration yielded a greater Cmax in that study,19 the IV CRI maintained a more sustained peak plasma concentration. The mean plasma concentration of our study was greater than 1 μg/mL from 4 to 10 hours after initiation of the 8-hour infusion, which was longer than the maintenance of a similar plasma concentration in the SC bolus group in the study by Levitan et al.19 Although the mean plasma concentration in our study dropped to less than 1 μg/mL after 10 hours, it is likely that a longer infusion with the Omnipod device could also result in a prolonged steady-state concentration comparable to a 24-hour IV CRI.

This study was limited by its enrollment requirements. Enrollment was only open to dogs weighing 11 kg or less because of the size of the vest used over the pod and the 2.00-mL maximum capacity of the pod. Because the pod cannot be reused and a second pod would require a second PDM, the 2.00-mL total dose of CA that could be delivered with a single pod prohibited the utility of this system in larger patients. Another limitation of this study was the number of sample collections and the selection of sample time points. Only 7 time points were collected to minimize blood drawn from each individual patient. After the initial 0-hour time point was collected, the next collection was 4 hours after initiation of the infusion, because a previous study by Crook et al7 demonstrated the Tmax of an IV CRI CA infusion at 4 hours. Because samples were not collected during the infusion prior to 4 hours, the plasma concentration of CA could potentially measure more than 1 μg/mL prior to 4 hours, which could not be demonstrated by our study methods. The potential for dogs to remove or ingest the pod physically, and the potential exposure of owners to CA are possible concerns for using the Omnipod in clinical outpatient cases.

In conclusion, this study showed that an SC CRI of CA using the Omnipod system was able to achieve a steady-state concentration greater than 1 μg/mL at the first measured time point (4 hours) throughout the duration of administration, and for approximately an additional 2 hours, which is similar to values previously reported with IV CRI administration. Although the Omnipod system is used primarily for insulin delivery in human medicine, it was adapted easily for CA in canine MUE cases in our study as it was applied easily to the skin, remained on the patient, and was well tolerated. Furthermore, the pharmacokinetic similarities between CA delivery in this study and previous studies confirmed successful delivery through an SC CRI. Therefore, CA delivery with the Omnipod appears to be a viable alternative route of administration of CA as part of the management of MUE in dogs. Still, further studies are needed to determine whether this system results in therapeutic efficacy comparable to currently used methods of CA delivery.

Acknowledgments

Financial support was provided by the CREATE Fund and the Department of Clinical Sciences at the North Carolina State University College of Veterinary Medicine. Insulet Corporation supplied the pods and PDM at no cost.

The authors declare there is no conflict of interest related to this study.

The authors thank Insulet Corporation for significant support of this study, and thank Arrichion for their inspiration and encouragement during the study.

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Contributor Notes

Corresponding author: Dr. Early (pjearly@ncsu.edu)