Amikacin is an antibiotic in the aminoglycoside class that is commonly used in veterinary medicine.1 Amikacin is bactericidal and concentration dependent with a broad spectrum of activity against many bacteria, particularly gram-negative bacilli, which may be resistant to other drugs.1 This spectrum of activity makes amikacin an attractive antibiotic for use in reptile medicine as many of the common pathogens identified in reptiles are gram negative.2 Common pathogens isolated from pet turtles include Pseudomonas spp, bacteria within the Enterobacteriaceae family, Aeromonas spp, Morganella spp, and Proteus spp, all of which are gram negative.2–4 Further, aminoglycosides are generally considered first- or second-line antimicrobial drugs and have been suggested as an appropriate empiric therapy choice in septic reptiles.5
The most commonly cited adverse effect associated with amikacin across taxa is nephrotoxicity.1,6 In mammalian animal models and humans, factors that contribute to renal toxicity appear to be dosing frequency, total milligrams per kilogram dosage, and accumulation of drug in renal tissue.7–9 Nephrotoxicity associated with amikacin has not been documented in reptiles, even in the face of frequent anecdotal use. However, gentamicin, another aminoglycoside, has been associated with nephrotoxicity in a ball python (Python regius) and a Haitian boa (Epicrates striatus) that were given doses that would have been considered safe in mammalian species.10 The effects of gentamicin in these snakes highlight the need for evidence-based, species-specific dosing of aminoglycosides in reptiles to help avoid preventable adverse effects.
Amikacin pharmacokinetic studies in reptiles are limited. Pharmacokinetics of IM amikacin were evaluated in gopher snakes (Pituophis catenifer) housed at 2 different temperatures; an initial dose of 5 mg/kg followed by 2.5 mg/kg every 72 hours in snakes housed at the high end of their optimum temperature zone was recommended based on temperature effects on pharmacokinetics.11 In contrast, when IM amikacin was evaluated in ball pythons (P regius) housed at 2 different temperatures, plasma concentrations did not reach goal trough concentrations even by 6 days after administration, concluding that one-time administration may be more appropriate to reduce bioaccumulation.12 Temperature effects were not observed in this study.12 In juvenile American alligators (Alligator mississippiensis), amikacin was given IM at 1.75 and 2.25 mg/kg, which resulted in measurable plasma concentrations and mean half-lives of 49.4 and 52.8 hours, respectively.13 Dosing recommendations were not made in this study.13 In chelonians specifically, amikacin pharmacokinetics have only been evaluated in gopher tortoises (Gopherus polyphemus) after a 5-mg/kg IM dose. In that study, clearance in tortoises housed at 30 °C was higher compared to 20 °C.14 Red-eared sliders (Trachemys scripta elegans) are freshwater turtles that are commonly kept as pets. Plasma concentrations after IM gentamicin administration at 6 and 10 mg/kg have been described in this species,15 but pharmacokinetic parameters for amikacin have not been reported. Despite the paucity of data, veterinary reference formularies suggest amikacin doses of up to 10 mg/kg IM once daily.6, 16
Further, no prior studies have evaluated amikacin after SC administration in reptiles, only IM. In goats and greyhounds, SC administration is comparable to IM administration, but this has not been evaluated for reptiles.17,18
In addition to scarce pharmacokinetic data, there are no studies that concurrently evaluate markers of renal function in reptiles following amikacin administration. In gopher snakes, histopathology of the kidney has been evaluated with increasing doses of gentamicin, documenting renal tubule necrosis and visceral gout.19 Despite documentation of this pathologic process, no documented attempts have been made to correlate plasma biochemistry parameters and aminoglycoside nephrotoxicity.
The objective of the current study is to provide pilot pharmacokinetic data after SC administration of amikacin at 5 and 10 mg/kg in red-eared sliders. Additionally, this study aimed to provide concurrent biochemistry data to monitor for any clinically detectable impairment in renal function during the study period.
Methods
This study protocol was approved by the University of Wisconsin-Madison School of Veterinary Medicine IACUC (protocol No. V006636).
Animals
Red-eared sliders (n = 8; 5 female and 3 male) with a mean body weight of 593 g (range, 470 to 750 g) were obtained from a commercial supplier (Niles Biological Inc). All 8 turtles were included in the first pharmacokinetic data collection period; only 7 were included in the second pharmacokinetic data collection period due to 1 turtle developing digit injuries that required medical treatment during the study period. Turtles were housed in a group pond enclosure with a filter pump, underwater hides, and multiple haulouts with a ceramic heat lamp and a full spectrum UV lamp. Average daily ambient temperature was maintained between 75 °F (23.9 °C) and 81 °F (27.2 °C), and average daily ambient humidity was maintained between 19% and 25%. Complete water changes were performed twice weekly, while water pH, ammonia levels, and nitrite levels were monitored weekly and maintained at 6.0 to 8.5, less than 1.0 mg/L, and less than 2 mg/L, respectively. Water temperature was monitored daily and kept between 68.1 °F (20 °C) and 75.1 °F (23.9 °C). Turtles were fed a pelleted diet formulated for aquatic turtles (TetraFauna ReptoMin) ad libitum every other day. Turtles were housed in their enclosure for at least 4 weeks before initiating this study. Two weeks before baseline samples were taken, each turtle underwent a physical examination and was administered 50 mg/kg fenbendazole (100 mg/mL; 10% Panacur Suspension; Merck Animal Health) orally via metal gavage needle for prophylactic endoparasite treatment. During the physical exam, 1 mL of blood was collected from the subcarapacial plexus and placed into lithium heparin microtainers (Becton Dickinson). This phlebotomy site was chosen based on ease of access as study animals were not amenable to restraint for alternative phlebotomy sites such as the jugular vein or brachial plexus. For each turtle, 200 µL of whole blood was submitted within 2 hours of the first blood collection for baseline biochemistry evaluation using the VetScan Whole Blood Analyzer with the Avian/Reptile Profile Plus rotors (Abaxis). The remainder of the sample for each animal was centrifuged (E8 Porta-Fuge; LW Scientific Centrifuge) at 1,534 X g for 10 minutes, and plasma was removed via pipette, pooled in cryovials, and frozen at –80 °C. This portion of the sample was used for development and validation of the analytical assay.
Study design
All 8 turtles were administered amikacin (250 mg/mL; amikacin sulfate at 500 mg per 2-mL vial; Sagent Pharmaceuticals Inc) at a target dose of 5 mg/kg SC (SC5), and then the remaining 7 turtles were administered a target dose of 10 mg/kg SC (SC10) in a sequential, 2-period study with a 3-week washout period between doses, meaning the higher dose was given exactly 3 weeks after the lower dose. Each dose was given in the antebrachial area of a forelimb. On the day of each drug administration, a new single-dose vial was opened and punctured for the first time. Amikacin was used within 1 hour of first puncture. Due to small volumes of administration, each dose was rounded to the nearest 0.01 mL, and the actual dose was calculated and reported. Just before drug administration for each sampling period, every turtle was handled for weight measurement and collection of blood from the subcarapacial plexus for baseline plasma amikacin measurement. The injection site was gently wiped with 70% isopropyl alcohol-soaked gauze before drug administration, and then gentle digital pressure was applied after injection for 5 to 10 seconds to prevent drug leakage. Animals were evaluated once daily by a veterinarian during the sample period for visible redness, swelling, or discoloration at the injection site. Additionally, the animals were monitored for expected behaviors including strong retraction into the shell during handling and rapid retreat into the water after handling. Between sample points, animals were not observed.
To monitor amikacin plasma concentrations over time, 0.5 mL blood was collected from the subcarapacial plexus from every turtle and placed in a lithium heparin microtainer at 24, 48, 72, and 96 hours after amikacin administration. Within 1 hour of sample collection, blood samples were centrifuged (E8 Porta-Fuge; LW Scientific Centrifuge) at 1,534 X g for 10 minutes, and plasma was removed via pipette and placed in cryovials. All plasma samples were frozen at –80 °C until the conclusion of both sampling periods. Samples were stored frozen for up to 5 weeks, before shipping to the analytical lab for concentration determinations. All samples were stored at –80 °C before analysis.
To monitor biochemistry parameters, 0.5 mL of blood was drawn from each turtle via the subcarapacial sinus and placed into a lithium heparin microtainer 7 days after administration of each amikacin dose. Whole blood samples were then submitted within 2 hours of collection for biochemistry evaluation as described above.
Amikacin plasma concentration analysis
Plasma calibrators were prepared by dilution of the amikacin standard solutions (Sigma-Aldrich) with drug-free turtle plasma to concentrations ranging from 0.5 to 40 µg/mL. Calibration curves and negative control samples were prepared fresh for each quantitative assay. In addition, quality control samples (drug-free turtle plasma fortified with analyte at 2 concentrations within the standard curve) were included with each sample set as an additional check of accuracy.
Before analysis, 100 µL of plasma was diluted with 150 µL of acetonitrile (ACN) + 0.1% heptafluorobutyric acid:1 M acetic acid (9:1, vol:vol) containing 2 ng/µL of the internal standard streptomycin (Sigma-Aldrich) and 50 µL of water to precipitate proteins. The samples were vortexed for 1 minute to mix, refrigerated for 20 minutes, vortexed for an additional 1 minute, and centrifuged at 16,500 rpm/13,844 g for 5 minutes at room temperature, and then 20 µL was injected into the liquid chromatography tandem mass spectrometry system.
The concentration of amikacin was measured in plasma by liquid chromatography tandem mass spectrometry using positive electrospray ionization. A partial validation, as described in the FDA Bioanalytical Method Validation Guidance for Industry,20 was performed for turtle plasma as a full validation of this method, including assessment of selectivity, robustness, precision, and accuracy. Specificity and susceptibility to interference were assessed by assaying several control matrix samples with and without the internal standard. The limit of quantitation was determined to be the lowest concentration on the calibration curve that could be measured with acceptable precision and accuracy. The limit of detection was the concentration at which the analyte peak signal-to-noise ratio was approximately 10. Quantitative analysis of plasma was performed on a TSQ Vantage triple quadrupole mass spectrometer (Thermo Scientific) having an 1100 series liquid chromatography system (Agilent Technologies). The system was operated using positive electrospray ionization. Product masses and collision energies were optimized by infusing the standards into the mass spectrometer. Chromatography employed an ACE 3 C18 10-cm X 2.1-mm column (Mac-Mod Analytical) and a linear gradient of ACN in water, with 0.1% heptafluorobutyric acid, at a flow rate of 0.40 mL/min. The initial ACN concentration was held at 5% for 0.33 minutes, ramped to 90% over 4.0 minutes, and held at that concentration for 0.1 minutes before reequilibrating for 3.0 minutes.
Detection and quantification were conducted using selective reaction monitoring of the initial precursor ion for amikacin (m/z, 586.3) and the internal standard streptomycin (m/z, 582.3). The response for the product ions for amikacin (m/z, 264.1) and the internal standard (m/z, 221.4, 246.3, and 263.3) was plotted, and peaks at the proper retention were time integrated, using Quanbrowser software (Thermo Scientific). Quanbrowser software was used to generate calibration curves and quantitate analytes in all samples by linear regression analysis. A weighting factor of 1/X was used for all calibration curves.
The response was linear and gave correlation coefficients of 0.99 or better. The precision and accuracy of the assay were determined by assaying quality control samples in replicates (n = 6). Accuracy was reported as percent nominal concentration and precision was reported as percent relative SD. For amikacin, accuracy was 100% for 2,000 ng/mL and 109% for 20,000 ng/mL. Precision was 4% for 2,000 ng/mL and 5% for 20,000 ng/mL. The technique was optimized to provide a limit of quantitation of 500 ng/mL and a limit of detection of approximately 200 ng/mL for amikacin.
Statistical analysis
Commercial statistics software (SigmaPlot 13; Systat Software) was used for all of the following statistical tests. Mean amikacin plasma concentrations and SEM were calculated for each treatment group at each time point. Pharmacokinetic parameters were not calculated due to limited sample points, especially within the first 24 hours after drug administration, in this study. Normality of biochemistry results for the distribution of each analyte was assessed using the Shapiro-Wilks test. Biochemistry analyte results after each amikacin dose were compared to baseline using the paired t test if the analyte data were normally distributed or the Wilcoxon rank-signed test if analyte data were not normally distributed. To assess for change in plasma concentrations from time point 24 to time point 96, a repeated measures ANOVA was performed for each sampling period. P values less than .05 were considered significant.
Results
Mean actual amikacin doses were 4.4 mg/kg (range, 3.8 to 6.3 mg/kg) and 8.4 mg/kg (range, 7.8 to 10.2 mg/kg) for SC5 and SC10, respectively. Amikacin plasma concentrations for each dose evaluated, SC5 and SC10, are summarized (Table 1). Amikacin was not detected in any plasma samples taken at time point 0 before the SC5 sampling period but was found in detectable quantities in all plasma samples taken at the SC10 time point 0, 3 weeks after drug administration during the SC5 sampling period, before the SC10 sampling period (Figure 1). The repeated measures ANOVAs evaluating for significant decreases in plasma concentrations after recorded peak concentrations showed a P value of less than .001 for SC5 and .30 for SC10. This indicates a significant decrease from peak plasma amikacin concentrations for SC5 but no change after peak plasma concentrations for SC10. VetScan biochemistry results were compared to published reference ranges, and all values from all 3 time points were within normal limits for each turtle.21–24 Biochemistry analyte results and statistical analysis are summarized (Table 2). No cutaneous redness, swelling, or discoloration was noted at any injection sites, and all turtles had strong retraction into their shells and rapid retreat into the water at each sampling point.
Plasma amikacin concentrations reported as mean (± SEM) from red-eared sliders (Trachemys scripta elegans) sampled after administration of 5 mg/kg amikacin SC (SC5; n = 8) and after administration of 10 mg/kg amikacin SC (SC10; n = 7).
| Time point (h) | SC5 plasma amikacin concentrations (µg/mL) | SC10 plasma amikacin concentrations (µg/mL) |
|---|---|---|
| 0 | 0 | 1.05 (± 0.22)* |
| 24 | 17.5 (± 2.17) | 23.6 (± 2.70) |
| 48 | 13.9 (± 1.29) | 17.2 (± 2.61) |
| 72 | 10.9 (± 1.03) | 23.4 (± 3.41) |
| 96 | 9.07 (± 0.92) | 18.9 (± 3.31) |
Time point was just before 10-mg/kg dosing and 3 weeks after 5-mg/kg dosing.
Mean ± SEM plasma amikacin concentrations in red-eared sliders (Trachemys scripta elegans) following administration of an amikacin dose at 5 mg/kg SC (n = 8; black circles) followed by an amikacin dose of 10 mg/kg SC after a 3-week washout period (n = 7; gray squares).
Citation: American Journal of Veterinary Research 85, 9; 10.2460/ajvr.24.03.0088
Plasma biochemistry parameters from red-eared sliders (Trachemys scripta elegans) before and after SC administration of amikacin.
| Biochemistry analyte/time point | Mean (± SEM) |
|---|---|
| AST (U/L) | |
| Baseline | 128.3 (± 10.8) |
| 1 | 126.1 (± 16.8) |
| 2 | 106.6 (± 16.1) |
| CK (U/L) | |
| Baseline | 865.5 (± 242.3) |
| 1 | 823.6 (± 181.5) |
| 2 | 774.7 (± 148.2) |
| Uric acid (mg/dL) | |
| Baseline | 0.6 (± 0.1) |
| 1 | 0.3 (± 0.1)* |
| 2 | 0.2 (± 0.1)* |
| Calcium (mg/dL) | |
| Baseline | 9.2 (± 0.3) |
| 1 | 8.8 (± 0.2) |
| 2 | 8.3 (± 0.2)* |
| Phosphorus (mg/dL) | |
| Baseline | 2.9 (± 0.3) |
| 1 | 3.2 (± 0.2) |
| 2 | 2.9 (± 0.2) |
| Total protein (g/dL) | |
| Baseline | 2.5 (± 0.2) |
| 1 | 2.4 (± 0.2) |
| 2 | 2.4 (± 0.2) |
| Potassium (mmol/L) | |
| Baseline | 4.7 (± 0.7) |
| 1 | 4.1 (± 0.5) |
| 2 | 4.9 (± 0.6) |
| Sodium (mmol/L) | |
| Baseline | 138.5 (± 1.1) |
| 1 | 135.6 (± 0.8)* |
| 2 | 133.4 (± 1.4)* |
| Albumin† (g/dL) | |
| Baseline | 0.6 (0.4–0.7) |
| 1 | 0.6 (0.4–0.8) |
| 2 | 0.5 (0.5–0.6) |
| Glucose† (mg/dL) | |
| Baseline | 59.5 (46.8–86.0) |
| 1 | 43.0 (43.0–51.5) |
| 2 | 30.0 (27.0–31.0) |
Baseline (n = 8) indicates blood samples taken before the study period. Time point 1 (n = 8) indicates blood samples taken 7 days after 5-mg/kg amikacin administration. Time point 2 (n = 7) indicates blood samples taken 1 month after 5-mg/kg amikacin administration, 7 days after 10-mg/kg amikacin administration.
CK = Creatinine kinase.
Discussion
Extralabel drug use complied with the provisions of AMDUCA and 21 CFR §530. The results of this study demonstrate measurable amikacin plasma concentrations of more than 9.07 (± 0.92) µg/mL for at least 96 hours after SC administration of amikacin in red-eared sliders at 5 and 10 mg/kg. Persistent, detectable plasma concentrations were still present 3 weeks after 5-mg/kg dosing, which has not previously been documented in reptiles after a single dose. After the 10-mg/kg dosing, plasma concentrations never decreased after the recorded mean peak concentration of 23.61 (± 2.70) µg/mL throughout the study period. Interestingly, the mean plasma concentrations at 72 hours after 10-mg/kg dosing were higher than the plasma concentrations at 48 hours. The difference between the 2 time points was not statistically significant but could potentially be a result of renal tubular reabsorption, which has been documented in mammals,25,26 or secondary to potential postrenal urinary reabsorption, which has not been documented in any species but may be worth further exploration. In contrast, previous data collected in gopher tortoises housed at 30 °C showed amikacin plasma concentrations of less than 1 µg/mL at 96 hours after IM administration of amikacin at 5 mg/kg.14 However, in tortoises housed at 20 °C, plasma concentrations were more similar to the results reported in this study at 96 hours after IM administration of amikacin at 5 mg/kg.14 While a temperature effect on amikacin pharmacokinetics has been demonstrated in gopher tortoises, no change in amikacin pharmacokinetics was demonstrated in ball pythons housed at different ambient temperatures.12 It appears that the temperature effect on amikacin pharmacokinetics is species dependent, so it is possible that the temperature at which these turtles were housed could have contributed to the prolonged persistence of plasma amikacin concentrations. Because all turtles in this study were housed in the same enclosure and within temperature ranges similar to prior pharmacokinetic studies for this species,27,28 effects of ambient temperature on pharmacokinetic data could not be assessed.
Route of administration also could have affected pharmacokinetic data, as this was the first study to evaluate plasma concentrations after SC amikacin in reptiles. In greyhounds, SC administration of amikacin produced lower peak plasma concentrations than IV administration, but half-lives were similar for both routes.18 In goats, the pharmacokinetics of SC amikacin was compared to IM amikacin, which showed nearly complete systemic availability for both routes but a slightly longer half-life for the SC route.17 Similar comparisons between routes of amikacin administration in reptiles have not been performed; therefore, the SC route could potentially contribute to the prolonged presence of amikacin plasma concentrations detected in this study.
The clinical implications of amikacin plasma concentrations persistent for at least 3 weeks are not fully known in red-eared sliders or reptiles in general. In humans, nephrotoxic effects of aminoglycosides have been associated with greater cumulative area under the curve and greater minimum plasma concentrations, suggesting that prolonged persistence of plasma amikacin concentrations may lend toward more toxic effects, with a reduction to once-daily dosing helping to ameliorate toxic effects.29–31 This line of reasoning implies that prolonged detectable amikacin plasma concentrations, which contribute to a greater area under the curve, have the potential to contribute to greater nephrotoxicity. Nephrotoxicity of gentamicin has been demonstrated in gopher snakes, resulting in tubular necrosis and visceral gout after doses of 50 mg/kg/day, but pharmacokinetic parameters were not concurrently provided.19 It is important to note that this dose is much higher than doses commonly used in reptile clinical practice. The nephrotoxic effects of amikacin are hypothesized to be the same in reptiles; however, they have not been previously documented. Furthermore, there has been no correlation between specific peak plasma concentrations or prolonged plasma concentrations and toxic effects for either gentamicin or amikacin in reptiles. Thus, a more complete pharmacokinetic profile for SC amikacin in this species with correlation to measured renal function would be helpful in determining the best dosing strategy while minimizing risks for nephrotoxicity development; however, based on our data alone, dosing recommendations cannot be made.
While this study did not assess histopathologic changes within the kidney, biochemistry results were evaluated as an antemortem marker of renal function during this study. Uric acid is the most commonly used marker of renal function in reptiles, with increases indicating impaired renal function.21 In addition to uric acid, changes in sodium, potassium, calcium, phosphorus, and total protein can be indications of underlying renal dysfunction in reptiles, although these values can be affected by many other systemic diseases making interpretation more nuanced.32 Although our study showed a significant difference between the baseline uric acid values and subsequent measurements, the values actually decreased, and all remained within normal for this species indicating adequate renal function throughout the entire study period.21–24 Additionally, calcium and sodium both showed a statistically significant decrease, although neither deviated from the previously published normal range, indicating these changes were not likely clinically significant.21–24 It is important to note that although uric acid is generally considered the most reliable renal marker in reptiles, significant increases often do not occur until substantial renal damage is done; therefore, biochemistry analysis cannot rule out subclinical renal toxicity could have been overlooked in this study.33 Additional renal function monitoring including iohexol clearance and histopathologic evaluation of the kidneys would be a more sensitive method to detect subclinical nephrotoxicity in future studies.33
Clinical efficacy of the amikacin doses evaluated in this study relies on both pathogen-dependent and pharmacokinetic-dependent factors. Amikacin is a concentration-dependent antibiotic, meaning the efficacy of this drug relies on reaching a certain optimum ratio of either maximum plasma concentration or area under the curve to MIC of the target pathogen.34 In human medicine, a ratio of peak amikacin concentrations and pathogen MIC of 8 has been predictive of therapeutic success.35 By this human standard, both of the doses in this study recorded plasma concentrations sufficient for pathogens with MICs of at least 2 µg/mL. However, the lack of data before 24 hours postadministration in this study likely prevented capture of the true peak plasma concentration. Thus, the doses studied here may actually be effective for pathogens with higher MICs. However, the optimum peak plasma concentration or area under the curve-to-MIC ratio has not been determined in reptiles, and some reptile sources allude that amikacin concentrations only 3 to 5 times the target pathogen's MIC may be needed.36 However, further study would be needed to substantiate these minimum MIC claims.
While the pharmacokinetic data presented in this pilot study add to the current body of knowledge on amikacin in red-eared sliders, infrequent sampling points and plasma concentrations that persisted beyond the sampling period for both doses prevent reliable dosing recommendations. Future studies should include more frequent initial sampling as well as longer sampling periods to obtain a more complete pharmacokinetic profile of SC amikacin in red-eared sliders. Previous pharmacokinetic studies27,37 on SC administration of ceftiofur sodium in iguanas and buprenorphine in red-eared sliders, 2 drugs that have historically shown more rapid clearance in reptiles than aminoglycosides, showed time of peak plasma concentration to be approximately 40 minutes and 1 hour, respectively. In contrast, time of peak plasma concentration after SC administration of ceftiofur crystalline free acid, a more long-acting drug, in bearded dragons was documented at 33 hours.38 Thus, more frequent initial sampling points can better define when the true peak plasma concentration occurs after SC administration of amikacin in red-eared sliders. Stress from more frequent handling or total blood draw volume limitations may be ameliorated with the use of a sparse sampling population pharmacokinetic study design.39 Additionally, more thorough adverse effect monitoring, including iohexol clearance studies or sampling of renal tissue to correlate potential toxic effects with pharmacokinetic parameters should be considered.
In conclusion, SC administration of amikacin at 5 and 10 mg/kg produced plasma concentrations of more than 9.07 (± 0.92) µg/mL and more than 17.22 (± 2.61) µg/mL for at least 96 hours. Detectable plasma concentrations persisted for at least 3 weeks after a 5-mg/kg dosing. Logistic challenges regarding sampling and analysis prevented evaluation of the long-term persistence of plasma concentrations after a 10-mg/kg dosing as results were not obtained until after both study periods. Future studies should ideally plan for long-term amikacin plasma concentration monitoring for up to several weeks after dose administration. Repeated biochemistry analyses did not show any detectable change in renal function over the study period. Further study is needed to better characterize the pharmacokinetic parameters of SC amikacin in red-eared sliders; based on data thus far, repeated dosing should be approached with caution given the long-term persistence in plasma and lack of data on the correlation between persistent plasma concentrations and resultant subclinical renal toxicity.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
Funding was provided by a University of Wisconsin-Madison School of Veterinary Medicine internal grant from the Companion Animal Fund.
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