Milk residues following multiple doses of meloxicam and gabapentin in lactating dairy cattle

Danielle A. Mzyk Department of Population Health and Pathobiology and the Food Animal Residue Avoidance Databank, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Claire B. Giles Department of Population Health and Pathobiology and the Food Animal Residue Avoidance Databank, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Ronald E. Baynes Department of Population Health and Pathobiology and the Food Animal Residue Avoidance Databank, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Geof W. Smith Department of Population Health and Pathobiology and the Food Animal Residue Avoidance Databank, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Abstract

OBJECTIVE

To determine the influence of stage of lactation on the pharmacokinetics in milk when multiple doses of meloxicam were administered alone or in combination with gabapentin to postpartum (PP) and mid-lactation (ML) cows.

ANIMALS

8 postpartum and 8 mid-lactation dairy cows.

METHODS

Cows were randomly divided into 2 groups (n = 8) which included 4 PP cows and 4 ML cows. Group I received only 6 oral daily doses of meloxicam (1.0 mg/kg for 6 doses). Group II received 6 oral daily doses of co-administered meloxicam (1.0 mg/kg) and gabapentin (20 mg/kg) for 6 doses. Meloxicam and gabapentin were quantified in plasma and milk samples by ultra–high-performance liquid chromatography–tandem mass spectrometry, and the pharmacokinetic analysis of milk and plasma was performed using a non-compartmental approach.

RESULTS

Regardless of lactation status, dairy cattle administered multiple doses of meloxicam and/or gabapentin showed low drug residue concentrations and little accumulation in milk. The terminal plasma half-life of meloxicam was significantly increased (P < .02) in PP cows (12.9 hr) compared to ML cows (9.4 hr). The apparent terminal half-life in milk for meloxicam and gabapentin was not affected by stage of lactation. Co-administration of gabapentin did not alter plasma or milk concentrations of meloxicam.

CLINICAL RELEVANCE

The results of this study suggest that milk from cows treated with multiple doses of meloxicam alone or in combination with gabapentin will have low drug concentrations and falls below our reported limit of detection for meloxicam or gabapentin 120 and 60 hours respectively, following the final dose regardless of their stage of lactation.

Abstract

OBJECTIVE

To determine the influence of stage of lactation on the pharmacokinetics in milk when multiple doses of meloxicam were administered alone or in combination with gabapentin to postpartum (PP) and mid-lactation (ML) cows.

ANIMALS

8 postpartum and 8 mid-lactation dairy cows.

METHODS

Cows were randomly divided into 2 groups (n = 8) which included 4 PP cows and 4 ML cows. Group I received only 6 oral daily doses of meloxicam (1.0 mg/kg for 6 doses). Group II received 6 oral daily doses of co-administered meloxicam (1.0 mg/kg) and gabapentin (20 mg/kg) for 6 doses. Meloxicam and gabapentin were quantified in plasma and milk samples by ultra–high-performance liquid chromatography–tandem mass spectrometry, and the pharmacokinetic analysis of milk and plasma was performed using a non-compartmental approach.

RESULTS

Regardless of lactation status, dairy cattle administered multiple doses of meloxicam and/or gabapentin showed low drug residue concentrations and little accumulation in milk. The terminal plasma half-life of meloxicam was significantly increased (P < .02) in PP cows (12.9 hr) compared to ML cows (9.4 hr). The apparent terminal half-life in milk for meloxicam and gabapentin was not affected by stage of lactation. Co-administration of gabapentin did not alter plasma or milk concentrations of meloxicam.

CLINICAL RELEVANCE

The results of this study suggest that milk from cows treated with multiple doses of meloxicam alone or in combination with gabapentin will have low drug concentrations and falls below our reported limit of detection for meloxicam or gabapentin 120 and 60 hours respectively, following the final dose regardless of their stage of lactation.

Introduction

Lameness is a leading animal welfare concern for all stakeholders in the dairy industry.1 There are significant economic losses due to loss of production, increased culling, and treatment costs for associated diseases. These consequences are mainly attributed to the pain caused by problems in the foot, which likely affects the locomotion of the cow.2 Prompt detection and appropriate treatment improve not only the welfare of the animal, but it also can improve the productivity of the animal.3

NSAIDs have been shown to have a modest improvement in lameness scores by decreasing pain associated with inflammation.2 However, neuropathic pain, either from nerve injury or dysregulation, can be refractory to commonly used analgesics and cause persistent pain. Chronic pain, regardless of whether it occurs by injury or disease, results in inflammation and increased excitability of the sensory neurons in the spinal cord and brain. As neurons become “wound-up” they become more sensitive to painful stimuli. Meloxicam, an NSAID, when administered alone or in combination with gabapentin, (a γ-aminobutyric acid analog), reduces the severity of experimentally induced lameness in beef calves.3 Meloxicam and flunixin showed differences in visual lameness scores when administered to dairy cattle in an acute-induced lameness model when compared to a placebo.4 In cattle, the “wind up” pain threshold of lame animals has been shown to last 28 days beyond the point of detection, indicating a need for multimodal and prolonged analgesic therapies.5 There are limited number of analgesic options to choose from when controlling pain in cattle. Meloxicam and gabapentin have demonstrated analgesic effects in cattle and are a commonly requested combination for milk withdrawal interval requests with the Food Animal Residue Avoidance Databank. To the author’s knowledge, there are no studies evaluating the potential for residues following multiple doses of either compound.

Current estimated pharmacokinetic parameters for cattle administered meloxicam were derived from plasma concentrations and are limited to single IV, oral, or SC doses.69 Meloxicam and gabapentin cross from the plasma into the milk following single oral administration at clinically relevant doses in dairy cattle.6 For both drugs, milk concentrations depleted to concentrations that were below 10 ng/mL after 3 days following single oral doses.6 The effect of lactation on the pharmacokinetics has been investigated in previous studies in dairy cattle, suggesting a longer milk withdrawal is needed for cows administered meloxicam in the postpartum (PP) cattle.7 To treat both inflammatory and neuropathic pain associated with lameness, a prolonged duration of treatment with multiple doses of analgesic medications for chronic pain management is necessary. The objective of this study is to determine the depletion of meloxicam and gabapentin following multiple doses in milk to determine a milk withdrawal interval.

Methods

Animals

Cows were eligible for enrollment if they had no history of meloxicam/gabapentin treatment in the previous 30 days. They were healthy before enrollment based on treatment history and milk production. Eight mixed parity PP Holsteins were enrolled within 3 days of freshening. They were matched on enrollment day to 8 mid-lactation (ML) cows of equal parity and between 100 and 240 days in milk. The animals weighed between 477 and 841 kg at the time of study. All cows were in their first, second, or third lactation. Cows were housed in a free-stall barn and received a total mixed ration consisting of cottonseed, alfalfa hay, and corn silage with ad-libitum water at the North Carolina State University Dairy Farm.

Animal phase study design

The animals were randomly assigned to 2 treatment groups comprising 8 animals per group. Each treatment enrolled 4 PP cows less than 3 days after calving and 4 ML cows between 100 and 240 days in milk. One group was co-administered gabapentin (400 mg and 100 mg capsules; Actavis LLC) and meloxicam (15 mg tablets; Unichem Pharmaceuticals) at a dose of 20 mg/kg and 1 mg/kg, respectively. The second group received only meloxicam at a dose of 1 mg/kg, respectively. Doses for each group were administered once daily for 6 days. The drugs were combined in a gelatin capsule and delivered orally with a balling gun into the oropharynx. Cows were evaluated for inclusion during a daily physical exam prior to the 8:00am milking. All cows were weighed prior to treatment. The study protocol was reviewed and approved by the Institutional Animal Care and Use Committee at North Carolina State University.

Plasma and milk collection

Blood was collected from all cows immediately prior to the administration of meloxicam ± gabapentin. Blood was collected via venipuncture from the jugular vein into a 10 mL lithium heparin tube and immediately placed on ice. Following assigned treatment, blood was collected at 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, and 264 hours. Blood samples were centrifuged for 20 minutes at 2,700 g within 30 minutes of sampling. Plasma was harvested and stored at −80 °C until analyzed for drug concentration by ultra–high-performance liquid chromatography–tandem mass spectrometry (UPLC-MS-MS).

Composite milk sampling from each cow was achieved using a proportional milk sampler (Tru129 Test WB Auto Sampler; Datamars) which continually samples a fraction of milk produced by each quarter throughout the milking process creating a representative sample of all milk produced. Thirty milliliters of milk were collected from each cow using the composite sampler just before drug administration and then every 12 hours coinciding with the milking schedules at the dairy farm for 11 days. The samples were collected from the auto-sampler vessel once the milking of the cow was completed. The milk from these cows was not added to the bulk tank to prevent potential drug residues from entering the human food chain. The volume of milk produced at each milking by each individual cow was also recorded at the time of sample collection. The samples were immediately brought back to the lab and frozen at −80 °C until further analysis.

Drug analysis

Gabapentin—The concentration of gabapentin in bovine plasma and milk was quantified with UPLC-MS-MS analysis of extracted samples using prepared calibration standards based on a previously published method in plasma.10 An initial stock solution of 3000 µg/mL was prepared by dissolving 15000 µg gabapentin reference standard in 5.0 mL of 50:50 acetonitrile:H2O (ACN:H2O) solvent. This was then serially diluted to create working solutions of 0.5, 2.5, 5.0, 25, 50, 250, 500, and 1500 µg/mL. Both plasma and milk calibration curves were prepared by diluting the working solutions with drug-free bovine plasma or milk for a final calibration curve of 0.01, 0.05, 0.1, 0.5, 1.0, 5.0, 10.0, 30.0, and 60.0 µg/mL. All calibration curves were prepared fresh each day of analysis. Pregabalin (Pregabalin; 148 US Pharmacopeia) internal standard was used as a control for variability in extraction, injection, and ionization. Pregabalin internal standard was prepared by preparing an initial concentration of 5 mg/mL in methanol. The solution was vortexed for approximately 1 minute and serially diluted to achieve a final concentration of 0.05 µg/mL. Concentrations of gabapentin API, m/z 172.1 → 154, and the internal standard pregabalin, m/z 160.2 → 142.1 were determined by UPLC-MS-MS. The standard curve was linear from 0.05 to 60 µg/mL (R2 = .99). A minimum of 4 replicates of 0.05, 0.5, 5, and 60 µg/mL were used to calculate intraday accuracies of 103.9%, 85.1%, 89.0%, and 101.6%, respectively. Intraday precisions were 7.53%, 3.23%, 7.36%, and 7.71%, respectively. The gabapentin limit of quantification was determined to be 0.05 µg/mL in milk and plasma, as it was the lowest concentration in the standard curve with acceptable accuracy (100 ± 15%) and precision (< 10%). The limit of detection (LOD) was 0.01 µg/mL for both matrices, as the concentration was repeatedly measurable with a signal-to-noise ratio of at least 2, though variability precluded accurate quantification. Sample preparation involved combining plasma or milk sample with pregabalin and processing as previously described.10 Separation was achieved at 40 °C using a phenyl column (Phenyl Column 2.1 × 100mm, 1.7 µm column; Waters Corp), using mobile phase of A: methanol with 0.1% formic acid and B: 0.1% formic acid, at a flow rate of 0.4 mL/min.

Meloxicam—The concentration of meloxicam in bovine plasma and milk was quantified with UPLC-MS-MS analysis of extracted samples using prepared calibration standards. For extraction, milk samples were thawed and processed using a previous method as described.6 Briefly, a 100 μL of each sample was combined with 500 μL of 0.5% citric acid in acetonitrile solvent. Samples were vortexed for approximately 10 seconds and then centrifuged at 4,500 RPM for 5 minutes. The supernatant from each sample was transferred into a clean glass borosilicate (16 mm × 100 mm) culture tube. The supernatant was then dried down via evaporation at 55 °C under a 24-psi stream of nitrogen for approximately 15 minutes. Each sample was then reconstituted in 300 μL of 50:50 acetonitrile:ddH2O with 0.1% formic acid. This mixture was vortexed for approximately 30 seconds per sample. The samples were then filtered through 0.2 μm syringe filter devices and injected onto a column (HSS 1.8 μm 2.1 × 100 mm column; Waters Corp) and analyzed by UPLC-MS-MS. The injection volume was 5 μL for all samples. Validation standards were prepared over a linear range for each matrix (plasma, milk, mobile phase) and were used to construct calibration curves. The limit of quantification for milk and plasma was 1 ng/mL, and the LOD was 5 ng/mL.

Pharmacokinetic analysis

Measured plasma and milk drug concentrations were plotted on linear and semi-logarithmic graphs for visual assessment of the best fit for pharmacokinetic analysis. Noncompartmental analysis was used to analyze plasma and milk drug concentration-time profiles for both meloxicam and gabapentin using a pharmacokinetic program (Phoenix WinNonlin, version 8.0; Certara Inc). Pharmacokinetic parameters analyzed included: maximum concentration (Cmax), volume of distribution per fraction of drug absorbed (Vd/F), clearance per fraction of drug absorbed at steady state (CLss/F), area under the curve following last dose extrapolated to infinity (AUC120-∞), terminal elimination half-life (t1/2λ) and slope of terminal phase (λz). Milk to plasma concentration ratio was calculated as a measure of the ratio of AUC120−264 (milk) over AUC120-264 (plasma) to determine the extent of secretion of the given drugs in milk following the final dose at 120 hours. Statistical analysis was performed using a commercially available software program (GraphPad Prism 7.04; GraphPad Software). Differences in pharmacokinetic variables between treatment groups were assessed using nonparametric Wilcoxon rank sum test. Values of P < .05 were considered significant.

Results

One PP cow was eliminated from final data set due to a diagnosis of post parturient hemoglobinuria prior to the third dose of meloxicam. A second PP cow administered only meloxicam was also eliminated from the final data set due to a diagnosis of clinical mastitis. This resulted in a total of n = 6 in PP group and n = 8 in the ML group. The plots of the geometric means (± SD) of both meloxicam and gabapentin concentrations in plasma (A and C) and milk (B and D) concentration-time profiles without the 2 cows discussed above are provided (Figure 1).

Figure 1
Figure 1
Figure 1
Figure 1
Figure 1

Drug concentrations in postpartum (black circle) and mid-lactation (white diamond) dairy cows before (0 hours) and at various points after the drug was administered orally once every 24 hours for 6 doses. A = meloxicam in plasma, B = meloxicam in milk, C = gabapentin in plasma, D = gabapentin in milk. All values reported are geometric means ± geometric SD.

Citation: Journal of the American Veterinary Medical Association 261, 12; 10.2460/javma.23.06.0329

Meloxicam

Pharmacokinetic parameters determined from noncompartmental analysis for meloxicam are displayed separately for plasma (Table 1) and milk (Table 2) for both groups. Cmax for meloxicam plasma concentrations was observed at 24 hours following the final dose for both PP and ML cows (1.4 µg/mL and 1.5 µg/mL), respectively. In ML cows, the plasma Cmax of meloxicam after the final dose was approximately 16% greater than the Cmax following the initial dose. A similar pattern was seen in PP cows, whose Cmax increased by approximately 8% from the initial to the final dose.

Table 1

Plasma pharmacokinetic parameters of meloxicam administered orally for multiple doses at 1.0 mg/kg in dairy cattle.

Postpartum (n = 6) Mid-lactation (n = 8) P value
Mean SD Range Mean SD Range
Cmax (μg/mL) 1.4 1 1.01–2.1 1.5 2 0.7–3.3 .99
Vd/F (mL/kg) 552 1 412.9–747.8 378 2 175.9–710.1 .16
CLss/F (mL/kg/h) 29.6 1 19.6–41.2 29.2 2 12.6–56.6 .99
AUC120-∞ (h × μg/mL) 77.9 2 42.1–115.1 72.4 2 22.1–297.8 .99
t1/2λ (h) 12.9a 1 10.3–19.9 9.4a 1 5.6–12.3 .02
λz (h−1) 0.05 1 0.03–0.06 0.07 1 0.06–0.12 .05

Results are presented in geometric means with SD and range.

Parameters included are maximum plasma concentration (Cmax), volume of distribution per fraction of drug absorbed (Vd/F), clearance per fraction of drug absorbed at steady state (CLss/F), area under the curve extrapolated to infinity (AUC0-∞), terminal elimination half-life (t1/2λ), and slope of terminal phase (λz).

aValues with different superscripts are significantly (P < .05) different.

Table 2

Milk pharmacokinetic parameters of meloxicam administered orally for multiple doses at 1.0 mg/kg in dairy cattle.

Postpartum (n = 6) Mid-lactation (n = 8) P value
Mean SD Range Mean SD Range
Cmax (μg/mL) 0.3 2 0.2–1.5 0.3 1 0.2–0.5 .62
CLss/F (mL/kg/h) 164 1 95.8–284.8 155 1 90.9–25.0 .71
AUC120-∞ (h × μg/mL) 17.5 2 9.2–25.7 19.6 2 7.4–66.5 .39
t1/2λ (h) 10.7 1 9.5–13.0 9.6 1 7.6–12.9 .09
λz (h−1) 0.06 1 0.05–0.07 0.07 1 0.05–0.09 .07
AUC120−264 (milk)/AUC120–264 (plasma) 0.2 1 0.1–0.3 0.3 1 0.2–0.4 .46

See Table 1 for key.

Data are reported in geometric means with SD and range.

The plasma t1/2λ was significantly increased in PP cows (12.9 ± 1.3 hours) when compared to ML cows (9.3 ± 1.3 hours). This difference was not identified in milk t1/2λ between groups. For cows administered meloxicam, 5 of 7 PP and 4 of 7 ML cows had measurable plasma concentrations 120 hours following the final dose. The original study design had all cows receiving meloxicam and only Group II receiving both meloxicam and gabapentin. A t-test was performed comparing the meloxicam concentrations (milk and plasma) in cows administered gabapentin vs no gabapentin and found no differences in meloxicam concentrations. The milk and plasma meloxicam concentrations were not affected by gabapentin administration in either group so cows administered meloxicam were evaluated as 1 group (either PP or ML).

Gabapentin

The noncompartmental pharmacokinetic parameters for multiple doses of gabapentin are summarized for both plasma (Table 3) and milk (Table 4) in PP and ML cows. Plasma concentrations of gabapentin were depleted below LOD in all cows 72 hours after final dose.

Table 3

Plasma pharmacokinetic parameters of gabapentin administered orally for multiple doses at 20 mg/kg in dairy cattle.

Postpartum (n = 3) Mid-lactation (n = 4) P value
Mean SD Range Mean SD Range
Cmax (μg/mL) 2.5 2 1.7–3.6 2 1 1.3–2.6 .63
Vd/F (mL/kg) 3,569 1 2,722.5–4,645.0 6,700 1 5,186.4–7,962.7 .99
CLss/F (mL/kg/h) 338.5 2 234.1–493.1 413.9 1 324.3–636.1 .63
AUC120-∞ (h × μg/mL) 63.3 1 53.1–82.3 56.4 2 25.8–99.6 .99
t1/2λ (h) 5.3 1 4.9–5.6 6.1 1 4.64–7.1 .88
λz (h−1) 0.1 1 0.1–0.14 0.11 1 0.1–0.2 .86

See Table 1 for key.

Data are reported in geometric means with geometric SD and range.

Table 4

Milk pharmacokinetic parameters of gabapentin administered orally for multiple doses at 20 mg/kg in dairy cattle.

Postpartum (n = 3) Mid-lactation (n = 4) P value
Mean SD Range Mean SD Range
Cmax (μg/mL) 0.5 1 0.4–0.6 0.86 1 0.7–1.1 .05
Vd/F (mL/kg) 15,477 1 14,755.8–15,870.5 10,540.7 2 6,201.8–13,615.1 .22
CLss/F (mL/kg/h) 2,418.9 1 1,984.1–2,824.9 1,206.5 1 845.2–1,543.2 .05
AUC120–264 (h × μg/mL) 18.5 2 13.1–28.8 21 1 14.7–28.0 .85
t1/2λ (h) 4.4 1 3.9–5.5 6.1 1 5.1–6.9 .4
λz (h−1) 0.2 1 0.1–0.2 0.1 2 0.1–0.1 .4
AUC120−264 (milk)/AUC120–264 (plasma) 0.3 1 0.3–0.4 0.4 2 0.2–0.6 .4

See Table 1 for key.

Data are reported in geometric means with geometric SD and range.

Concentrations in milk fell below the current study’s LOD (0.01 µg/mL) by 120 hours and 60 hours for meloxicam and gabapentin respectively following the final administered dose in all cows.

Discussion

There are currently no analgesic drugs labeled for pain control in lactating dairy cattle in the US and previous reports evaluated pharmacokinetics following single doses of meloxicam and/or gabapentin. Studies evaluating meloxicam and gabapentin concentrations following multiple doses are necessary for judicious extra-label drug use of analgesics in dairy cattle.

Overall, lactation status had a minimal impact on plasma pharmacokinetics and milk distribution of either meloxicam or gabapentin. In the PP period, dairy cattle undergo significant physiologic changes that may impact the absorption, distribution, metabolism and elimination of many therapeutics. Current estimated pharmacokinetic parameters for dairy cattle administered meloxicam have been derived from plasma concentrations and are limited to a single oral, SC, IM, or IV dose. Plasma Cmax from the current study was similar to previously reported values after 24 hours in dairy cattle administered meloxicam (1 mg/kg) and/or gabapentin (20 mg/kg) orally, in PP and ML cows.68 Postpartum dairy cattle have demonstrated increased maximum plasma concentrations of meloxicam when compared to ML cows following a single oral dose, which was not identified in our study for either gabapentin or meloxicam.7,8 A difference in our targeted sampling times may limit the evaluation of maximum concentration. Our study sampled plasma concentrations only at 24 hours after each dosing, therefore our blood sampling time points did not encompass the true physiologic Cmax in plasma.

Another possible explanation for this difference may also be due to bioavailability. Only when a drug is injected IV can we assume complete systemic bioavailability (F = 100%). Bioavailability of meloxicam has been reported in PP cows at 101.6% versus ML cows at 87.2% following oral administration of meloxicam, which would possibly explain highly variable plasma concentrations in both groups.8 Similar variability in multiple dose regimens have been observed in sheep following multiple oral doses of meloxicam at 1 mg/kg.11 Due to lack of a formulation available for IV administration of gabapentin, the bioavailability was not able to be determined for cows administered gabapentin.

In the current study, an increased average apparent volume of distributions following meloxicam administration were noted in PP cows (551.9 ± 1.3 mL/kg) than ML cows (378.2 ± 1.7 mL/kg), although not statistically significant. The opposite was noted for gabapentin, where ML cows demonstrated higher Vd/F as compared to PP cows. Volume of distribution is the apparent volume needed to account for the total amount of drug in the body if the drug was evenly distributed throughout the body and in the same concentration as the site of sample collection such as peripheral venous plasma.12 Volume of distribution is directly proportional with the amount of drug distributed into tissue. Drugs with larger Vd/F can indicate a greater amount of tissue distribution, leading to potentially violative residues in edible tissues. Drugs that are extensively bound to plasma proteins may have a low volume of distribution and may have prolonged plasma half-lives. Although not evaluated in this study, future research should examine the extent of plasma protein binding of meloxicam at different stages of lactation to evaluate the unbound fraction of meloxicam and gabapentin in plasma.

Warner et al8 investigated differences in plasma pharmacokinetics of PP and ML cows following IV and PO administration of meloxicam. This revealed that PP cows had lower clearance, which resulted in a longer estimated terminal half-life and increased systemic exposure in PP cows.8 CLss/F of meloxicam in PP cows in the current study did not differ significantly from ML cows, and had similar values (approx 0.03 L/kg/h) reported following single dose studies.9 No differences in CLss/F was noted between PP and ML cows administered gabapentin. The current study did not evaluate absolute bioavailability in each group for each drug, so the CLss/F and Vd/F values may not reflect the true clearance of either drug in cattle.

The terminal plasma half-life of meloxicam was significantly increased in PP cows (12.9 hours) compared to ML cows (9.4 hours), similar to previously reported studies.7,8 Small sample size and high interindividual variability of individual parameters of volume of distribution and clearance values may account for the lack of difference noted in these variables but a significant increase in the PP cows elimination half-life, which is dependent on both volume of distribution and systemic clearance.

For both meloxicam and gabapentin, milk concentrations depleted to concentrations that were below the LOD (0.01 µg/mL) of the analytical technique within approximately 4 days following the final dose. However, the authors recognize that tolerances for meloxicam and gabapentin have not been established for any target tissues in cattle in the US, therefore any residue detected is violative.

The milk pharmacokinetic parameters from this study are comparable to those previously reported in dairy cattle administered meloxicam and/or gabapentin.6,7 Clearance from milk at steady state of meloxicam was 164.4 ± 1.4 mL/h, similar to previously calculated milk clearance (166.5 ± 82.2 mL/h), confirming that milk from treated cows will have low drug concentrations soon after plasma drug concentrations have fallen below effective levels even after multiple doses.6

Lactation has been reported to affect the pharmacokinetics of some drugs by means of drug penetration into milk.13 In general, drug penetration into milk can be described using the AUCmilk/plasma ratio. A ratio value over 1 indicates relatively higher drug contents in the milk compared to blood with the potential for drug milk accumulation. Milk to plasma ratio was higher in the current study for meloxicam (approximately 0.2) as compared to previous reports in cattle (0.14), but lower than ratios reported in lactating goats (0.3).14 The most likely reason for this difference is the lower plasma AUC reported for meloxicam and gabapentin in our study, likely due to sampling times and differences in bioavailability, which would decrease our calculated plasma AUC and therefore account for the higher ratio. Unlike previous reports in cattle, pharmacokinetic parameters of meloxicam were not significantly altered by lactation for either the IV or IM routes of administration in lactating goats.14 Although cows that were administered gabapentin had a higher CLss in milk and increased milk to plasma ratio, this is likely due to a suspected lower oral bioavailability.

Two cows were eliminated from the original study enrollment. One PP cow was diagnosed with post parturient hemoglobinuria the morning of the third dose of meloxicam. The diagnosis was made by recognition of clinical signs, particularly dark urine and anemia from a complete blood count and a low blood phosphorus concentration. Although milk data was not included in the final analysis, the authors have highlighted the impact of disease on this cow’s milk residues (Supplementary Figure S1). A second PP cow administered meloxicam only was eliminated from the final data set due to a diagnosis of clinical mastitis at onset of trial. Clinical mastitis prolonged milk residues in this cow (Supplementary Figure S2). Meloxicam was detected in milk of both cows at concentrations exceeding the European Union maximum residue limit at 164 hours following the final dose. Disease has been shown to alter the distribution and metabolism of drugs in cattle, particularly highly protein-bound drugs including NSAIDs.15 Thus, it is likely that the current withdrawal interval recommendations, which was determined on the basis of pharmacokinetic data obtained from a reference population of healthy animals, likely underestimate the time required for tissue clearance of the drug to below tolerances in diseased animals. Therefore, data obtained from both healthy and diseased animals should be considered to more accurately estimate the withdrawal interval for drugs administered to food-producing species under normal practice conditions.

The intent of the present study was not to endorse extra-label use of drugs in lactating dairy cattle over the currently available FDA-approved options. Rather, the doses and residue data reported here could serve as a starting point for additional studies to explore the effectiveness of these drugs in the multi-modal treatment of pain in lactating cattle.

In summary, cows administered multiple doses of meloxicam and/or gabapentin showed low drug residue concentrations and little accumulation, regardless of location status. The results of this study suggest that milk from healthy cows treated with multiple doses of meloxicam alone or in combination with gabapentin will have low drug concentrations and falls below our reported LOD for meloxicam or gabapentin 120 and 60 hours respectively, following the final dose. Future efficacy studies are needed to evaluate the clinical usefulness of administering these drugs for the long-term control of pain in food-producing animals.

Acknowledgments

The authors thank Dr. Mark Papich and Delta Dise of the Clinical Pharmacology Program at North Carolina State University for their assistance in assay development.

Disclosures

The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.

Funding

Funding for this study was provided by the American Association of Bovine Practitioners and the Hoof Trimmers Association.

Supplementary Materials

Supplementary materials are posted online at the journal website: avmajournals.avma.org

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