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Keywords:

  • COX ;
  • Cyclcooxygenase;
  • Gastric ulceration;
  • Horse;
  • Nonsteroidal anti-inflammatory drugs;
  • NSAIDs;
  • Right dorsal colitis

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Background

The pharmacokinetics, efficacy, and safety of meloxicam have been evaluated in adult horses, but not foals. Physiologic differences between neonates and adults might alter drug pharmacokinetics and therapeutic index.

Hypotheses

The pharmacokinetics of meloxicam will be different in foals compared with adult horses, and foals could be at increased risk for adverse drug effects.

Animals

Twenty lightbreed foals less than 6 weeks of age at commencement of the study.

Methods

Single and repeated oral dose pharmacokinetics were determined for meloxicam (0.6 mg/kg) in 10 foals. The safety of the drug was further evaluated in a 2nd group of 10 foals in a randomized blinded prospective study.

Results

Plasma concentrations after a single oral dose of meloxicam (0.6 mg/kg) and time to maximum plasma concentration were similar to adult horses. However, drug clearance was much more rapid in foals (elimination half-life 2.48 ± 0.25 hours). Administration of 0.6 mg/kg every 12 hours was well tolerated by foals for up to 3 weeks, with no evidence of drug accumulation in plasma. Adverse effects observed in adult horses at higher dose rates were not observed in foals given 1.8 mg/kg twice daily for 7 days.

Conclusions and clinical importance

Meloxicam at an oral dose rate of 0.6 mg/kg every 12 hours provided plasma concentrations likely to be therapeutic. In contrast to findings for other NSAIDs, foals appeared more resilient to the adverse effects of this drug than was observed in adult horses.

Abbreviations
COX

cyclooxygenase

NSAIDs

nonsteroidal anti-inflammatory drugs

PBZ

phenylbutazone

PO

per os

SEM

standard error of mean

SD

standard deviation

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogenous group of compounds widely used in veterinary practice for their anti-inflammatory, analgesic, and antipyretic effects. These beneficial effects are achieved by inhibition of the cyclooxygenase enzyme (COX), which catalyzes the rate limiting step in prostanoid production from membrane-derived phospholipids and arachidonic acid, and the consequent reduction in the formation of proinflammatory mediators (prostaglandins, prostacyclin, and thromboxanes).

Adverse effects associated with the administration of NSAIDs include ulceration of the stomach or right dorsal colon and, less commonly, renal damage. Foals are believed to be at increased risk for such effects.[1, 2] The absorption, distribution, metabolism, and elimination of medication might vary in young animals relative to adults attributable to physiologic differences, particularly increased total body water, increased extracellular fluid compartment, lower serum protein concentrations (important for drugs, which demonstrate a high degree of plasma protein binding), and impaired drug metabolism. To date, only 4 NSAIDs have been specifically evaluated in foals. Phenylbutazone,[1, 3] flunixin,[4] ketoprofen,[5] and ibuprofen[6] all have an increased volume of distribution and prolonged clearance in healthy foals. For these reasons, dose rates and dose intervals might require adjustment for treatment of foals.

Meloxicam is a potent anti-inflammatory of the oxicam class. Previous studies[7-10] have demonstrated analgesic and anti-inflammatory effects after oral administration to adult horses and more selective COX2 inhibition in vitro.[11, 12] The aims of this study were to determine plasma concentrations achieved after single and multiple oral doses of meloxicam to healthy foals less than 6 weeks of age, and to evaluate the safety of this drug in these animals.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

This study was conducted in 3 parts, over 2 consecutive breeding seasons: the pharmacokinetics of a single oral dose of meloxicam1 were investigated in Part I; in Part II, the pharmacokinetics of repeated daily doses were investigated; and in Part III, the safety of an increased dose rate and increased duration of treatment were investigated.

Experimental Animals

Part I comprised 10 Thoroughbred foals (3 colts, 7 fillies) of age 2–23 days at the commencement of the study; six of these foals (3 colts and 3 fillies, mean age 24 days) continued in Part II of the study. Four foals received 0.6 mg/kg meloxicam PO every 12 hours for 14 days and 2 foals were untreated controls, receiving the vehicle only. Treatment (meloxicam or vehicle) was assigned by random number generation. In Part III, conducted the following season, a further 10 lightbreed (Thoroughbred and Standardbred) foals (9 colts and 1 filly) were randomly assigned to treatment groups (Table 1).

Table 1. Experimental design. Studies were conducted in 3 parts over 2 consecutive breeding seasons. Part I involved 10 Thoroughbred foals, six of which were available for Part II of the study. In Part III, conducted during the subsequent breeding season, 10 lightbreed (Thoroughbred or Standardbred) foals were randomly assigned to 3 treatment groups: Group 1 received meloxicam (0.6 mg/kg q12 h) PO for 3 weeks commencing within 5 days of birth; the single Group 2 foal received an equivalent volume of product vehicle only (placebo) for 3 weeks. After a 7-day washout, Group 1 and Group 2 foals received 3 times the initial dose rate (1.8 mg/kg PO q12 h) for a further 7 days. Group 3 foals received 3 times the higher dose rate (1.8 mg/kg PO q12 h) for 7 days, commencing within 3 days of birth. Age and weight at the commencement of study are given as mean ± SEM
Study GroupSexAge at Commencement of StudyWeight at Commencement of Study

Part I

n = 10

0.6 mg/kg meloxicam PO (once)

3 colts,

7 fillies

11.2 ± 2.2 days

(2–23 days)

71.9 ± 5.3 kg

(53.5–96.5 kg)

Part II    

Group A

n = 4

0.6 mg/kg meloxicam PO every 12 hours for 14 days3 colts, 3 fillies

24.3 ± 3.8 days

(17–33 days)

89.8 ± 8.5 kg

(64.5–101.0 kg)

Group B

n = 2

Placebo treatment (vehicle only) for 14 days 

24.0 ± 3.0 days

(21–27 days)

94.7 ± 12.7 kg

(82.0–107.5 kg)

Part III    

Group 1

(1× then 3×)

n = 5

0.6 mg/kg meloxicam PO every 12 hours for 21 days; followed by 7 day ‘washout’ period and then 1.8 mg/kg meloxicam every 12 hours for a further 7 days

4 colts,

1 filly

3.6 ± 0.7 days

(2–5 days)

52.6 ± 4.6 kg

(47.0–74.5 kg)

Group 2

(placebo then 3×)

n = 1

Placebo treatment (vehicle only) for 21 days; followed by 7-day ‘washout’ period and then 1.8 mg/kg meloxicam every 12 hours for a further 7 days1 colt4 days64.0 kg

Group 3

(3×) n = 4

1.8 mg/kg meloxicam PO every 12 hours for 7 days4 colts

2.3 ± 0.3 days

(2–3 days)

63.1 ± 0.7 kg

(36.0–76.5 kg)

Parturition was observed for all foals. All foals remained with their dams for the duration of the study. Mare-foal pairs were individually stabled and mares were fed a maintenance ration of lucerne hay (ad lib) supplemented with a pelleted complete feed to cover increased metabolic demands associated with lactation. Foals were considered healthy and suitable for inclusion in the study if they were of normal demeanor and mentation, nursing well and demonstrating acceptable daily weight gains (1–2 kg every 2–3 days), and with no evidence on serum biochemistry of renal or hepatic compromise. A number were treated for abnormalities in the immediate postpartum period including profuse diarrhea and neutropenia (1 foal), septic physitis (1 foal), failure of passive transfer (2 foals), and flexor laxity (2 foals). Posthoc evaluation suggested that results from these foals were within the range of values obtained from other foals in the same treatment group, so data were retained in all subsequent analyses.

An overview of clinical and laboratory examinations performed on foals in each treatment group is provided (Table 2). All foals were examined twice daily, or more frequently as required, for the duration of the study. Staff members responsible for the daily care and veterinary examination of foals were blinded to meloxicam treatment. Throughout the study, foals were weighed daily. Blood was collected twice weekly by jugular venipuncture for routine hematology and serum biochemistry (including total protein, albumin, globulin, urea, creatinine, sodium, potassium, chloride, total calcium, phosphate, magnesium, bicarbonate, glucose and bilirubin concentrations, and serum activity of alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and creatine kinase) performed by a commercial laboratory,2 except for Part I foals, where hematology and serum biochemistry were evaluated immediately before and 24 hours after a single treatment. During Part III of the study, feces were collected twice weekly for fecal occult blood determination using guaiac-based slides3 as reported for adult horses.[13] Urine was collected weekly by free catch or urethral catheterization from all foals in Parts II and III, and urine analysis was performed on all samples by reagent strip and urine enzyme analysis. Sediment examination was performed within 4 hours of collection on all urine samples that returned a positive result for protein. Reagent strip and sediment examination were performed at Charles Sturt University, within 120 minutes of sample collection. Samples for urine enzyme analysis were chilled (4°C) within 30 minutes of collection and dispatched overnight on ice to a commercial laboratory2 for analysis. Results were expressed relative to urine creatinine concentration (mmol/L).

Table 2. Sample and diagnostic schedule for study foals. Staff members responsible for subjective diagnostic procedures (physical examination, gastroscopy, and ultrasonography) were blinded to treatment
 Part IPart IIPart III
Group AGroup BGroup 1Group 2Group 3
Physical examinationTwice dailyTwice dailyTwice dailyTwice dailyTwice dailyTwice daily
Body weightPre- and 24 hours post treatmentDailyDailyDailyDailyDaily
Hematology & serum biochemistryPre- and 24 hours post treatment

Twice weekly

(Day 0, 3, 6, 10, 13, 17)

Twice weekly

(Day 0, 3, 6, 10, 13, 17)

Twice weekly

(Day 0, 3, 6, 10, 13, 17, 20; Day 28, 31, 35, 38)

Twice weekly

(Day 0, 3, 6, 10, 13, 17, 20; Day 28, 31, 35, 38)

Twice weekly

(Day 0, 3, 6, 10)

Fecal occult blood testPre- and 24 hours posttreatment

Twice weekly

(Day 0, 3, 6, 10, 13, 17)

Twice weekly

(Day 0, 3, 6, 10, 13, 17)

Twice weekly

(Day 0, 3, 6, 10, 13, 17, 20; Day 28, 31, 35, 38)

Twice weekly

(Day 0, 3, 6, 10, 13, 17, 20; Day 28, 31, 35, 38)

Twice weekly

(Day 0, 3, 6, 10)

Gastroscopy 

Weekly

(Day 0, 6, 13)

Weekly

(Day 0, 6, 13)

Weekly

(Day 0, 6, 13, 20; Day 28, 35)

Weekly

(Day 0, 6, 13, 20; Day 28, 35)

Weekly

(Day 0, 6)

Abdominal ultrasound 

Weekly

(Day 0, 6, 13)

Weekly

(Day 0, 6, 13)

Weekly

(Day 0, 6, 13, 20; Day 28, 35)

Weekly

(Day 0, 6, 13, 20; Day 28, 35)

Weekly

(Day 0, 6)

Urinalysis

(reagent strip & urine enzymes)

 

Weekly

(Day 0, 6, 13)

Weekly

(Day 0, 6, 13)

Weekly

(Day 0, 6, 13, 20; Day 28, 35)

Weekly

(Day 0, 6, 13, 20; Day 28, 35)

Weekly

(Day 0, 6)

Gastroscopy was performed at the commencement of the study, and weekly for the duration of Part II and Part III with a 3-m endoscope4 (outer diameter 9.8 mm). Lesions of the squamous and glandular gastric mucosa were graded subjectively as previously described[14] by 2 independent observers (SLR and GN) blinded to treatment. Foals were sedated for this procedure with either diazepam (0.1–0.2 mg/kg IV) or xylazine (0.1–0.3 mg/kg IV). Right abdominal ultrasound5 was performed weekly for foals in Parts II and III according to published techniques[15-17] by means of a 7.5–5 MHz microconvex array, a 8–1 MHz convex array, or both, to evaluate the right intestinal tract and right kidney.

All procedures were approved by the Animal Care and Ethics Committee at Charles Sturt University (ACEC Approval Numbers 07/114 and 08/099). Approval for gastroscopy was conditional on foals not being fasted before the procedure. All foals were rehomed or returned to their previous owner at the completion of the study.

Plasma meloxicam concentrations were determined on venous blood samples collected according to the following schedule:

Part I: A single oral dose of 0.6 mg/kg of meloxicam, delivered as a 12 mg/mL suspension, was given to each foal at 8 am on the day of treatment, after collection of pretreatment blood samples for pharmacology and clinical pathology. Blood samples were withdrawn from indwelling jugular or cephalic venous catheters at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 36, 48, 72, and 96 hours after treatment.

Part II: Blood was collected by jugular venipuncture from Group A (0.6 mg/kg PO q12 h) and Group B (placebo) foals immediately before (trough concentrations) and 2 hours after each morning dose. Additional samples were taken at the same time points relative to the evening dose on Day 0. The elimination half-life after chronic dosing was determined by taking blood samples immediately before and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 12 hours after the final dose.

Part III: Group 1 (meloxicam 0.6 mg/kg PO q 12 h) foals were sampled via jugular catheters at the following intervals: 0 (immediately before dosing), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 8, and 12 hours post administration on treatment Days 0, 7, and 21. The sole member of Group 2 (F17) received a placebo treatment (vehicle only) and was subjected to an identical blood collection schedule. After a 7-day ‘washout’ period, Group 1 and 2 foals received a higher meloxicam dose (1.8 mg/kg PO q 12 h) for a further 7 days. These foals were sampled during this period as described below for Group 3 foals. Note that the age at which these foals received the higher dose (mean 31.4 ± 0.5 days at commencement of this part of the study) was significantly greater than that of Group 3 foals receiving the same dose (mean age 2.3 days at the commencement of the study). Samples from treatment Group 3 (meloxicam at 1.8 mg/kg PO q 12 h) foals were obtained on Days 0, 3, and 7 at the following intervals: 0 (immediately before dosing), 0.5, 1, 1.5, and 12 hours post administration. Excretion data were determined by sampling foals 24, 48, and 72 hours after their final dose. Sham collections were performed at other times to preserve blinding of personnel responsible for foal care.

All samples were kept at room temperature before separation of plasma by centrifugation within 2 hours of collection, and were thereafter stored at −20°C before evaluation by high performance liquid chromatography (UPLC) with UV detection, using piroxicam as an internal standard for meloxicam assays followed by protein denaturing using acetonitrile, as previously described.[14] Method precision was assessed by analyses of 6 replicate assays performed on fortified plasma samples from 4 foals containing meloxicam (20–1500 ng/mL). Coefficients of variation for replicate analyses were considered within limits set for this plasma study (<3%).

Pharmacokinetic Analysis

Pharmacokinetic parameters were determined for each horse by noncompartmental analysis with a commercial software program.6 Maximum plasma concentration (Cmax) of meloxicam and time to Cmax (tmax) were read directly from the data. Terminal half-life (t½) was determined by log-linear regression. All results are expressed as mean ± SD.

Statistical Analysis

Clinical pathology results obtained before and after a single dose of meloxicam (Group I foals) were compared by paired t-test. In Parts II and III of the study (repeated administration of meloxicam), body weight and clinical pathology results were compared between treatment groups by two-way repeated measures analysis of variance with time of collection and treatment group as fixed effects, after checking for normal distribution and equal variance. Multiple pairwise comparisons were performed within and between groups by the Tukey test when a significant time or treatment effect was determined. Results are reported as mean ± SEM. Given small numbers of foals in each group and limitations with the assessment of ordinal data,[18] results of gastroscopic evaluation of squamous and glandular mucosa for each foal are presented as raw data only.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Part I

As is evident in Figure 1, the administration of a single dose of 0.6 mg/kg meloxicam to foals resulted in a peak plasma concentrations approximating 1,000 ng/mL. Foals demonstrated rapid apparent oral clearance of meloxicam (154 ± 5.92 mL/kg/h), higher than observed in any adult studies. Consequently, the elimination half-life (2.48 ± 0.25 hours) was less than that reported for adult horses (10.24 ± 3.04 hours). On the basis of these results, a treatment interval of 12 hours was investigated in foals.

image

Figure 1. Plasma meloxicam concentrations after administration of a single oral dose to 10 foals and 10 adult horses in a previous study.[14] Results are presented as mean ± SD.

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No adverse effects were apparent upon physical examination of treated foals. Routine hematology and serum biochemistry results before and 24 hours after the administration of a single dose of meloxicam were available for 6 foals. Comparison of clinical pathology results obtained before and after medication by paired t-test demonstrated no significant differences, except for serum sodium (Na+) concentrations, which were increased in posttreatment samples, from 135 ± 1 mmol/L to 138 ±1 mmol/L (mean ± SEM) (P = .005).

Part II

Repeated dosing of meloxicam (0.6 mg/kg q12 h) was associated with peak plasma concentrations between 500 and 1200 ng/mL, and trough concentrations of approximately 100 ng/mL (Fig 2). The drug did not appear to accumulate as the elimination half-life after chronic administration (3.15 ± 0.19 hours) was similar to that obtained after a single dose, suggesting that drug elimination was unchanged by repeated administration. All foals remained well for the duration of the study and there were no abnormalities in clinical parameters evident in any foal. Average daily weight gain (1.48 ± 0.1 kg, mean ± SEM) was consistent with normal growth rates for both groups, and there was no difference between groups.

image

Figure 2. Repeated doses of meloxicam given to 4 foals (0.6 mg/kg PO every 12 hours for 14 days). Results are given as mean ± SD from samples collected before morning medication (trough) and 2 hours after morning medication (peak). Samples were obtained before and after the initial evening dose (Day 0) and on multiple occasions after the final dose (Day 14).

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Results of hematology and serum biochemistry assays demonstrated no clinically significant differences between treated and control foals. Pooled results from both groups demonstrated a significant time of collection effect in some parameters (notably hemoglobin, PCV, glucose, and GGT). Decreases in these parameters during the experimental period could reflect progressive acceptance of handling procedures by foals and physiologic adaptations during the first weeks of life. Significantly, there was no evidence of changes in serum urea or creatinine concentrations, nor in serum total protein or albumin concentrations.

Gastroscopic examination of all foals demonstrated minor changes (Grade 1) of dubious clinical significance before the commencement of the study in 3 (of 6) foals. Similarly, small, well-circumscribed areas of superficial ulceration (Grade 1) of the squamous or glandular mucosa adjacent to the margo plicatus were observed in 2 (of 4) treated foals, and 1 (of 2) control foals. Abdominal ultrasound was unremarkable on all occasions and fecal occult blood testing was negative on all occasions. Urinalysis was unremarkable on all occasions and no increase in urine enzyme concentrations was evident.

Part III

All foals receiving meloxicam (0.6 mg/kg PO q12 h) for 3 weeks (Group 1) and receiving the higher dose (1.8 mg/kg PO q12 h) for 7 days in week 1 or week 4 of life remained well for the duration of the study. All study foals developed self-limiting diarrhea during the course of the study, typically commencing at 5–6 days of age. None of the foals required treatment. One foal (F18, Group 1) developed pyrexia and a mucoid nasal discharge at 13 days of age. He was treated with procaine penicillin for 3 days and recovered uneventfully. All foals in Part III demonstrated a growth rate of approximately 1.77 ± 0.14 kg/d (mean ± SEM), comparable to that observed in Part II and industry standards.

Plasma meloxicam concentrations, determined for foals receiving 0.6 mg/kg PO every 12 hours on Day 0, Day 7, and Day 21, were not different from results obtained after a single dose (Part I). The administration of the higher dose (3.0 mg/kg PO q12 h) of meloxicam to Part III foals was associated with plasma meloxicam concentrations ranging from 970 to 6,239 ng/mL (Fig 3).

image

Figure 3. Plasma meloxicam concentrations after the oral administration of 1.8 mg/kg PO every 12 hours to 10 healthy foals (combined data from Groups 1 and 3), compared with previous results from studies in adult horses.14 Results are shown as mean ± SD.

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Routine hematology and serum biochemistry before commencing the study demonstrated minor deviations from laboratory reference ranges. Hematology results demonstrated no significant change in erythrocyte parameters (red blood cell count, hemoglobin concentration, or packed cell volume) associated with repeated administration of meloxicam at either dose rate. As in Part II, a gradual decrease in hematocrit and hemoglobin concentration was observed across all treatment groups and was considered likely to be an age-related change. Platelet, lymphocyte, and monocyte numbers did not change significantly associated with treatment. Although total leukocyte and neutrophil numbers increased significantly for Group 3 foals, results were within age-appropriate laboratory reference ranges (5.5–12.5 × 109/L and 3.99–10.55 × 109/L, respectively) on Day 3 and at the completion of the study for all Group 3 foals, and this finding was considered of no biological importance.

Treatment was not associated with any change in plasma total protein, albumin (Fig 4), globulin, or fibrinogen concentrations. Other serum biochemistry parameters, including serum creatinine and urea, did not change significantly during the course of the study. Urinalysis demonstrated a trace of blood on 2 occasions for 1 foal (Group 1, Days 14, and 21), a trace of protein on 1 occasion for another Group 1 foal (Day 28), and iatrogenic hemorrhage associated with catheterization on 2 occasions for a 3rd foal (Group 3). Microscopic examination of urine sediment at these times was unremarkable. Urine ALP and GGT concentrations were highly variable throughout the study, and did not increase associated with treatment.

image

Figure 4. Serum albumin concentrations for all treatment groups (mean ± SEM) and compared with Group B (control) foals from Part II of this study. Analysis of variance demonstrated no significant effect attributable to treatment group (P = .056), time of collection (P = .885), or interaction between factors (P = .430). Laboratory reference ranges, adapted from previous studies,[40] are 18–38 g/L for 2- to 7-day-old foals, 21–39 g/L for 8- to 14-day-old foals, and 25–40 g/L to 6 weeks of age.

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Gastroscopy of Part III foals demonstrated Grade 1 lesions of the squamous mucosa (2 foals) or Grade 1 lesions of the glandular mucosa (2 foals) before treatment. Grade 1 lesions of the squamous mucosa were present at the end of treatment in only 1 foal receiving the lower dose rate of meloxicam. A 2nd foal developed minor (Grade 1) lesions of the glandular mucosa, characterized by a single small lesion evident on the glandular mucosa. The pyloric antrum could not be clearly visualized for 2 foals during the final 2 weeks of the study, although areas of glandular mucosa evident during examination were considered normal. Of 4 foals administered 1.8 mg/kg of meloxicam during the 1st week of life (Group 3), only 1 foal had Grade 1 lesions of the squamous mucosa, similar to findings on Day 0 for this foal. Of 6 foals receiving 1.8 mg/kg PO in the 3rd week of life (Group 1), 1 foal developed Grade 2 lesions of the squamous mucosa during the 7 days of treatment. Grade 1 lesions were noted in this foal, and 2 others, before 1st treatment. For the other 2 foals, lesions healed or were unchanged during treatment. Lesions of the glandular mucosa were not appreciated in the 5 foals where complete gastroscopic examinations were possible after 7 days treatment at 1.8 mg/kg.

Abdominal ultrasound demonstrated normal thickness of the wall of the right dorsal colon and normal renal parenchyma for all foals at every examination. Fecal occult blood tests were positive on a single occasion only (Group 1, Day 19) and did not correlate with gastroscopic findings.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

This study demonstrated that oral administration of meloxicam to foals less than 2 weeks of age yielded peak plasma concentrations approximating 1,000 ng/mL, consistent with results obtained from adult horses in earlier studies by our group.[14] In whole-blood assays, maximal inhibition of COX2 (circa IC80), with minimal COX1 effects, has been observed at meloxicam concentrations of approximately 1,000 ng/mL (10−5.5M).[11] Similar values have been reported to decrease lameness and joint inflammation in adult horses[7, 9] and to have anti-inflammatory effects in vitro.[12] Hence, plasma concentrations demonstrated in these studies are likely to be therapeutic in foals. However, plasma concentrations decreased rapidly after oral administration such that, despite a 12-hour dose interval, trough plasma concentrations were slightly lower (approximating 100 ng/mL) than we reported for adult horses treated every 24 hours (200 ng/mL).[14] Consistent with studies in adult horses, foals demonstrated rapid absorption of meloxicam after oral administration (Tmax < 1.5 hours). Although oral bioavailability has not been reported in foals, our results suggest that values of 85–98% reported in adult studies[19] are likely to be accurate for foals.

As evident in this study, differences in pharmacokinetics are observed commonly between adults and neonates or juveniles, and mandate determination of paediatric dosing schedules. The clearance of meloxicam after oral administration to foals was more rapid than has been reported for adult horses.[8-10, 14, 19, 20] Although clearance of NSAIDs is typically prolonged in foals/neonates,[3, 4, 21] our findings are consistent with human pediatric studies, where the clearance of meloxicam was increased in juvenile patients.[22] The metabolism and elimination of meloxicam by adult horses differs slightly from reports in other species,[23] but in all species studied to date, the compound is metabolized by hepatic oxidation utilizing the cytochrome P450 2C subgroup to 4 principal, inactive metabolites, which are then excreted in urine and feces.[24, 25] As only very low levels of parent compound are present in urine, bile, or feces, meloxicam is evidently cleared almost exclusively by metabolism, and biotransformation governs elimination in all species studied to date.[26] Although limited in vitro data suggest that carrier mediated uptake is deficient in infants,[27] phase 1 and phase 2 enzyme systems mature rapidly (reviewed by Bartelink et al[28]). Although species differences might exist, the CYP2C enzyme systems are among the most abundant liver enzymes,[29] and liver volume normalized to body weight is inversely proportional to age. Hence, children or young animals have a relative abundance of this enzyme system, facilitating rapid drug clearance by this pathway,[30] and likely governing the rapid elimination of drug by foals in our study.

Because of rapid drug elimination, a dose frequency of 12 hours was selected for foals in this study. Elimination of meloxicam in horses and particularly donkeys is more rapid than reported in other species.[20] Although plasma concentrations of meloxicam do not coincide with peak anti-inflammatory effects,[10] the rapid clearance of meloxicam by foals less than 7 weeks of age suggests that dose intervals less than 12 hours could be considered, but this was not evaluated in this study. As for many NSAIDs with rapid clearance and short half-life values in species of veterinary interest,[31] preferential accumulation and relatively slow clearance from inflammatory exudates could prolong the efficacy of meloxicam beyond what might be predicted from plasma concentration–time profiles,[10, 20] in which case a longer treatment interval may be satisfactory. The administration of repeated doses was well tolerated by healthy foals in our study, and was not associated with drug accumulation, as predicted with a dose interval approximately 4 times the chronic elimination half-life.[32]

Healthy foals appeared remarkably resistant to adverse effects associated with protracted administration of meloxicam and with the administration of a higher drug dose (1.8 mg/kg). On the basis of observed adverse effects associated with the administration of higher doses of meloxicam to adult horses,[14] and reports that foals might be more sensitive to the adverse effects of NSAIDs than adults, foals in this were treated for a shorter time (3 weeks) than adult horses in our previous study, and did not receive the highest dose (3.0 mg/kg PO) evaluated in that study. Foals in this study demonstrated maximum plasma meloxicam concentrations higher than adults receiving 1.8 mg/kg PO q24 h, and of approximately the same concentration as adults receiving 3.0 mg/kg PO q24 h in our previous studies.14 Plasma meloxicam concentrations greater than 2,000 ng/mL were associated with adverse effects in adult horses in our previous study, notably gastrointestinal protein loss, right dorsal colitis, myeloid dyscrasia, or renal damage. Gastroscopy changes in this study were minor and not substantively different during or after treatment when compared with pretreatment findings. It is possible that endoscopy could underestimate the occurrence of mucosal ulceration, particularly of lesions involving the glandular mucosa.[1, 33] However, there were no clinical or ultrasound changes that could be associated with gastrointestinal[14] or renal damage,[34, 35] and no foal in this study demonstrated changes in circulating white cell numbers or plasma protein concentrations. Such changes were clearly demonstrated associated with the administration of phenylbutazone or high doses of meloxicam to adult horses in our previous studies.[14] Decreased serum protein has been reported as a sensitive indicator of NSAID toxicosis in studies of adult horses[36, 37] and foals.[1, 38] The apparent safety of this drug in foals, relative to findings in adult horses, can likely be attributed to rapid drug clearance.

The findings of this study support the oral administration of meloxicam suspension at 0.6 mg/kg PO every 12 hours in healthy foals less than 7 weeks of age. While adverse effects reported with the administration to foals of high doses of other, nonselective, COX inhibitors such as phenylbutazone[1, 35, 38] and flunixin[2, 39] were not observed in this study, caution must be exercised in extrapolating these results, obtained from healthy foals, to the use of this drug in compromised neonates. Cardiovascular compromise in septic or compromised foals might decrease hepatic blood flow and hence delay or decrease metabolism. Although NSAIDs have demonstrated no effects on renal blood flow in euhydrated animals, the contribution of local prostaglandins in maintaining renal blood flow in the face of systemic dehydration or hypotension is well recognized and mandates care in the administration of meloxicam to compromised foals.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The assistance of Kellie Tinworth, Heather Clegg, Tara Campbell, Fiona Schneiders, Sarah Hanlon, Kristie Hann, Hunter Doughty, and Ken Jacobs is gratefully acknowledged. Equine science (Whitney Chapple, Freya Colvern, Fiona Edwards, Megan Glenn, Jaymie Loy, Sally Pitts, Alecia Sheridan) and veterinary science students (Naomi Bakker, Amanda-Lee Charman, Greg Dale, Shahid Khalfan, Tara Mills, Emily Roberts, Anneliese Seagar, Sarah Ward) assisted with sample collection.

This study was funded by Troy Laboratories.

Conflict of Interest Declaration: Joe Pippia was employed by Troy Laboratories at the time these studies were conducted.

Footnotes
  1. 1

    Ilium Meloxicam 12 Oral Suspension for Foals (12 mg/mL), Troy Ilium Pty Ltd, Smithfield, NSW, Australia

  2. 2

    Idexx Laboratories, Rydalmere, NSW, Australia

  3. 3

    Haemoccult Sensa, Beckman Coulter Australia Pty Ltd, Gladesville, NSW, Australia

  4. 4

    Olympus CV160, Ausvet Endoscopy, Melbourne, VIC, Australia

  5. 5

    MyLab70, Biosound; distributed by Medical Plus, Crows Nest, NSW, Australia

  6. 6

    Topfit 2.0, Gustav Fischer Verlag, Stuttgart, Germany

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References