Pharmacokinetic interactions between fexuprazan, a potassium-competitive acid blocker, and nonsteroidal anti-inflammatory drugs in healthy males.

Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open-label, multicenter, six-sequence, one-way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1-2 days in the second period. Serial blood samples for PK analysis were collected until 48- or 72-h post-dose at steady state. PK parameters including maximum plasma concentration at steady state (Cmax,ss) and area under plasma concentration-time curve over dosing interval at steady state (AUCτ,ss) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in Cmax, 19% in AUCτ,ss) were observed when co-administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for Cmax,ss and AUCτ,ss was 1.22 (1.02-1.46) and 1.19 (1.00-1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions.

The Evaluation of Meloxicam Nanocrystals by Oral Administration with Different Particle Sizes.

Meloxicam (MLX) is a non-steroidal anti-inflammatory drug used to treat rheumatoid arthritis and osteoarthritis. However, its poor water solubility limits the dissolution process and influences absorption. In order to solve this problem and improve its bioavailability, we prepared it in nanocrystals with three different particle sizes to improve solubility and compare the differences between various particle sizes. The nanocrystal particle sizes were studied through dynamic light scattering (DLS) and laser scattering (LS). Transmission electron microscopy (TEM) was used to characterize the morphology of nanocrystals. The sizes of meloxicam-nanocrystals-A (MLX-NCs-A), meloxicam-nanocrystals-B (MLX-NCs-B), and meloxicam-nanocrystals-C (MLX-NCs-C) were 3.262 ± 0.016 µm, 460.2 ± 9.5 nm, and 204.9 ± 2.8 nm, respectively. Molecular simulation was used to explore the distribution and interaction energy of MLX molecules and stabilizer molecules in water. The results of differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) proved that the crystalline state did not change in the preparation process. Transport studies of the Caco-2 cell model indicated that the cumulative degree of transport would increase as the particle size decreased. Additionally, plasma concentration-time curves showed that the AUC0-∞ of MLX-NCs-C were 3.58- and 2.92-fold greater than those of MLX-NCs-A and MLX-NCs-B, respectively. These results indicate that preparing MLX in nanocrystals can effectively improve the bioavailability, and the particle size of nanocrystals is an important factor in transmission and absorption.

Combination anesthetic therapy: co-delivery of ropivacaine and meloxicam using transcriptional transactivator peptide modified nanostructured lipid carriers in vitro and in vivo.

Combination therapy combining two drugs in one modified drug delivery system is used to achieve synergistic analgesic effect, and bring effective control of pain management, especially postoperative pain management. In the present study, a combination of drug delivery technologies was utilized. Transcriptional transactivator (TAT) peptide modified, transdermal nanocarriers were designed to co-deliver ropivacaine (RVC) and meloxicam (MLX) and anticipated to achieve longer analgesic effect and lower side effect. TAT modified nanostructured lipid carriers (TAT-NLCs) were used to co-deliver RVC and MLX. RVC and MLX co-loaded TAT-NLCs (TAT-NLCs-RVC/MLX) were evaluated through in vitro skin permeation and in vivo treatment studies. NLCs-RVC/MLX showed uniform and spherical morphology, with a size of 133.4 ± 4.6 nm and a zeta potential of 20.6 ± 1.8 mV. The results illustrated the anesthetic pain relief ability of the present constructed system was significantly improved by the TAT modification through the enhanced skin permeation efficiency and the co-delivery of MLX along with RVC that improved pain management by reducing inflammation at the injured area. This study provides an efficient and facile method for preparing TAT-NLCs-RVC/MLX as a promising system to achieve synergistic analgesic effect.

Physiologically based pharmacokinetic (PBPK) modeling of meloxicam in different CYP2C9 genotypes.

Meloxicam, a non-steroidal anti-inflammatory drug, is used for the treatment of rheumatoid arthritis and osteoarthritis. Cytochrome P450 (CYP) 2C9 and CYP3A4 are major and minor enzymes involved in the metabolism of meloxicam. Impaired enzyme activity of CYP2C9 variants increases the plasma exposures of meloxicam and the risk of adverse events. The objective of our study is to develop and validate the physiologically based pharmacokinetic (PBPK) model of meloxicam related to CYP2C9 genetic polymorphism using the PK-Sim® software. In vitro kcat of CYP2C9 was optimized in different CYP2C9 genotypes. The demographic and pharmacokinetic dataset for the development of the PBPK model was extracted from two previous clinical pharmacokinetic studies. Thirty-one clinical datasets, representing different dose regimens and demographic characteristics, were utilized to validate the PBPK model. The shapes of simulated plasma concentration-time profiles in each CYP2C9 genotype were visually similar to observed profiles. The predicted exposures (AUCinf) of meloxicam in CYP2C9*1/*3, CYP2C9*1/*13, and CYP2C9*3/*3 genotypes were increased by 1.77-, 2.91-, and 8.35-fold compared to CYP2C9*1/*1 genotype, respectively. In all datasets for the development and validations, fold errors between predicted and observed pharmacokinetic parameters were within the two-fold error criteria. As a result, the PBPK model was appropriately established and properly described the pharmacokinetics of meloxicam in different CYP2C9 genotypes. This study is expected to contribute to reducing the risk of adverse events of meloxicam through optimization of meloxicam dosing in different CYP2C9 genotypes.

Formulation and Evaluation of Baclofen-Meloxicam Orally Disintegrating Tablets (ODTs) Using Co-Processed Excipients and Improvement of ODTs Performance Using Six Sigma Method.

PURPOSE: This study aimed to formulate an orally disintegrating tablet (ODT) containing both baclofen and meloxicam together for treating osteoarthritis. METHODS: Direct compression method was used to prepare ODTs using three types of co-processed excipients (Prosolv ODT G2®, F-melt®, and Pharmaburst®500). ODTs were evaluated according to weight variation, thickness, friability, hardness, drug content, wetting time, in-vitro disintegration time, in-vitro dissolution test, and palatability. To enhance the in-vitro dissolution of meloxicam and palatability of ODT, a six sigma methodology was used, and an improvement phase was established where ODTs were prepared using lyophilization and levigation techniques. Finally, a pharmacokinetic study of the improved ODT was accomplished in comparison to the conventional oral tablet. RESULTS: Pharmaburst-based formula (F4) showed the shortest wetting time and, consequently, the shortest disintegration time and the highest percentage of drug dissolved within 3 min compared to the other formulae. All the improved ODTs had a bitterness taste score vary from (0) palatable and (+1) tasteless. The current sigma level was 3.628 σ and 3.33 σ for palatability and solubility of ODT, respectively, which indicated the process was successfully improved compared with the previous sigma level of 2.342 σ of both processes. Pharmacokinetic study of the improved ODTs showed a significant decrease of Tmax to 120 and 30 min instead of 180 and 120 min for meloxicam and baclofen, respectively. CONCLUSION: ODTs were successfully improved using the six sigma methodology, the pharmacokinetic parameters of both drugs were enhanced due to rapid absorption through the oral mucosa.

Using a stable isotope-labeled internal standard for liquid chromatography-tandem mass spectrometry quantitation of meloxicam in human plasma.

A sensitive and highly efficient LC-ESI-MS/MS method using a stable isotope-labeled internal standard (SIL IS) to detect meloxicam in human plasma was developed and validated. Sample preparation used only 50 µL human plasma with one-step methanol protein precipitation. A gradient mobile phase system was adopted for chromatographic separation on a Poroshell 120 SB-C18 column (2.1 × 50 mm, 2.7 µm). Positive ion pattern was chosen for quantification under multiple reaction monitoring. Ion pairs were [M + H]+ m/z 352.1 → 115.1 for meloxicam and [M + H]+ m/z 355.1 → 187.1 for meloxicam-d3 (SIL IS). Total run time was 4.0 min. Standard curve was linear over a concentration range from 8.00 to 1600 ng mL-1 . This method was fully validated to evaluate its performance, including specificity, carryover, sensitivity, linearity, accuracy, precision, recovery, matrix effects, stability, dilution reliability and incurred sample reanalysis, which provided a reliable basis for pharmacokinetic studies of meloxicam in 28 healthy Chinese volunteers. After a single-dose oral administration of 7.5 mg meloxicam, the main pharmacokinetic parameters were as follows: Cmax , 814.79 ± 201.37 ng mL-1 ; Tmax , 4.54 ± 1.42 h; AUC0-t , 24,572.04 ± 5766.93 ng·h mL-1 ; AUC0-∞ , 25,810.89 ± 6796.60 ng·h mL-1 and t1/2 , 21.11 ± 5.35 h.

Comparative pharmacokinetics of meloxicam oil suspension in pigs at different dosages following intramuscular administration.

This study aimed to evaluate the preliminary safety of self-developed meloxicam (MEL) oil suspension and determine the comparative pharmacokinetics of it at 0.8 and 2mg/kg body weight (b.w.) dosages in pigs following a single intramuscular administration. Six rabbits were used for the study of preliminary safety and six healthy pigs were used for pharmacokinetics study by a crossover design in two periods. The muscle irritation results showed that both of the MEL oil suspension and the conventional injection had no significant changes at the dosage of 0.4 mg/kg b.w.. However, at the dosage of 2 mg/kg b.w., both of the self-developed MEL oil suspension and the MEL conventional injection showed mild irritation to muscle. Plasma concentrations of MEL were measured by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The MEL plasma concentrations were quantified up to 30 h and 72 h after intramuscular administration at the low- and high-dosage, respectively. The difference was statistically significant (P < 0.05) between different dosages in pharmacokinetic parameters of t1/2λz, Cmax, AUC0-t, AUC0-µ, MRT, and Vd. The Cmax values of MEL were 1.92 ± 0.34 µg/ml and 3.03 ± 1.25 µg/ml at dosages of 0.8 and 2 mg/kg b.w. while the tmax values were 3.25 ± 1.04 h and 4.00 ± 1.26 h, respectively. The pharmacokinetics results of self-developed MEL oil suspension demonstrated that the retention time of it in pigs was prolonged, showing the sustained-release effect. Therefore, Oil suspension was an ideal new drug loading form of MEL.

PHARMACOKINETIC BEHAVIOR OF MELOXICAM IN LOGGERHEAD (CARETTA CARETTA), KEMP'S RIDLEY (LEPIDOCHELYS KEMPII), AND GREEN (CHELONIA MYDAS) SEA TURTLES AFTER SUBCUTANEOUS ADMINISTRATION.

The objective of this study was to determine the pharmacokinetics of a single dose of meloxicam administered subcutaneously (SQ) to three species of sea turtles: loggerheads (Caretta caretta), Kemp's ridley (Lepidochelys kempii), and greens (Chelonia mydas). A dose of 1 mg/kg was given to the Kemp's ridleys and greens, whereas the loggerheads received 2 mg/kg. After SQ administration, the half-life (t1/2) of meloxicam administered at 1 mg/kg in the Kemp's ridleys was 5.51 hr but could not be determined in the greens. The half-life of meloxicam administered at 2 mg/kg in the loggerheads was 2.99 hr. The maximum concentration (Cmax) for meloxicam after SQ administration at 1 mg/kg in the Kemp's ridleys was 6.76 µg/ml and in the greens was 9.35 µg/ml. The Cmax in loggerheads for meloxicam after SQ administration at 2 mg/kg was 3.63 µg/mL. Meloxicam administered SQ at a dose of 1 mg/kg to the Kemp's ridley and greens provided measurable plasma concentrations of meloxicam for 48 and 120 hr, respectively, with no adverse side effects. In loggerheads, meloxicam administered SQ at a dose of 2 mg/kg provided measurable plasma levels of meloxicam for only 24 hr. Plasma levels of meloxicam of greater than 0.5 µg/ml are considered to be therapeutic in humans. Results suggested that administration of meloxicam SQ at 1 mg/kg in Kemp's ridleys and greens would result in plasma concentrations greater than 0.5 µg/ml for 12 and 120 hr, respectively. The administration of 2 mg/kg meloxicam to loggerhead turtles resulted in plasma concentrations greater than 0.5 µg/ml for only 4 hr.

Pharmacokinetics of a Single Dose of Oral Meloxicam in Rehabilitated Wild Brown Pelicans (Pelecanus occidentalis).

Because of concerns regarding potential adverse effects of meloxicam in pelicans reported by several zoos and wildlife rehabilitation facilities, this study was undertaken to determine the pharmacokinetics of a single oral dose of meloxicam in brown pelicans (Pelecanus occidentalis). A pilot study was performed with 6 apparently healthy wild adult brown pelicans of unknown sex during rehabilitation, administered a single oral dose of meloxicam at 0.2 mg/kg. Plasma drug concentrations were monitored for 24 hours but failed to capture the elimination phase of the drug. Consequently, a principal study monitored plasma concentrations for 120 hours. Six additional adult wild brown pelicans, 3 males and 3 females, approaching releasable condition in rehabilitation were split into 3 groups and each orally administered 0.2 mg/kg meloxicam. Blood samples were collected at baseline and at 4 additional time points that differed between groups. Plasma concentrations were measured with liquid chromatography-mass spectrometry. The mean maximum plasma concentration was 1.22 µg/mL and was achieved at 24 hours after drug administration. The elimination half-life was 36.3 hours, the longest reported to date for any avian species. Further studies are needed to determine the pharmacokinetics of multiple doses of meloxicam and other routes of administration, as well as the pharmacodynamics and safety profile of meloxicam in brown pelicans. On the basis of the results of these investigations, caution is advised when dosing brown pelicans with meloxicam until more studies are completed. By extrapolation, close taxonomic relatives in the order Pelecaniformes may also warrant additional studies.

Pharmacokinetics of Sustained-release, Oral, and Subcutaneous Meloxicam over 72 Hours in Male Beagle Dogs.

In cynomolgus macaques, plasma levels of sustained-release formulations of meloxicam meet or exceed efficacious concentrations for 48 to 72 h, thereby allowing less animal handling and providing more consistent efficacy than standard formulations of meloxicam. The goal of this study was to compare the pharmacokinetics of a single subcutaneous dose of a sustained-release formulation of meloxicam (Melox-SR) with those of oral (Melox-PO) and standard subcutaneous (Melox-SC) formulations dosed every 24 h for 3 consecutive days. Dogs (5 or 6 adult male Beagles) each received the following 3 treat- ments: first, Melox-SR (10 mg/mL, 0.6 mg/kg SC once), next Melox-SC (0.2 mg/kg SC once, followed by 0.1 mg/kg SC every 24 h), and finally Melox-PO (same dosage as Melox-SC), with a washout period of at least 2 wk between formulations. Blood was collected at 0 (baseline), 1, 4, 8, 12, 24, 48, and 72 h after the initial administration of each formulation for comparison of meloxicam plasma concentrations. Blood was also collected before administration and at 48 h after Melox-SR injection for CBC and chemistry analysis. Plasma concentrations (mean ± 1 SD) of Melox-SR peaked at the 1-h time point (2180 ± 359 ng/ mL), whereas those of Melox-PO (295 ± 55 ng/mL) and Melox-SC (551 ± 112 ng/mL) peaked at the 4-h time point. Melox-SR yielded significantly higher plasma concentrations than Melox-PO and Melox-SC until the 48 and 72-h time points, respec- tively. Melox-SC plasma concentrations were significantly higher than those of Melox-PO at 4, 8, 12, 24, 48 and 72 h. No lesions were noted at the Melox-SR injection sites, and Melox-SR administration was not associated with changes in the CBC and serum chemistry panels. A single 0.6-mg/kg dose of Melox-SR can yield plasma concentrations that exceed 350 ng/mL for at least 72 h in adult male dogs.

Plasma, urine and tissue concentrations of Flunixin and Meloxicam in Pigs.

BACKGROUND: The objective of this study was to determine the renal clearance of flunixin and meloxicam in pigs and compare plasma and urine concentrations and tissue residues. Urine clearance is important for livestock show animals where urine is routinely tested for these drugs. Fourteen Yorkshire/Landrace cross pigs were housed in individual metabolism cages to facilitate urine collection. This is a unique feature of this study compared to other reports. Animals received either 2.2 mg/kg flunixin or 0.4 mg/kg meloxicam via intramuscular injection and samples analyzed by mass spectrometry. Pigs were euthanized when drugs were no longer detected in urine and liver and kidneys were collected to quantify residues. RESULTS: Drug levels in urine reached peak concentrations between 4 and 8 h post-dose for both flunixin and meloxicam. Flunixin urine concentrations were higher than maximum levels in plasma. Urine concentrations for flunixin and meloxicam were last detected above the limit of quantification at 120 h and 48 h, respectively. The renal clearance of flunixin and meloxicam was 4.72 ± 2.98 mL/h/kg and 0.16 ± 0.04 mL/h/kg, respectively. Mean apparent elimination half-life in plasma was 5.00 ± 1.89 h and 3.22 ± 1.52 h for flunixin and meloxicam, respectively. Six of seven pigs had detectable liver concentrations of flunixin (range 0.0001-0.0012 µg/g) following negative urine samples at 96 and 168 h, however all samples at 168 h were below the FDA tolerance level (0.03 µg/g). Meloxicam was detected in a single liver sample (0.0054 µg/g) at 72 h but was below the EU MRL (0.065 µg/g). CONCLUSIONS: These data suggest that pigs given a single intramuscular dose of meloxicam at 0.4 mg/kg or flunixin at 2.2 mg/kg are likely to have detectable levels of the parent drug in urine up to 2 days and 5 days, respectively, after the first dose, but unlikely to have tissue residues above the US FDA tolerance or EU MRL following negative urine testing. This information will assist veterinarians in the therapeutic use of these drugs prior to livestock shows and also inform livestock show authorities involved in testing for these substances.

Effect of castration procedure on the pharmacokinetics of meloxicam in goat kids.

The aim of this study was to determine the changes in the pharmacokinetics of meloxicam in goat kids who were castrated following the administration of xylazine. Six goat kids were used for the study. The study was performed in two periods according to a longitudinal study, with a 15-day washout period between periods. In the first period (Control group), 1 mg/kg meloxicam was administered by i.v. route to kids. In the second period (Castration group), the kids were sedated with 0.3 mg/kg xylazine and castration was performed following meloxicam administration. Plasma meloxicam concentration was analyzed using HPLC-UV, and pharmacokinetic parameters were calculated by noncompartmental model. In the control group following the administration of meloxicam, mean elimination half-life (t1/2 ʎz ), area under the concentration-time curve (AUC0-∞ ), total body clearance (ClT ), and volume of distribution at steady-state (Vdss ) were 13.50 ± 0.62 hr, 41.10 ± 2.86 hr µg/ml, 24.43 ± 1.75 ml hr-1  kg-1 , and 0.45 ± 0.03 L/kg, respectively. In the castration group, the t1/2 ʎz of meloxicam prolonged, AUC0-∞ increased, and ClT and Vdss decreased. In conclusion, the excretion of meloxicam from the body slowed and the t1/2 ʎz was prolonged in the castrated goat kids following xylazine administration. However, there is a need to determine the pharmacodynamics of meloxicam in castrated goat kids.

Acetone-assisted co-processing of meloxicam with amino acids for enhanced dissolution rate.

Meloxicam is a widely used non-steroidal anti-inflammatory agent. However, its erratic and poor dissolution delays its onset of action. Dissolution enhancement of such medicine is essential to obtain rapid pain relief. Amino acids showed high potential to enhance the dissolution rate of drugs after co-processing. Accordingly, the objective of this work was to investigate the effect of co-processing of meloxicam with arginine, cysteine, and glycine on its crystalline structure and dissolution rate. Meloxicam was mixed with increasing molar ratios of amino acids before acetone-assisted kneading. The resulting products were examined using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction in addition to monitoring the dissolution behavior. Combined instrumental analysis indicated salt formation with a possibility of further crystalline changes at high concentration of amino acids. Salt formation and crystalline structure modification were associated with a significant increase in the dissolution rate of meloxicam. The study introduced amino acids as potential excipients for enhanced dissolution of meloxicam after wet co-processing.

Formulation design, characterization and in vitro drug release study of orodispersible film comprising BCS class II drugs.

Fast dissolving orodispersible film (ODF) was prepared for concurrent administration of biopharmaceutical classification system (BCS) class II drugs, i.e., meloxicam (MX) and tizanidine (TZ), using natural (xanthan gum), semisynthetic (hydroxypropyl methylcellulose and hydroxyethyl cellulose) and synthetic (polyvinyl alcohol) polymers. Compatibility of the ingredients of ODFs was ascertained through Fourier transform infra-red spectroscopy and differential scanning calorimetry. ODFs were characterized through disintegration time, pH of the surface of film, tensile strength, folding endurance, % elongation and content uniformity (MX and TZ) which were found in the range between 17±1.3-56±3.1 s, 5.11±0.07-6.28±0.05, 14.721±1.2-33.084±3.1 N/m2, > 100, 3.33±0.53-10.04±0.77 % and 98.01-99.34 % (MX) and 97.48-99.03 % (TZ), respectively. The values of moisture uptake, moisture loss and loss on drying of all formulations were in the range from 1.06±0.09-7.51±0.93 %, 0.06±0.01-2.3±0.08 % and 0.008±0.002-0.03±0.03 %, respectively. In vitro drug release study in simulated saliva fluid of pH 7.4 has shown that > 90 % MX and TZ was released within 5 min. Visual inspection, scanning electron microscope and X-ray diffraction analysis of all ODFs expressed their smooth surfaces. ODF prepared from xanthan gum (F5) exhibited better physicochemical and mechanical properties as compared to other formulations.

Estimation of the Effect of OAT2-Mediated Active Uptake on Meloxicam Exposure in the Human Liver.

Active uptake mediated by organic anion transporter 2 (OAT2) has been previously hypothesized as a key player in hepatic disposition of its substrates. Previous studies have shown that another hepatic uptake transporter, organic anion transporting polypeptides (OATP) 1B1, significantly elevates liver concentrations of drugs transported by it. As tissue concentration typically governs pharmacodynamics, drug-drug interactions, and toxicity in the liver, it is important to understand if OAT2 functions similarly to OATP1B1 in raising liver exposure. Since this is a research problem that cannot be easily assessed in clinical studies at this time, here we estimated human liver exposure of an OAT2 substrate meloxicam using a deduction method based on physiologically based pharmacokinetic (PBPK) modeling of clinical systemic exposure data. Although in vitro data suggest that OAT2-mediated active uptake is involved in meloxicam disposition, the modeling result concludes that its unbound liver exposure is unlikely significantly different from its unbound systemic exposure. This conclusion is further supported by data and modeling from a terminal monkey study and in vitro hepatocyte studies with bovine serum albumin. Overall, based on currently available data, we do not expect that OAT2 has a strong impact on the liver exposure of meloxicam.

Pharmacokinetic profiles of meloxicam after single IV and PO administration in Bilgorajska geese.

The purpose of this study was two-fold: I) to determine the pharmacokinetic profile of meloxicam (MLX) in geese after intravenous (IV) and oral (PO) administration and II) to assess tissue residues in muscle, heart, liver, lung, and kidney. Ten clinically normal female Bilgorajska geese were divided into two groups (treated, n = 8; control, n = 2). Group 1 underwent a 3-phase parallel study with a 1-week washout period. In phase I, animals received MLX (0.5 mg/kg) by IV administration; the blood was collected up to 48 hr. In phases II and III geese were treated orally at the same dosage for the collection of blood and tissue samples, respectively. Group 2 served as control. After the extraction procedure, a validated HPLC method with UV detection was used for plasma and organ analysis. The plasma concentrations were quantifiable up to 24 hr after both the administrations. The elimination phase of MLX from plasma was similar in both the administration groups. The clearance was slow (0.00975 L/hr*Kg), the volume of distribution small (0.0487 L/kg), and the IV half-life was 5.06 ± 2.32 hr. The average absolute PO bioavailability was 64.2 ± 24.0%. Residues of MLX were lower than the LOQ (0.1 µg/kg) in any tested tissue and at any collection time. The dosage used in this study achieved the plasma concentration, which provides analgesia in Hispaniolan Amazon parrots for 5 out of 24 hr after PO administration. MLX tissue concentrations were below the LOD of the assay in tissue (0.03 µg/ml). A more sensitive technique might be necessary to determine likely residue concentrations in tissue.

Impact of lactation on pharmacokinetics of meloxicam in goats.

Use of drug in lactating animal should be carefully considered due to its possibility of changes in pharmacokinetics as well as drug penetration in milk. The aim of this study was to assess the effect of lactation on pharmacokinetics of meloxicam after IV and IM administrations in goats. A crossover design (2 × 2) was used for each lactating and nonlactating group of goats with a 3-week washout period. Meloxicam (0.5 mg/kg) was administered into the jugular vein and upper gluteal muscle by IV and IM routes, respectively. The plasma and milk drug concentrations were determined by high-performance liquid chromatography with diode array detector, and the pharmacokinetic analysis was carried out by noncompartmental analysis. The pharmacokinetic parameters of meloxicam in lactating and nonlactating goats were not significantly different. The IM bioavailability of meloxicam was relatively lower in lactating (75.3 ± 18.6%) than nonlactating goats (103.8 ± 34.7%); however, the difference was not statistically significant. Moreover, AUC ratio between milk and plasma, which represent drug milk penetration, for both IV and IM administrations was less than 1 (about 0.3). In conclusion, pharmacokinetic parameters of meloxicam are not significantly altered by lactation for either the IV or IM routes of administration and this drug does not require a different dosage regimen for lactating animals.

Pharmacokinetics and relative bioavailability of meloxicam oil suspension in pigs after intramuscular administration.

This study aimed to develop one novel meloxicam (MEL) oil suspension for sustained-release and compare the pharmacokinetic characteristics of it with MEL conventional formulation in pigs after a single intramuscular administration. Six healthy pigs were used for the study by a crossover design in two periods with a withdrawal interval of 14 days. Plasma concentrations of MEL were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Pharmacokinetic parameters were calculated by noncompartmental methods. The difference was statistically significant (p < .05) between MEL oil suspension and MEL conventional formulation in pharmacokinetic parameters of mean residence time (6.16 ± 4.04) hr versus (2.66 ± 0.55) hr, peak plasma concentration (Cmax ) (0.82 ± 0.12) µg/ml versus (1.12 ± 0.22) µg/ml, time needed to reach Cmax (Tmax ) (2.33 ± 0.82) hr versus (0.59 ± 0.18) hr, and terminal elimination half-life (t1/2λz ) (3.74 ± 2.66) hr versus (1.55 ± 0.37) hr. The mean area under the concentration-time curve (AUC0-∝ ) of MEL oil suspension and MEL conventional formulation was 5.35 and 3.43 hr µg/ml, respectively, with a relative bioavailability of 155.98%. Results of the present study demonstrated that the MEL oil suspension could prolong the effective time of drugs in blood, thereby reducing the frequency of administration on a course of treatment. Therefore, the novel MEL oil suspension seems to be of great value in veterinary clinical application.

Canine Albumin Polymorphisms and Their Impact on Drug Plasma Protein Binding.

Drug binding to plasma proteins is routinely determined during drug development. Albumin polymorphisms c.1075G>T (p.Ala359Ser) and c.1422A>T (p.Glu474Asp) were previously shown to alter plasma protein binding of a drug candidate (D01-4582, 4-[1-[3-chloro-4-[N'-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]methoxybenzoic acid) in a colony of Beagles. Our study investigated the hypothesis that drug-protein binding in plasma from dogs with the albumin H1 (reference) allele would be greater than in plasma from dogs with the albumin H2 allele (c.1075G>T and c.1422A>T) (n = 6 per group). The plasma protein binding extent of four drugs (D01-4582, celecoxib, mycophenolic acid, and meloxicam) was evaluated using ultracentrifugation or equilibrium dialysis. Free and total drug concentrations were analyzed by liquid chromatography-mass spectrometry. The albumin gene coding region was sequenced in 100 dogs to detect novel gene variants, and H1/H2 allele frequency was determined in a large and varied population (n = 1446 from 61 breeds and mixed-breed dogs). For meloxicam, H1 allele plasma had statistically significant higher free drug fractions (P = 0.041) than H2 allele plasma. No significant difference was identified for plasma protein binding of D01-4582, celecoxib, or mycophenolic acid. c.1075G>T and c.1422A>T were the most common single nucleotide polymorphisms in canine albumin, present concurrently in most study dogs and occasionally identified independently. Our findings suggest a potential influence of c.1075G>T and c.1422A>T on plasma protein binding. This influence should be confirmed in vivo and for additional drugs. Based on our results, albumin genotyping should be considered for canine research subjects to improve interpretation of pharmacokinetic data generated during the drug development process for humans and dogs.

Pharmacokinetics and Safety of Intramuscular Meloxicam in Zebra Finches (Taeniopygia guttata).

Meloxicam is the most frequently used NSAID in birds; however, its elimination t1/2 is highly variable among species. Because zebra finches that require analgesia could benefit from receiving meloxicam, we performed a pharmacokinetic study involving a single intramuscular dose of 1 or 2 mg/kg. Data analysis showed that Cmax, t1/2, and elimination rate constants were not significantly different between the 2 doses. In contrast, Cmax for 1- and 2-mg/kg doses of meloxicam approached a significant difference, and those for AUC0-∞ were significantly different. Importantly, a plasma concentration of 3500 ng/mL, considered a target level for meloxicam in other avian species, was maintained for approximately 9.5 h in finches that received 2 mg/kg, which was 4 h longer than in birds given 1 mg/kg. Both doses reached low plasma concentrations by 12 h after administration. Subsequently, 8 total doses of 1 or 2 mg/kg were administered to birds at 12-h intervals; these regimens caused no significant changes in select biochemical analytes or the Hct of meloxicam-treated birds. In addition, histopathologic changes for injection sites, kidney, liver, proventriculus, and ventriculus were minimal and similar between control and experimental groups after the multiple doses. These results suggest a 12-h or more frequent dosing interval is likely needed in zebra finches and that meloxicam at 1 or 2 mg/kg IM twice daily for 4 d is safe. The higher dose might provide longer analgesia compared with the lower dose, but a pharmacodynamics evaluation of meloxicam in zebra finches is needed to confirm analgesic efficacy.