Plasma Concentrations Of Meloxicam Research Articles

Comparative Disposition Kinetics of Meloxicam Following a Single Intravenous Bolus Dose and Its Concurrent Administration with Ofloxacin in Yak and Cattle

Present study describes the comparative pharmacokinetic (PK) profile of meloxicam (0.5 mg.kg-1) alone its concurrent administration with ofloxacin (7.5 mg.kg-1) by intravenous route in yak and cattle. Plasma concentration of meloxicam was determined by HPLC assay and pharmacokinetic parameters by compartmental method using “PHARMKIT” software. Following intravenous administration of meloxicam alone, t1/2α, t1/2β, AUC, Vdarea and ClB values were found to be 0.21+0.04 h, 4.65+0.40 h, 25.46+1.22 μg/ml.h, 1.97+0.11 L/kg and 0.35+0.02 L/h/kg, respectively in yak and all these values were almost comparable to those found in cattle. But the values of K12/K21, Vc, Vp and fc differed significantly between yak and cattle. Further, no significant differences were observed in values of majority of the pharmacokinetic parameters between meloxicam alone or its concurrent administration with ofloxacin in yak and cattle except the values of Vc, Vp and T/P which differed significantly between alone and concurrent administration in yak but not in cattle. Based on pharmacokinetic variables, the loading and maintenance doses of meloxicam were found to be 1.05 and 0.88 mg.kg-1 body weight for yak and 0.97 and 0.79 mg.kg-1 for cattle and be repeated at 12 h interval. Results of present study further suggest that important pharmacokinetic parameters do not significantly differ between yak and cattle and meloxicam can be used at same dose levels in both the species and adjustment in dosage regimen of meloxicam is not warranted in either of the species, if to be used concurrently with ofloxacin.

Pharmacokinetic parameters of meloxicam after its oral administration in goat

Aim: The objective of the present study was to find out the levels of analgesic drug meloxicam in the blood plasma of young goats. The drug was given to them through oral route. Data was used to elucidate the Pharmacokinetic determinants of the drug which were employed to arrive at the dose schedule and frequency of the drug in goats. Materials and Methods: Elaborate pharmacokinetic research of the drug meloxicam was done on 18 to 24 months old, five adult male local goats (Capra hircus) of Assam weighing 20 to 25 kg.The drug was given orally at the dose rate of 0.35 mg/kg at the Goat Rearing farm, Guwahati, Assam. Analysis of blood was done by high performance liquid chromatography (HPLC) system. Results: The mean values of area under curve (AUC) and mean area under curve (AUMC) were 3137.488 ± 125.3749 2 µg.min/ml and 4650460 ± 380892.4744 µg.min /ml respectively .The mean peak plasma level of meloxicam was 1.972 ± 0.0477 µg/ml at 600 min. The mean values of elimination half life (t ) and absorption half life (t ) were 693±0.00 min and 1/2‚ 1/2Ka 170.6 ± 17.0076 min respectively. The mean values of volume of distribution (Vd) and mean residence time (MRT) were 0.114 ± 0.0156 L/kg and 1472.264 ± 63.336 min respectively. The mean value of T was found to be 497 ± 19.8040 min. Following max single oral administration the minimum effective therapeutic concentration or minimum effective plasma concentration of meloxicam was detectable up to 1200 min. The bioavailibity (F) of the drug was 80.5 ± 10.0150%. Conclusion: These pharmacokinetic determinants were used to determine the frequency and dose schedule of meloxicam in goats. The minimum effective concentration of the drug is 0.7 µg/ml in plasma. To maintain this, an initial loading dose of 0.5 mg/kg body weight should be followed by a maintenance dose of 0.4 mg/kg body weight/10 hour.

Pharmacokinetics of meloxicam administered orally to rabbits (Oryctolagus cuniculus) for 29 days

To determine the pharmacokinetics and safety of meloxicam in rabbits when administered orally for 29 days. 6 healthy rabbits. Meloxicam (1.0 mg/kg, PO, q 24 h) was administered to rabbits for 29 days. Blood was collected immediately before (time 0) and 2, 4, 6, 8, and 24 hours after drug administration on days 1, 8, 15, 22, and 29 to evaluate the pharmacokinetics of meloxicam. On day 30, an additional sample was collected 36 hours after treatment. Plasma meloxicam concentrations were quantified with liquid chromatography-mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. Weekly plasma biochemical analyses were performed to evaluate any adverse physiologic effects. Rabbits were euthanatized for necropsy on day 31. Mean ± SD peak plasma concentrations of meloxicam after administration of doses 1, 8, 15, 22, and 29 were 0.67 ± 0.19 μg/mL, 0.81 ± 0.21 μg/mL, 1.00 ± 0.31 μg/mL, 1.00 ± 0.29 μg/mL, and 1.07 ± 0.19 μg/mL, respectively; these concentrations did not differ significantly among doses 8 through 29. Results of plasma biochemical analyses were within reference ranges at all time points evaluated. Gross necropsy and histologic examination of tissues revealed no clinically relevant findings. Plasma concentrations of meloxicam for rabbits in the present study were similar to those previously reported in rabbits that received 1. 0 mg of meloxicam/kg, PO every 24 hours, for 5 days. Results suggested that a dosage of 1. 0 mg/kg, PO, every 24 hours for up to 29 days may be safe for use in healthy rabbits.

Strongly increased exposure of meloxicam in CYP2C9*3/*3 individuals

The effects of CYP2C9*1/*3 and *3/*3 genotypes on the pharmacokinetics and pharmacodynamics of meloxicam were evaluated in healthy Korean subjects. After oral administration of 15 mg meloxicam, the plasma concentrations of meloxicam were assessed in 11 CYP2C9*1/*1 individuals, eight CYP2C9*1/*3 individuals, and three CYP2C9*3/*3 individuals. The pharmacodynamic effects were determined by measuring thromboxane B2 generated in blood. A nine-fold lower apparent oral clearance and an eight-fold higher AUC0-∞ of single-dose meloxicam were observed in CYP2C9*3/*3 individuals when compared with CYP2C9*1/*1 individuals. CYP2C9*3/*3 individuals also showed markedly increased inhibition of thromboxane B2 generation by meloxicam. These results indicate that CYP2C9*3/*3 individuals may be at a higher risk for concentration-dependent adverse effects during long-term treatment with standard doses of meloxicam.

Pharmacokinetics of meloxicam in rabbits after oral administration of single and multiple doses

To determine the pharmacokinetics of meloxicam (1 mg/kg) in rabbits after oral administration of single and multiple doses. 6 healthy rabbits. A single dose of meloxicam (1 mg/kg, PO) was administered to the rabbits. After a 10-day washout period, meloxicam (1 mg/kg, PO) was administered to rabbits every 24 hours for 5 days. Blood samples were obtained from rabbits at predetermined intervals during both treatment periods. Plasma meloxicam concentrations were determined, and noncompartmental pharmacokinetic analysis was performed. The mean peak plasma concentration and area under the plasma concentration-versus-time curve extrapolated to infinity after administration of a single dose of meloxicam were 0.83 μg/mL and 10.37 h•μg/mL, respectively. After administration of meloxicam for 5 days, the mean peak plasma concentration was 1.33 μg/mL, and the area under the plasma concentration-versus-time curve from the time of administration of the last dose to 24 hours after that time was 18.79 h•μg/mL. For single- and multiple-dose meloxicam experiments, the mean time to maximum plasma concentration was 6.5 and 5.8 hours and the mean terminal half-life was 6.1 and 6.7 hours, respectively. Plasma concentrations of meloxicam for rabbits in the present study were proportionally higher than those previously reported for rabbits receiving 0.2 mg of meloxicam/kg and were similar to those determined for animals of other species that received clinically effective doses. A dose of 1 mg/kg may be necessary to achieve clinically effective circulating concentrations of meloxicam in rabbits, although further studies are needed.

English

The main purpose of this study was to predict the efficacy, potency and sensitivity of meloxicam (a preferential cyclooxygenase-2 (COX-2) inhibitor) antipyretic effect by using a simple indirect response model in rat, evaluated by Brewer’s yeast induced model. The rats received 1, 3, 7 and 10 mg/kg of meloxicam, after subcutaneous (sc) injection of Brewer’s yeast. The plasma concentrations of meloxicam were determined by high performance liquid chromatography-ultraviolet (HPLC-UV) method. Rectal temperature (Ta) was measured for the assessment of the pharmacodynamic (PD) of the meloxicam. Before injection of yeast, basal fever mediator’s synthesis (prostaglandin E2; PGE2) is maintained by physiological mechanism to regulate body temperature which is described by a constant rate synthesis (Ksyn) and a first order degradation of Kout. Ksyn is calculated by the equation, Ksyn = E0 Kout, where E0 is the baseline body temperature. After injection of yeast, the additional fever mediators’ synthesis is regulated by input rate (IR (t)). This process is governed by a first order rate constant (KIN), which can be inhibited by meloxicam. The pharmacokinetic (PK) parameters showed dose proportionality, with a Vd (4124.52, 4236.73, 4657.15, and 5912.1 ml/kg), CL (78.55, 149.25, 1313.57, and 1519.41 ml/h/kg), and Cmax (84.72, 258.29, 547.74, and 617.85 ng/ml). Indirect response PD model (inhibitory Emax model), estimated KIN (1.43, 0.63, 0.51, and 0.42 1/h), Kout (0.005, 0.008, 0.015, and 0.028 1/h), and Ksyn (0.29, 0.42, 0.076, and 0.03 h); estimates for IC50 (concentration of meloxicam in plasma eliciting half of maximum inhibition of IR(t) or KIN) were 146.19, 379.51, 645.05, and 676.44 ng/ml of 1, 3, 7 and 10 mg/kg dose received by groups, respectively. This model appropriately describes the time course of pharmacological response to meloxicam to various doses, in terms of its mechanism of action and pharmacokinetics.   Key words: Brewer’s yeast, cyclo-oxygenase-2, fever mediators (PGE2), meloxicam, pharmacokinetic/ pharmacodynamic modeling.

Development of meloxicam in situ implant formulation by quality by design principle

Objective: The focus of this study was to develop and optimize in situ implant formulation of meloxicam by quality by design (QbD) principle for long-term management of musculoskeletal inflammatory disorders.Methods: The formulation was optimized by Box–Behnken design with polylactide-co-glycolide (PLGA) level (X1), N-methyl pyrrolidone level (X2) and PLGA intrinsic viscosity (X3) as the independent variables and initial burst release of drug (Y1), cumulative release (Y2), and dissolution efficiency (Y3) as the dependent variables. The formulation was physicochemically characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and powder X-ray diffraction (PXRD). Pharmacokinetic studies of the optimized formulation were performed on Sprague--Dawley rats.Results: Y1 was significantly affected by X2 and X3. Y2 was affected by X1 and X3 while Y3 was affected by all three independent variables employed in the formulations. Responses for the optimized formulation were in close agreement with the values predicted by the model. SEM photomicrographs indicated uniform gel formulation. No chemical interaction between the components of formulation was observed by FT-IR and meloxicam was found to be present in the amorphous form in the gel matrix as revealed by PXRD. The maximum plasma concentration (Cmax), time to achieve Cmax and area under plasma concentration curve were significantly different from those of the solution formulation used as the control. Plasma concentration of meloxicam was maintained above its IC50 concentration required for COX-2 inhibition for 23 days.Conclusion: Meloxicam in situ implant may provide long-term management of inflammatory conditions with improved patient compliance and better therapeutic index.

Pharmacokinetic and Bioequivalence Study of Meloxicam Tablets in Healthy Male Subjects

Meloxicam (CAS 71125-38-7), a non-steroidal anti-inflammatory drug (NSAID), is used for the treatment of osteoarthritis and rheumatic arthritis. In the present study, two different oral meloxicam formulations (Melcam 15 mg tablets as test preparation and tablets of a reference preparation) were investigated in 24 healthy male subjects in order to prove bioequivalence between both preparations. A single 15 mg oral dose was administered according to an open, randomised, two-period cross-over design in the fasted state. Blood samples for the determination of meloxicam plasma concentrations were collected at pre-defined time points up to 96 h following drug administration. A wash-out period of 7-8 days separated both treatment periods. Meloxicam plasma concentrations were determined by means of a validated HPLC method with UV-detection. Maximum plasma concentrations (C(max)) of 1,146.9 ng/ml (test) and 1,064.8 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity) of 34,499.0 ng x h/ml (test) and 33,784.3 ng x h/ml (reference) were determined. The results showed nearly identical rate and extent of drug absorption. Also further pharmacokinetic parameters were well comparable. Thus, t(max) showed values of 5.00 h for both test and reference. The plasma elimination half-life (t1/2) was 18.29 h (test) und 18.94 h (reference). Both primary target parameters C(max). and AUC(0-infinity, were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 99.46%-105.24% (AUC0-infinity)) and 103.37%-112.46% (C(max)). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and C(max) the 90% confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.

PPF microsphere depot sustains NSAID blood levels with infusion‐like kinetics without ‘burst’

Management of pain is of paramount importance for a myriad of indications in human and animal health. Unfortunately, the administration of pain therapeutics is often complicated by insufficient control over pharmacokinetic profiles as a result of frequent oral dosing. Attempts to sustain and tightly control the concentration of these drugs in the blood via controlled release injectable formulations have typically resulted in drug 'burst', followed by marginal control over the ensuing pharmacokinetics. Here, precision particle fabrication (PPF) technology was used to produce uniform microspheres encapsulating the nonsteroidal anti-inflammatory drug meloxicam. After subcutaneous injection, plasma concentrations of meloxicam were held constant in canines for more than 2 weeks without initial drug burst. Pharmacokinetic profiles were accurately modeled using equations typically applied to steady-state infusion. PPF microsphere depots of pain therapeutics or other compounds may ultimately improve safety and sustain the efficacy of medications where such controlled uniform exposure would be therapeutically beneficial.

모빅캡슐(멜록시캄 7.5mg)에 대한 멜록시펜캡슐의 생물학적 동등성

The purpose of the present study was to evaluate the bioequivalence of meloxicam capsule, capsule( Boehringer Ingelheim Ltd., Korea) as a reference drug and capsule (Kukje Pharma Ind. Co., Ltd., Korea) as a test drug, according to the guidelines of Korea Food and Drug Administration(KFDA). Thirty two healthy male Korean volunteers received capsule containing meloxicam 7.5 mg in a crossover study. There was a one-week above washout period between the doses. Plasma concentrations of meloxicam were monitored for over a period of 72 hr after administration by using a high performance liquid chromatography-tandem mass spectrometer(LC-MS/MS). (the area under the plasma concentration-time curve from time zero to 72 hr), (maximum plasma drug concentration) and (time to reach ) were complied from the plasma concentration-time data. Analysis of variance(ANOVA) test was utilized for the statistical analysis of the parameters using logarithmically transformed and . The 90% confidence intervals of the ratio and the ratio for were log 0.8605-log 0.9847 and log 0.9765-log 1.1503, respectively. These values were within the acceptable bioequivalence intervals of log 0.80-log 1.25, recommended by KFDA. In all of these results, we concluded that capsule was bioequivalent to capsule, based on the rate and extent of absorption.

Bioequivalence study of two meloxicam tablet formulations after single-dose administration in healthy Thai male volunteers

To compare the bioavailability of two meloxicam tablet formulations (MEL-OD, Zydus Cadila Healthcare Limited, India, as a test formulation and Mobic, Boehringer Ingelheim International GmbH, Germany, as a reference formulation) in healthy Thai male volunteers under fasting condition. A randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover with a washout period of 2 weeks, was conducted in 26 healthy Thai male volunteers. Blood samples were collected 0, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 24, 36, 48, 72 and 96 h post dose. Plasma concentrations of meloxicam were determined using a validated HPLC method. The pharmacokinetic parameters of meloxicam were determined using a non-compartmental model. The mean Cmax was 1,027.32 +/- 251.91 and 1,151.89 +/- 282.58 ng/ml while the mean AUC0-t was 34,024.31 +/- 11,811.68 and 35,137.66 +/- 11,970.47 ng x h/ml for the test and reference formulation, respectively. In addition, the mean AUC0-infinity for test formulation was 37,241.44 +/- 14,888.85 ng x h/ml and for the reference formulation was 39,541.04 +/- 16,624.64 ng x h/ml. The median tmax for the test and reference formulation was 4.50 (range 2.00 - 12.00) and 4.50 (range 3.00 - 10.00), respectively. The geometric means (90% confidence intervals) of the ratio for the log-transformed pharmacokinetic parameters, Cmax, AUC0-t and AUC0-inf were 0.8919 (82.58 - 96.32%), 0.9697 (89.46 - 105.10%) and 0.9525 (87.68 - 103.47%), respectively. It can be concluded that two meloxicam tablet formulations are bioequivalent both in term of rate and extent of absorption after single-dose administration under fasting condition.

Voriconazole Increases while Itraconazole Decreases Plasma Meloxicam Concentrations

This study investigated the effect of voriconazole, an inhibitor of cytochrome P450 2C9 (CYP2C9) and CYP3A4, and itraconazole, an inhibitor of CYP3A4, on the pharmacokinetics and pharmacodynamics of meloxicam. Twelve healthy volunteers in a crossover study ingested 15 mg of meloxicam without pretreatment (control), after voriconazole pretreatment, and after itraconazole pretreatment. The plasma concentrations of meloxicam, voriconazole, itraconazole, and thromboxane B(2) (TxB(2)) generation were monitored. Compared to the control phase, voriconazole increased the mean area under the plasma concentration-time curve from 0 to 72 h (AUC(0-72)) of meloxicam by 47% (P < 0.001) and prolonged its mean half-life (t(1/2)) by 51% (P < 0.01), without affecting its mean peak concentration (C(max)). In contrast, itraconazole decreased the mean AUC(0-72) and C(max) of meloxicam by 37% (P < 0.001) and by 64% (P < 0.001), respectively, and prolonged its t(1/2) and time to C(max). The plasma protein unbound fraction of meloxicam was unchanged by voriconazole and itraconazole. Lowered plasma meloxicam concentrations during the itraconazole phase were associated with decreased pharmacodymic effects of meloxicam, as observed by weaker inhibition of TxB(2) synthesis compared to the control and voriconazole phases. Voriconazole increases plasma concentrations of meloxicam, whereas itraconazole, unexpectedly, decreases plasma meloxicam concentrations, possibly by impairing its absorption.

Comparative plasma pharmacokinetics of meloxicam in sheep and goats following intravenous administration

Meloxicam, a novel cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug (NSAID), has been used extensively in humans and recently in some domestic animal species. Although it is an attractive NSAID for use in small ruminants, meloxicam pharmacokinetics have not been investigated in sheep and goats and this information is essential for rational therapeutic use of the drug in these species. In this investigation, comparative pharmacokinetic properties of meloxicam were studied in sheep and goats after a single intravenous dose of 0.5 mg kg − 1 body mass. Blood samples were collected via jugular venepuncture into heparinised tubes at predetermined times after drug administration. Plasma concentrations of meloxicam were determined by reversed-phase high performance liquid chromatography. The plasma concentrations of meloxicam were detectable in sheep and goats up to 72 and 48 h, respectively. The plasma concentration versus time data of meloxicam in both sheep and goats were adequately described by a two-compartment open model. The values obtained for sheep and goats for distribution half-life, volume of distribution at steady state and volume of the central compartment were almost similar in sheep and goats. The elimination half-life ( t 1/2β), area under the plasma concentration–time curve (AUC), mean residence time (MRT) and total systemic clearance (Cl B ) in sheep were significantly different from those of goats. The mean ± S.E. values of t 1/2β, MRT, AUC and Cl B in sheep were 10.85 ± 1.21 h, 15.13 ± 1.67 h, 31.88 ± 2.97 μg h mL − 1 and 0.016 ± 0.002 L h − 1 kg − 1 , respectively whereas the respective values in goats were 6.73 ± 0.58 h, 9.37 ± 0.83 h, 19.23 ± 2.23 μg h mL − 1 and 0.03 ± 0.01 L h − 1 kg − 1 . The results indicate that elimination kinetics of meloxicam differ significantly between sheep and goats and the elimination of the drug tends to be faster in goats compared to sheep.

Meloxicam pharmacokinetics in renal impairment

Aims The aim of the present study was to determine how the pharmacokinetics of meloxicam are affected by kidney dysfunction and consequently to define the appropriate dose for the use of meloxicam in patients with mild or moderate renal impairment. Methods Meloxicam was administered to subjects with mild (creatinine clearance 41–60 ml min−1) to moderate (20–40 ml min−1) renal impairment compared with normal renal function (&gt;60 ml min−1). Thirty‐eight subjects received meloxicam 15 mg once daily over 9 days. Meloxicam plasma concentrations were determined from blood samples taken during the study and pharmacokinetic parameters calculated according to noncompartmental methods. Results Subjects with no or mild renal impairment showed sinular pharmacokinetic profiles (geometric mean AUCSS (%gCV) 55 (33%) vs 55 (38%) μg ml−1 h). Subjects with moderate renal impairment demonstrated lower total plasma meloxicam concentrations (AUCSS 35 (50%) μg ml−1 h, with corresponding higher plasma clearance (P= 0.013) compared with subjects with no renal impairment. However, this was combined with higher meloxicam free fractions in moderately impaired subjects such that free meloxicam concentrations were similar in all three groups. Meloxicam was well tolerated with few adverse events occurring and no difference in incidence observable between groups. Conclusions On the basis of these results there is no necessity for a dosage adjustment when administering meloxicam to patients with mild to moderate renal impairment.

Meloxicam pharmacokinetics in renal impairment.

The aim of the present study was to determine how the pharmacokinetics of meloxicam are affected by kidney dysfunction and consequently to define the appropriate dose for the use of meloxicam in patients with mild or moderate renal impairment. Meloxicam was administered to subjects with mild (creatinine clearance 41-60 ml min-1) to moderate (20-40 ml min-1) renal impairment compared with normal renal function (> 60 ml min-1). Thirty-eight subjects received meloxicam 15 mg once daily over 9 days. Meloxicam plasma concentrations were determined from blood samples taken during the study and pharmacokinetic parameters calculated according to noncompartmental methods. Subjects with no or mild renal impairment showed similar pharmacokinetic profiles (geometric mean AUCSS (%gCV) 55 (33%) vs 55 (38%) micrograms ml-1 h). Subjects with moderate renal impairment demonstrated lower total plasma meloxicam concentrations (AUCSS 35 (50%) micrograms ml-1 h, with corresponding higher plasma clearance (P = 0.013) compared with subjects with no renal impairment. However, this was combined with higher meloxicam free fractions in moderately impaired subjects such that free meloxicam concentrations were similar in all three groups. Meloxicam was well tolerated with few adverse events occurring and no difference in incidence observable between groups. On the basis of these results there is no necessity for a dosage adjustment when administering meloxicam to patients with mild to moderate renal impairment.