ETODOLAC: A PHARMACOECONOMIC AND CLINICALLY EFFECTIVE NSAID FOR ARTHRITIS

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CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption:  The systemic bioavailability of etodolac tablet  is 100% as compared to solution and at least80% as determined from mass balance studies. Etodolac is well absorbed and had arelative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (± 1 SD) peak plasma concentrations (Cmax) range from approximately 14 ± 4 to37 ± 9 μg/mL after 200 to 600 mg single doses and are reached in 80 ± 30 minutes. The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear following doses up to 600 mg every 12 hours. Peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg very 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis  of lower doses.4

Distribution: The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390 mL/kg. Etodolac ismore than 99% bound to plasma proteins, primarily to albumin. The free fraction is less than 1% and isindependent of etodolac total concentration over the dose range studied. It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Data from in vitro studies, using peak serum concentrations at reported therapeutic doses in humans, show that the etodolac free fraction is not significantly altered by a cetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid.4

Metabolism: Etodolac is extensively metabolized in the liver. The role, if any, of a specific cytochrome P450 systemin the metabolism of etodolac is unknown. Several etodolac metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8-hydroxylated-etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated etodolac metabolite does not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.4

Excretion
The mean oral clearance of etodolac following oral dosing is 49 (± 16) mL/h/kg. Approximately 1% of dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite:
— etodolac, unchanged 1%

— etodolacglucuronide 13%

— hydroxylated metabolites (6-, 7-, and 8-OH) 5%

— hydroxylated metabolite glucuronides 20%

— unidentified metabolites 33%

Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild to moderate renal dysfunction is generally necessary. The terminal half-life (t1/2) of etodolac is 6.4 hours (22% CV). In patients with severe renal dysfunction orundergoing hemodialysis, dosing adjustment is not generally necessary.Fecal excretion accounted for 16% of the dose.4

INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of etodolac    and other treatment options before deciding to use etodolac. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

Etodolac ( capsules and tablets) is indicated:

For acute and long-term use in the management of signs and symptoms of the following:
1. Osteoarthritis

2. Rheumatoid arthritis

For the management of acute pain4

Potentially hazardous interactions with other drugs15

  • ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect, increased risk of nephrotoxicity and hyperkalaemia
  • Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with  ketorolac, increased risk of side effects and haemorrhage
  • Antibacterials: possibly increased risk of convulsions with quinolones
  • Anticoagulants: effects of coumarins enhanced; possibly increased risk of bleeding with heparins and coumarins
  • Antidepressants: increased risk of bleeding with SSRIs and venlafaxine
  • Antidiabetic agents: effects of sulphonylureas enhanced
  • Anti-epileptics: possibly increased phenytoin concentration
  • Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir
  • Ciclosporin: may potentiate nephrotoxicity
  • Cytotoxic agents: reduced excretion of methotrexate; increased risk of bleeding with erlotinib
  • Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect;hyperkalaemia with potassium-sparing diuretics
  • Lithium: excretion decreased
  • Pentoxifylline: increased risk of bleeding
  • Tacrolimus: increased risk of nephrotoxicity.

HOW SUPPLIED
Lonine (etodolac capsule) is available as:
200 mg capsules (light gray with one wide red band with LONINE 200/white with two narrow redbands)

—in box, plastic or glass bottles of 4-1000 capsules

Store at controlled room temperature 20°-25°C (68°-77°F), protected from moisture. 4

Published Researchs of etodolac

COLON SPECIFIC COMPRESSION COATED TABLETS OF ETODOLAC: The Etodolac colon specific compression coating tablets were successfully prepared by wetgranulation method. The investigation was carried out to develop colon targeted drug delivery system for Etodolac using HPMC,EudragitL100,EudragitS100 as a carriers for effective and safe drug delivery. From invitro drug release studies it was concluded that The maximum drug release was observed from the formulations based on HPMC polymer. Varying the amount of 89.48% affect the drug release.The drug release from HPMC was slower owing to its showing high viscosity in water. Other Polymers (Eudragit L100 and S100) was less permeability of water and their also showing better drug release profile in both dissolution media.14

DEXTRAN-ETODOLAC CONJUGATES: SYNTHESIS, IN VITRO AND IN VIVO EVALUATION:This investigations suggest that the dextran can be employed as carrier to obtain dextran-etodolac conjugates, which may represent potentially useful conjugates for oral administration of etodolac with improved aqueous solubility and remarkably diminished gastrointestinal side effects, while retaining comparable biological activities of the parent drug.17

Polymeric Surfactant Based Etodolac Chewable Tablets: Formulation and In Vivo Evaluation: Formulation of etodolac chewable tablets not only improved its dissolution rate-dependent bioavailability butalso provides a useful tool to improve patient convenience and compliance. Chewable tablets are suitable for administration of large tablets to geriatrics and pediatrics that have difficulty in swallowing solid dosage forms.18

Etodolac Loaded Poly (Lactide-Co-Glycolide) Nanoparticles: Formulation and In Vitro Characterization: nanoparticulate delivery system for etodolac has been designed and evaluated for in vitro properties. it can be concluded that etodolac loaded PLGA nanoparticles of appropriate particle size are obtained by nanoprecipitation technique. High drug loading and yield values were achieved. 21

Development and In Vitro/In Vivo Evaluation of Etodolac Controlled Porosity Osmotic Pump Tablets: In vitro delivery of more than 90% of etodolac over 24 hwith nearly constant zero-order release kinetics was successfully achieved by optimization of the variables influencing the design of controlled porosity osmotic pump tablets of the drug. The rate of drug release from CPOP tablets could be tailored by controlling the osmotic pressure of the core tablet (osmogent type and drug/osmogent ratio), the composition of the coating solution, the membrane weight gain percentages, and the concentration of pore-forming agent. When compared to the immediate-release Napilac® capsules, the best achieved CPOP tablets provided enhanced bioavailability and extended duration of effective etodolac plasma concentration with minimum expected potential for side effects. 22

FORMULATION AND IN-VITRO EVALUATION OF ETODOLAC ENTRAPPED IN MICROSPONGE BASED DRUG DELIVERY SYSTEM: Etodolac was entrapped in the microsponge drug delivery system formed by using ethyl cellulose and eudragit RS 100. Alteration in the release rate of the drug may be due to the entrapment which modifies the release of drug that causes reduction in the severity of the side effects.27

Formulation and Evaluation of Extended Release Etodolac Tablets:The tablets were resulted in more uniform extended drug release. This may be due to Zero-order release kinetics. Extended drug release dosage forms release drug slowly, so that plasma concentrations are maintained at a therapeutic levels for aprolonged period of time usually between 8 to 12 hours.28

CONCLUSION
Clinically effectiveness ofthe Cox-II inhibitors  to that of other NSAIDs in terms of their ability to reduce pain andimprove physical and global function of both OA and RA patients. Thesecond finding of this review was that there is evidence that the four Cox-IIinhibitors are effective in reducing the incidence of GI adverse events of OAand RA patients compared to NSAID therapy. When these two findings areput together, it can be concluded that there is evidence to support the use ofthese four Cox-II inhibitors in preference to NSAIDs for the management of OA and RA.

The cost-effectiveness of Cox-II inhibitors remains inconclusive. Economic models developed by manufacturers generate favourable outcomes for the Cox-II inhibitors versus standard NSAIDs, including cost-savings, for all OA and RA patients, …. (in confidence). There are no published economic evaluations for Cox-II inhibitors in the UK context, other than the one meloxicam study.16

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