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A Step Toward Flexible Dosing: Chemical Stability of Clopidogrel in Various Aqueous Media

A Step Toward Flexible Dosing: Chemical Stability of Clopidogrel in Various Aqueous Media. Jen Steiner with Kurt Dolence and Glaucia Teixeira University of Wyoming School of Pharmacy. Overview. What Clopidogrel is Why we need flexible dosing Research Method Results Discussion

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A Step Toward Flexible Dosing: Chemical Stability of Clopidogrel in Various Aqueous Media

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  1. A Step Toward Flexible Dosing: Chemical Stability of Clopidogrel in Various Aqueous Media Jen Steiner with Kurt Dolence and Glaucia Teixeira University of Wyoming School of Pharmacy

  2. Overview • What Clopidogrel is • Why we need flexible dosing • Research Method • Results • Discussion • Future Research

  3. Clopidrogrel… Plavix® • Approved 1997 • Platelet aggregation inhibitor • Indicated for: • Acute coronary syndrome: non-ST-segment elevation, ST-elevation myocardial infarction • Recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease.

  4. Prodrugs and Genetics • Clopidogrel is a prodrug – must be converted into its active form by the liver enzyme, CYP2C19 in order to stop platelet clumping • 3% of population are poor metabolizers • Stop, time for some research – And Chocolate!!!!

  5. A little more about Plavix… • Inhibits clotting by selectively binding to adenosine diphosphate (ADP) receptors

  6. How did that taste? • Fast Metabolizers: • How much chocolate effect did you get? • Slow Metabolizers: • How much chocolate effect did YOU get?

  7. Pharmacogenetics of Clopidogrel • Normally, poor metabolizers = more drug effect (like the chocolate effect) • But, prodrugs aren’t active yet until they are converted (metabolized) • Clopidogrel + CYP2C19 = active Clopidogrel • Consequently, the less CYP2C19 activity (slower metabolization), the less effect Clopidogrel has and the more may need to be taken to avoid clotting events

  8. One size fits… ALL? • Some people may require a different amount of Clopidogrel in their systems to be as effective • Why is there only the 75mg size for daily maintenance? • Too much = increased bleeding • Too little = increased clotting

  9. The BIG Idea • Liquid dosage forms allow for flexible dosing • BUT – the drug must be stable: • Microbial Stability – 28 days stable proven by Yamreudeewong, W, “Mui” Cheyenne, 2009 • Chemical Stability – 28 days, same compound (Proven?? – Let’s see…)

  10. Compounded Solutions • Mixed triturated clopidogrel in three aqueous solutions: • Apple Juice • Sugar Free Maple Syrup • Water • Stored at: • Room Temp & Fridge • Measured at • 0, 7,14, 21, and 28 days

  11. Measurement • High Pressure Liquid Chromatography • Measures the amount of a pre-identified compound in solution by measuring the time it takes for a sample to travel through a specific column - creating peaks • Can indicate whether a compound has changed • FIRST calibrate the graph to properly identify the compound and measure the area under the curve to determine that concentration • If Clopidogrel degrades, a smaller area under the curve is expected over time

  12. Naproxen (Control) and Clopidogrel Chromatograph of a mixture of Clopidogrel test suspension and Naproxen

  13. Preparing the HPLC Sample • Method of Preparation: • Shake the bottle • Pipette Sample • Pull and thaw Naproxen Sample • Shake both samples • Pipette Clopidogrel Mix into Naproxen sample • Shake (distribute into suspension) • Centrifuge (don’t want to clog the HPLC) • Withdraw and “Shoot” Sample

  14. Analysis • All samples shot in triplicate • Analysis of Clopidogrel content average with standard deviation • All samples were collected at the appropriate times and frozen at -80° C until combination with Clopidogrel analyzed via HPLC • Monitored for any new peak formation (new compound) during tests

  15. Anticipated Results Concentration of Clopidogrel in Water, Apple Juice, and SF Syrup Mixtures over 20 Day Exposure to 40°C Thermal Accelerated Decomposition Clopidogrel Concentration (ng/10 μl) Time Stored (days)

  16. Results Stability of Refrigerated and Room Temperature Clopidogrel/Water Mixture Over Time Clopidogrel Concentration (ng/10 μl) Time Stored (days)

  17. Results Stability of Refrigerated and Room Temperature Clopidogrel/Apple Juice Mixture Over Time Clopidogrel Concentration (ng/10 μl) Time Stored (days)

  18. Results Stability of Refrigerated and Room Temperature Clopidogrel/SF Syrup Mixture Over Time Clopidogrel Concentration (ng/10 μl) Time Stored (days)

  19. Discussion • Shouldn’t the Clopidogrel decrease at a linear rate? • Possible Causes: • Poor Pipetting • Apple Juice – low concentration from the start • Fast Sedimentation Rate • Is Clopidogrel Chemically Stable?

  20. Recall…..Preparing the HPLC Sample • Method of Preparation: • Shake the bottle (sedimentation) • Pipette Sample • Pull and thaw Naproxen Sample • Shake both samples (sedimentation) • Pipette Clopidogrel Mix into Naproxen sample • Shake (distribute into suspension) (sedimentation) • Centrifuge (don’t want to clog the HPLC) • Withdraw and “Shoot” Sample

  21. Clopidogrel Is Chemically Stable • The reason for the uneven results from sample to sample has a lot to do with its sedimentation rate • Upon compounding the apple juice suspension, the carnauba wax coating of the Clopidogrel tablet probably trapped much of the drug • Future Mixtures to Research should include a different viscous vehicle such as Sorbitol, although diluting it for sample analysis will likely reduce its suspending properties as well.

  22. When to Try New Research? • Generic Clopidogrel will be available to the public when the patent runs out in 2012 • New research should begin with the generic in order to save patients money and still give them therapeutic dosing.

  23. Acknowledgements • Kurt Dolence and Glaucia Teixeira, Mentors • Jesse Robinson, Pharmacy Student • University of Wyoming EPSCoR • University of Wyoming Honors Program • University of Wyoming School of Pharmacy

  24. References • 1. "FDA Grants Priority Review To Plavix(R) (Clopidogrel Bisulfate) Supplemental New Drug Application (sNDA) For Additional Type Of Heart Attack." Medical News Today: Health News. 30 Jan. 2006. 10 Feb. 2009 http://www.medicalnewstoday.com/articles/36782.php . • 2. Mitakos A, Panderi I. “A validated LC method for the determination of clopidogrel in pharmaceutical preparations.” J Pharm Biomed Anal. 431.8 (2002): 28. • 3. Dow Jones Company, Inc. “US Patent Office Orders Re-examination of Plavix Patent” Aug. 18. Aug. 2009. 24 Aug. 2009. http://money.cnn.com/news/newsfeeds/articles/djf500/200908181126DOWJONESDJONLINE000222_FORTUNE5.htm. • 4. White R, Brandam V. Handbook of Drug Administration via Enteral Feeding Tubes. London: Pharmaceutical Press, 2006. 169. • 5. Freedman J, Hylek E. “Clopidogrel, genetics, and drug responsiveness.” New England Journal of Medicine 360.4 (2009): 411 - 413. • 6. Mega J, et al. “Cytochrome P-450 Polymorphisms and response to clopidogrel.” New England Journal of Medicine. 360.4 (2009): 354-362. • 5. Rueters. "USATODAY.com - Apotex delivering generic Plavix soon." News, Travel, Weather, Entertainment, Sports, Technology, U.S. & World - USATODAY.com. 8 Aug. 2006. 10 Feb. 2009. http://www.usatoday.com/money/industries/health/2006-08-08-generic-plavix_x.htm

  25. References • 6. Dailey, R. "Sanofi-Aventis and Bristol-Myers Squibb Victorious Over Apotex in Plavix Case -- Seeking Alpha." Stock Market News, Opinion & Analysis, Investing Ideas -- Seeking Alpha. 26 June 2007. 10 Feb. 2009. http://seekingalpha.com/article/39363-sanofi-aventis-and-bristol-myers-squibb-victorious-over-apotex-in-plavix-case • 7. Camara MG, Almeda FQ. “Clopidogrel (Plavix) desensitization: a case series.” Catheter • Cardiovascular Interv. 2005; 65(4):525-527. • 8. Dolence E, Yamreudeewong, W, Teixeira, M. “Evaluating Microbial Growth and Stability of Clopidogrel in Various Extemporaneously Prepared Oral Liquid Mixtures.” University of Wyoming, School of Pharmacy, 2008. • 9. Trissel L. An Update on USP Chapter 797, The New National Standard for Sterile Preparation. 07 April 2005. 10 Feb. 2009. http://www.hospira.com/Files/Hospira797_final4-7-05.pdf • 10. Butler M, et al. 2009 “The effect of intended duration of clopidogrel use on early and late mortality and major adverse cardiac events in patients with drug-eluting stents.” American Heart Journal. 2009. May. 157;5. 899-907 • 11. Urooj M, Farkouh M, Badimon JJ, et al. :Early and greater bioavailability of crushed vs. whole tablet clopidogrel [abstract]. Circulation. 2003. 108;17. IV-570. Abstract 2599. • 12. Angiolillo, Dominick J., Fernandez-Ortiz, Antonio, Bernardo, Esther, Alfonso, Fernando, Macaya, Carlos, Bass, Theodore A., Costa, Marco A.Variability in Individual Responsiveness to Clopidogrel: Clinical Implications, Management, and Future PerspectivesJ Am CollCardiol2007 0: j.jacc.2006.11.044

  26. Questions?

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