TDM MPA

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Dr Chow Yok Wai

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TDM MPA

  1. 1. Therapeutic Drug Monitoring of Mycophenolic Acid Chow YW Hospital Kuala Lumpur
  2. 2. MPA therapies <ul><li>Mycophenolate mofetil (Cellcept) </li></ul><ul><li>Mycophenolate sodium (Myfortic) </li></ul>
  3. 3. MOA of MPA <ul><li>Immunosuppression </li></ul><ul><ul><li>Reversible </li></ul></ul><ul><ul><li>Uncompetitive inhibition </li></ul></ul><ul><ul><ul><li>Inosine Monophosphate Dephydragenase (IMPDH) </li></ul></ul></ul><ul><ul><ul><li>Results in inhibition og guanine nucleotide biosynthesis </li></ul></ul></ul><ul><ul><ul><li>Suppression of new DNA </li></ul></ul></ul>
  4. 4. MPA TDM use is not widespread <ul><li>Lack of FDA approved automated simple asays </li></ul><ul><li>Already low rejection rates with emperical dosing of MMF </li></ul><ul><li>Complex pharmacokinetics of MPA </li></ul><ul><li>No organ toxicity </li></ul>
  5. 5. MPA pharmacokinetics <ul><li>MMF (morpholinoethylester of MPA) is rapidly hydrolyzed in upper GIT </li></ul><ul><li>Largely distributed in plasma </li></ul><ul><li>Avidly bound to serum albumin </li></ul><ul><li>Rapid absoprtion (Max by 1 hr) </li></ul><ul><li>Plateau within 3-4 hours </li></ul><ul><li>Small MPA fraction is in free form </li></ul>
  6. 6. MPA pharmacokinetics <ul><li>MPA is metabolized mostly via the Uridine diphosphate glucoronyl transferase (UDP) system </li></ul><ul><li>Primary inactive metabolite is Mycophenolic acid glucoronide (MPAG) </li></ul><ul><li>MPAG is transported into bile from liver cells by transporters </li></ul>
  7. 7. MPA pharmacokinetics <ul><li>Biliary MPAG is hydrolyzed back to MPA in GIT by glucoronidase produced by intestinal bacteria </li></ul><ul><li>MPA recycled via Enterohepatic Circulation </li></ul>
  8. 8. MPA pharmacokinetics
  9. 9. MPA pharmacokinetics <ul><li>Secondary peaks </li></ul><ul><ul><li>MMF --> 4-8 hours </li></ul></ul><ul><ul><li>Myfortic --> later </li></ul></ul>
  10. 11. Renal dysfunction <ul><li>MPA can be increased by 2-3 folds </li></ul><ul><li>But Free MPA concentrations remain stable </li></ul><ul><li>MPAG increased </li></ul><ul><ul><li>Displace MPA from albumin </li></ul></ul>
  11. 12. Liver Dysfunction <ul><li>Increased MPAG </li></ul><ul><li>Higher free MPA </li></ul><ul><li>Normal total MPA concentrations </li></ul>
  12. 13. Drug-Drug interaction
  13. 14. Other facts <ul><li>Genetic variation is important in PK of MPA </li></ul><ul><li>PK models </li></ul><ul><ul><li>2 compartment model with time lagged absoprtion </li></ul></ul><ul><ul><li>1st: GIT </li></ul></ul><ul><ul><li>2nd: Liver </li></ul></ul>
  14. 15. MPA exposure and Clinical Outcomes <ul><li>MPA dose interval AUC (0-12h) keeping it 30-40mg/h/L in CsA treated renal Tx pt --> minimisation of acute rejection </li></ul><ul><ul><ul><ul><li>Van Gelder. Transplantation 1999 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hale. Clin Phar Ther 1998 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Le Meur. Transplantation 2006 </li></ul></ul></ul></ul>
  15. 16. MPA exposure and Clinical Outcomes <ul><li>Fixed Dose versus Concentration Control Study (FDCC) </li></ul><ul><li>Opticept trial </li></ul><ul><ul><li>Abbreviated MPA AUC and C0 MPA vs emperical dosing </li></ul></ul><ul><li>1 dose fits all? </li></ul><ul><li>Dose doesn’t correlate with MPA levels </li></ul>
  16. 18. TDM usefulness <ul><li>Liver dysfunction </li></ul><ul><li>CKD </li></ul><ul><li>DGF </li></ul><ul><li>Compliance </li></ul><ul><li>Infection </li></ul><ul><li>Rejection </li></ul><ul><li>Suspect drug interaction </li></ul>
  17. 19. Guidelines for TDM <ul><li>With Csa </li></ul><ul><ul><li>1-3.5mg/L (C0 MPA), 30-60mg/h/l (AUC) </li></ul></ul><ul><li>With Tacrolimus </li></ul><ul><ul><li>1.9-4.0mg/L (C0 MPA), 30-60mg/h/L (AUC) </li></ul></ul>
  18. 20. Literature <ul><li>TDM in MPA, cJASN August 2007 </li></ul>

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