Clin Pharmacokinet. 2007;46(1):13-58. doi: 10.2165/00003088-200746010-00002.
Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients.
Clinical pharmacokinetics
Christine E Staatz, Susan E Tett
PMID: 17201457
DOI: 10.2165/00003088-200746010-00002
Abstract
This review aims to provide an extensive overview of the literature on the clinical pharmacokinetics of mycophenolate in solid organ transplantation and a briefer summary of current pharmacodynamic information. Strategies are suggested for further optimisation of mycophenolate therapy and areas where additional research is warranted are highlighted. Mycophenolate has gained widespread acceptance as the antimetabolite immunosuppressant of choice in organ transplant regimens. Mycophenolic acid (MPA) is the active drug moiety. Currently, two mycophenolate compounds are available, mycophenolate mofetil and enteric-coated (EC) mycophenolate sodium. MPA is a potent, selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), leading to eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate mofetil and EC-mycophenolate sodium are essentially completely hydrolysed to MPA by esterases in the gut wall, blood, liver and tissue. Oral bioavailability of MPA, subsequent to mycophenolate mofetil administration, ranges from 80.7% to 94%. EC-mycophenolate sodium has an absolute bioavailability of MPA of approximately 72%. MPA binds 97-99% to serum albumin in patients with normal renal and liver function. It is metabolised in the liver, gastrointestinal tract and kidney by uridine diphosphate gluconosyltransferases (UGTs). 7-O-MPA-glucuronide (MPAG) is the major metabolite of MPA. MPAG is usually present in the plasma at 20- to 100-fold higher concentrations than MPA, but it is not pharmacologically active. At least three minor metabolites are also formed, of which an acyl-glucuronide has pharmacological potency comparable to MPA. MPAG is excreted into the urine via active tubular secretion and into the bile by multi-drug resistance protein 2 (MRP-2). MPAG is de-conjugated back to MPA by gut bacteria and then reabsorbed in the colon. Mycophenolate mofetil and EC-mycophenolate sodium display linear pharmacokinetics. Following mycophenolate mofetil administration, MPA maximum concentration usually occurs in 1-2 hours. EC-mycophenolate sodium exhibits a median lag time in absorption of MPA from 0.25 to 1.25 hours. A secondary peak in the concentration-time profile of MPA, due to enterohepatic recirculation, often appears 6-12 hours after dosing. This contributes approximately 40% to the area under the plasma concentration-time curve (AUC). The mean elimination half-life of MPA ranges from 9 to 17 hours. MPA displays large between- and within-subject pharmacokinetic variability. Dose-normalised MPA AUC can vary more than 10-fold. Total MPA concentrations should be interpreted with caution in patients with severe renal impairment, liver disease and hypoalbuminaemia. In such individuals, MPA and MPAG plasma protein binding may be altered, changing the fraction of free MPA available. Apparent oral clearance (CL/F) of total MPA appears to increase in proportion to the increased free fraction, with a reduction in total MPA AUC. However, there may be little change in the MPA free concentration. Ciclosporin inhibits biliary excretion of MPAG by MRP-2, reducing enterohepatic recirculation of MPA. Exposure to MPA when mycophenolate mofetil is given in combination with ciclosporin is approximately 30-40% lower than when given alone or with tacrolimus or sirolimus. High dosages of corticosteroids may induce expression of UGT, reducing exposure to MPA. Other co-medications can interfere with the absorption, enterohepatic recycling and metabolism of mycophenolate. Most pharmacokinetic investigations of MPA have involved mycophenolate mofetil rather than EC-mycophenolate sodium therapy. In population pharmacokinetic studies, MPA CL/F in adults ranges from 14.1 to 34.9 L/h (ciclosporin co-therapy) and from 11.9 to 25.4 L/h (tacrolimus co-therapy). Patient bodyweight, serum albumin concentration and immunosuppressant co-therapy have a significant influence on CL/F. The majority of pharmacodynamic data on MPA have been obtained in patients receiving mycophenolate mofetil therapy in the first year after kidney transplantation. Low MPA AUC is associated with increased incidence of biopsy-proven acute rejection. Gastrointestinal adverse events may be dose related. Leukopenia and anaemia have been associated with high MPA AUC, trough concentration and metabolite concentrations in some, but not all, studies. High free MPA exposure has been identified as a risk factor for leukopenia in some investigations. Targeting a total MPA AUC from 0 to 12 hours (AUC12) of 30-60 mg.hr/L is likely to minimise the risk of acute rejection and may reduce toxicity. IMPDH monitoring is in the early experimental stage. Individualisation of mycophenolate therapy should lead to improved patient outcomes. MPA AUC12 appears to be the most useful exposure measure for such individualisation. Limited sampling strategies and Bayesian forecasting are practical means of estimating MPA AUC12 without full concentration-time profiling. Target concentration intervention may be particularly useful in the first few months post-transplant and prior to major changes in anti-rejection therapy. In patients with impaired renal or hepatic function or hypoalbuminaemia, free drug measurement could be valuable in further interpretation of MPA exposure.
References
- Nephrol Dial Transplant. 2004 Oct;19(10 ):2630-3 - PubMed
- Ther Drug Monit. 2005 Jun;27(3):354-61 - PubMed
- Pediatr Nephrol. 2000 Feb;14 (2):95-9 - PubMed
- Transplantation. 1998 Jan 27;65(2):242-8 - PubMed
- Br J Clin Pharmacol. 2005 Sep;60(3):249-56 - PubMed
- Transplant Proc. 2005 Mar;37(2):856-8 - PubMed
- Ther Drug Monit. 2005 Jun;27(3):315-21 - PubMed
- Transplant Proc. 2004 Nov;36(9):2787-90 - PubMed
- Drug Saf. 2001;24(9):645-63 - PubMed
- Transplant Proc. 1998 Aug;30(5):1773-4 - PubMed
- Am J Transplant. 2004 Dec;4(12 ):2045-51 - PubMed
- Clin Chem Lab Med. 2000 Nov;38(11):1213-6 - PubMed
- Clin Transplant. 2000 Jun;14 (3):179-88 - PubMed
- Transpl Int. 1998;11 Suppl 1:S82-5 - PubMed
- Transplant Proc. 2003 Sep;35(6):2369-71 - PubMed
- Clin Pharmacokinet. 1998 Jun;34(6):429-55 - PubMed
- Ther Drug Monit. 2000 Feb;22(1):20-6 - PubMed
- Clin Pharmacol Ther. 2005 Jul;78(1):81-8 - PubMed
- Eur J Clin Pharmacol. 2005 Aug;61(7):507-16 - PubMed
- Ther Drug Monit. 2004 Jun;26(3):284-6 - PubMed
- Clin Sci (Lond). 2004 Jul;107(1):63-8 - PubMed
- Ann Pharmacother. 2003 Nov;37(11):1685-93 - PubMed
- Br J Clin Pharmacol. 2005 Mar;59(3):271-80 - PubMed
- Ther Drug Monit. 2001 Apr;23(2):119-28 - PubMed
- Clin Pharmacokinet. 2004;43(4):253-66 - PubMed
- Br J Clin Pharmacol. 2006 Oct;62(4):477-84 - PubMed
- Transpl Int. 2000;13 Suppl 1:S333-5 - PubMed
- Ther Drug Monit. 1999 Oct;21(5):498-506 - PubMed
- Nephrol Dial Transplant. 1999;14 Suppl 4:34-5 - PubMed
- Ther Drug Monit. 2001 Oct;23(5):514-9 - PubMed
- Liver Transpl. 2001 Aug;7(8):739-42 - PubMed
- Br J Clin Pharmacol. 1996 Jun;41(6):513-6 - PubMed
- Clin Chem. 1995 Jul;41(7):1011-7 - PubMed
- Clin Pharmacol Ther. 1999 Jun;65(6):640-8 - PubMed
- Ther Drug Monit. 2001 Dec;23 (6):717-21 - PubMed
- Am J Transplant. 2004 Mar;4(3):299-310 - PubMed
- J Clin Pharmacol. 2001 Mar;41(3):268-76 - PubMed
- J Clin Pharmacol. 2004 Jul;44(7):743-50 - PubMed
- Am J Transplant. 2004;4 Suppl 9:38-53 - PubMed
- Transplant Proc. 2004 Sep;36(7):2079-81 - PubMed
- Pediatr Nephrol. 2000 Feb;14 (2):100-4 - PubMed
- J Heart Lung Transplant. 1999 Feb;18(2):143-9 - PubMed
- Ther Drug Monit. 2005 Jun;27(3):378-88 - PubMed
- Transplantation. 2004 Jan 27;77(2):206-9 - PubMed
- Br J Pharmacol. 2001 Mar;132(5):1027-34 - PubMed
- Clin Pharmacol Ther. 2005 Jul;78(1):34-42 - PubMed
- Lancet. 1995 May 27;345(8961):1321-5 - PubMed
- Ther Drug Monit. 2000 Feb;22(1):14-9 - PubMed
- Liver Transpl. 2004 Apr;10 (4):492-502 - PubMed
- Clin Chem. 2001 Jan;47(1):88-94 - PubMed
- Lupus. 2005;14 Suppl 1:s2-8 - PubMed
- Transplant Proc. 2004 Apr;36(3):687-9 - PubMed
- J Clin Pharmacol. 2003 Aug;43(8):866-80 - PubMed
- Transplant Proc. 2000 Nov;32(7):1753-4 - PubMed
- Ther Drug Monit. 1994 Dec;16(6):602-7 - PubMed
- Clin Biochem. 2001 Feb;34(1):17-22 - PubMed
- Transplant Proc. 1998 Dec;30(8):4090-1 - PubMed
- Transplant Proc. 1998 Jun;30(4):1192-3 - PubMed
- Nephrol Dial Transplant. 2003 Apr;18(4):819-22 - PubMed
- Transplant Proc. 1995 Feb;27(1):1421-4 - PubMed
- J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Jan 5;799(1):157-63 - PubMed
- Transplant Proc. 2005 Mar;37(2):864-6 - PubMed
- Clin Pharmacol Ther. 2000 Dec;68(6):613-6 - PubMed
- Transplant Proc. 2000 Mar;32(2):388-90 - PubMed
- Pediatr Transplant. 2005 Dec;9(6):780-7 - PubMed
- Transplant Proc. 1996 Apr;28(2):925-9 - PubMed
- Transplant Proc. 2001 Feb-Mar;33(1-2):1052-3 - PubMed
- Clin Pharmacokinet. 2005;44(8):837-47 - PubMed
- Transplantation. 1996 Apr 15;61(7):1029-37 - PubMed
- J Zhejiang Univ Sci B. 2005 Sep;6(9):885-91 - PubMed
- J Heart Lung Transplant. 2002 Oct;21(10 ):1074-9 - PubMed
- J Clin Pharm Ther. 2003 Feb;28(1):17-22 - PubMed
- Clin Chem. 2002 Sep;48(9):1497-504 - PubMed
- Pediatr Nephrol. 2001 Dec;16(12 ):978-84 - PubMed
- Transpl Immunol. 1997 Sep;5(3):225-32 - PubMed
- Transplant Proc. 2004 Sep;36(7):2076-8 - PubMed
- Drug Metab Dispos. 2005 Jan;33(1):139-46 - PubMed
- Br J Clin Pharmacol. 2001 Nov;52(5):605-9 - PubMed
- Transplant Proc. 2002 Aug;34(5):1745-7 - PubMed
- Am J Kidney Dis. 2004 Jun;43(6):1098-103 - PubMed
- Ther Drug Monit. 2001 Oct;23 (5):520-5 - PubMed
- Clin Sci (Lond). 2004 Jul;107(1):69-74 - PubMed
- Drug Metab Rev. 2001 Aug-Nov;33(3-4):273-97 - PubMed
- J Clin Pharmacol. 1996 Apr;36(4):315-24 - PubMed
- Ther Drug Monit. 2002 Apr;24(2):310-4 - PubMed
- Ther Drug Monit. 2004 Dec;26(6):600-8 - PubMed
- J Am Soc Nephrol. 1998 Aug;9(8):1511-20 - PubMed
- Br J Clin Pharmacol. 2003 Aug;56(2):188-97 - PubMed
- Clin Pharmacol Ther. 2004 May;75(5):434-47 - PubMed
- J Am Soc Nephrol. 2002 Mar;13(3):759-68 - PubMed
- Clin Biochem. 2001 Feb;34(1):77-81 - PubMed
- Ther Drug Monit. 2003 Oct;25(5):609-22 - PubMed
- Ther Drug Monit. 1999 Oct;21(5):536-9 - PubMed
- Pharmacotherapy. 1997 May-Jun;17 (3):591-8 - PubMed
- J Clin Pharmacol. 2002 Nov;42(11):1275-80 - PubMed
- Ther Drug Monit. 1999 Feb;21(1):35-43 - PubMed
- Clin Pharmacol Ther. 1998 Dec;64(6):672-83 - PubMed
- Kidney Int. 2002 Sep;62(3):1060-7 - PubMed
- Am J Transplant. 2003 Dec;3(12 ):1581-6 - PubMed
- Transplant Proc. 2002 Nov;34(7):2983-4 - PubMed
- Ther Drug Monit. 2003 Apr;25(2):137-57 - PubMed
- Clin Pharmacol Ther. 2005 Oct;78(4):351-61 - PubMed
- Transplantation. 1997 Jan 15;63(1):39-47 - PubMed
- Am J Transplant. 2004 Sep;4(9):1495-500 - PubMed
- Pharmacol Toxicol. 2000 Oct;87(4):182-4 - PubMed
- Transplant Proc. 1998 Aug;30(5):2237-9 - PubMed
- Ther Drug Monit. 2004 Aug;26(4):453-5 - PubMed
- Transplant Proc. 2005 May;37(4):1751-3 - PubMed
- Clin Chem. 2004 Jan;50(1):152-9 - PubMed
- Am J Transplant. 2005 Feb;5(2):199-200 - PubMed
- J Clin Pharmacol. 1996 Apr;36(4):332-44 - PubMed
- Am J Transplant. 2003 May;3(5):534-42 - PubMed
- Ann Clin Biochem. 2002 May;39(Pt 3):173-83 - PubMed
- Transpl Int. 2000;13 Suppl 1:S301-5 - PubMed
- Clin Transplant. 2005 Apr;19(2):199-206 - PubMed
- Transplant Proc. 1998 Jun;30(4):1185-7 - PubMed
- Liver Transpl Surg. 1999 Mar;5(2):101-6 - PubMed
- Clin Chem. 2001;47(7):1241-8 - PubMed
- Clin Biochem. 1998 Jul;31(5):323-8 - PubMed
- Drugs. 2005;65(8):1037-50 - PubMed
- Clin Pharmacol Ther. 2005 Oct;78(4):317-21 - PubMed
- Ann Pharmacother. 2003 Dec;37(12):1761-7 - PubMed
- Clin Chem. 2000 Mar;46(3):365-72 - PubMed
- J Clin Pharmacol. 2000 Jun;40(6):624-33 - PubMed
- Transplantation. 1995 Aug 15;60(3):225-32 - PubMed
- Am J Transplant. 2005 May;5(5):987-94 - PubMed
- Transplant Proc. 2004 Sep;36(7):2065-7 - PubMed
- Transplantation. 1999 Jul 27;68(2):261-6 - PubMed
- J Pharmacol Exp Ther. 2003 Aug;306(2):688-93 - PubMed
- J Chromatogr B Biomed Sci Appl. 1998 Apr 24;708(1-2):229-34 - PubMed
- Ther Drug Monit. 2002 Jun;24(3):390-9 - PubMed
- Transpl Int. 2005 Feb;18(2):140-50 - PubMed
- Clin Biochem. 1998 Jul;31(5):329-33 - PubMed
- Nephrol Dial Transplant. 1999;14 Suppl 4:33-4 - PubMed
- Clin Pharmacokinet. 2004;43(10 ):685-92 - PubMed
- Ther Drug Monit. 1998 Dec;20(6):685-90 - PubMed
- Ther Drug Monit. 1997 Jun;19(3):358-60 - PubMed
- J Chromatogr B Biomed Sci Appl. 2000 Oct 1;748(1):151-6 - PubMed
- Clin Pharmacol Ther. 1999 Nov;66(5):492-500 - PubMed
- Ther Drug Monit. 2001 Feb;23(1):35-8 - PubMed
- Transplantation. 1999 Nov 27;68(10):1603-6 - PubMed
- Transplant Proc. 2001 Feb-Mar;33(1-2):1040-3 - PubMed
- J Clin Pharmacol. 1999 Jul;39(7):715-20 - PubMed
- Transplantation. 1992 Feb;53(2):428-32 - PubMed
- Ther Drug Monit. 2004 Dec;26(6):620-5 - PubMed
- Transplant Proc. 1998 Jun;30(4):1299-302 - PubMed
- Transplant Proc. 2005 May;37(4):1748-50 - PubMed
- Clin Transplant. 2001 Dec;15(6):402-9 - PubMed
- Clin Biochem. 1998 Jul;31(5):317-22 - PubMed
- Transplantation. 2003 Mar 15;75(5):665-72 - PubMed
- Clin Transplant. 2003 Dec;17 (6):511-7 - PubMed
- Transplantation. 1997 Nov 15;64(9):1277-82 - PubMed
- Ther Drug Monit. 2004 Dec;26(6):609-19 - PubMed
- Transpl Int. 1998;11(1):53-7 - PubMed
- Am J Transplant. 2004 Feb;4(2):231-6 - PubMed
- J Clin Pharmacol. 2005 Jan;45(1):34-41 - PubMed
- J Am Soc Nephrol. 2003 Mar;14 (3):721-7 - PubMed
- Clin Biochem. 2001 Oct;34(7):543-9 - PubMed
- Ther Drug Monit. 2000 Oct;22(5):549-54 - PubMed
- Drug Metab Dispos. 2004 Jul;32(7):768-73 - PubMed
- Ther Drug Monit. 2005 Apr;27(2):132-8 - PubMed
- Ther Drug Monit. 2004 Aug;26(4):347-51 - PubMed
- Ther Drug Monit. 2002 Oct;24(5):598-606 - PubMed
- J Heart Lung Transplant. 2000 Nov;19(11):1071-6 - PubMed
- Transplant Proc. 2005 Jun;37(5):2320-3 - PubMed
- J Clin Pharmacol. 2005 Feb;45(2):219-26 - PubMed
- Clin Pharmacokinet. 2005;44(10 ):1083-96 - PubMed
- Transplant Proc. 1999 Feb-Mar;31(1-2):1135-7 - PubMed
- Transplant Proc. 2005 Mar;37(2):852-5 - PubMed
- J Pharmacol Exp Ther. 2003 Oct;307(1):117-28 - PubMed
- Clin Transplant. 2005 Aug;19(4):551-8 - PubMed
- Transplantation. 1998 Apr 27;65(8):1127-9 - PubMed
- J Clin Pharmacol. 1998 Mar;38(3):268-75 - PubMed
- J Heart Lung Transplant. 2003 May;22(5):587-90 - PubMed
- Ther Drug Monit. 2000 Feb;22(1):27-30 - PubMed
- Clin Biochem. 2000 Mar;33(2):107-13 - PubMed
- Ther Drug Monit. 2003 Feb;25(1):1-16 - PubMed
- Ther Drug Monit. 1995 Dec;17 (6):690-9 - PubMed
- Transplant Proc. 1998 Jun;30(4):1182-4 - PubMed
- Transplantation. 2000 Jun 15;69(11):2326-30 - PubMed
- Int J Clin Pharmacol Ther. 2003 Oct;41(10 ):470-6 - PubMed
- Transplant Proc. 2005 Mar;37(2):861-3 - PubMed
- Transplant Proc. 2001 Nov-Dec;33(7-8):3241-4 - PubMed
- Arzneimittelforschung. 2000 Oct;50(10):936-40 - PubMed
- Pharmacogenetics. 2004 Aug;14(8):501-15 - PubMed
- Ther Drug Monit. 2001 Aug;23 (4):305-15 - PubMed
- Br J Pharmacol. 1999 Mar;126(5):1075-82 - PubMed
- J Pharmacol Exp Ther. 2004 Jun;309(3):1029-35 - PubMed
- Transplant Proc. 2002 Nov;34(7):2985-7 - PubMed
- Transplantation. 2004 Aug 27;78(4):591-8 - PubMed
- Nephrol Dial Transplant. 1999 Mar;14 (3):706-8 - PubMed
- Ther Drug Monit. 2000 Apr;22(2):169-73 - PubMed
- Pharm Res. 1990 Feb;7(2):161-6 - PubMed
- Clin Pharmacol Ther. 1998 May;63(5):512-8 - PubMed
- Transplant Proc. 2005 Mar;37(2):859-60 - PubMed
- Drug Metab Dispos. 2004 Aug;32(8):775-8 - PubMed
- Transplant Proc. 2001 May;33(3):2163-4 - PubMed
- Clin Chem. 1999 Mar;45(3):419-22 - PubMed
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