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.
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Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
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Acknowledgements
Dr Staatz would like to acknowledge financial support from an Australian National Health and Medical Research Council Neil Hamilton Fairley Fellowship. The authors have no pharmaceutical industry affiliation and have no pecuniary interests (personal or professional), grants or other potential conflicts of interest with any pharmaceutical company that are directly relevant to the content of this review.
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Staatz, C.E., Tett, S.E. Clinical Pharmacokinetics and Pharmacodynamics of Mycophenolate in Solid Organ Transplant Recipients. Clin Pharmacokinet 46, 13–58 (2007). https://doi.org/10.2165/00003088-200746010-00002
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DOI: https://doi.org/10.2165/00003088-200746010-00002