test-icon Mycophenolic acid – LC-MS/MS:

(Assayed daily, Monday to Friday)

Mycophenolic acid (MPA) monitoring is recommended for all patients receiving immunosuppression with mycophenolate mofetil (CellCept, Arzip, Myfenax) for preventing graft rejection or autoimmune-based disorders. MPA monitoring is not yet of proven value in Myfortic therapy (slow release mycophenolate sodium).

The increasing rationale for monitoring mycophenolic acid is based on considerable inter-individual variability relating to (a) genetic variants in transport proteins and metabolic activity, (b) physiological variables such as renal function, plasma proteins, drug interactions and gastrointestinal colonisation, and (c) evidence of an association of low plasma concentrations with rejection, and of high concentrations with side-effects. Evidence is available from studies in liver (Tredger et al., Liver Transplantation 2004; 10: 492–502) and renal graft recipients (Borrows et al., American Journal of Transplantation 2006; 6: 121–128), with consensus data available in Kuypers et al. (Clinical Journal of the American Society of Nephrology 2010; 5: 341–358). Based on our own experience, we suggest that monitoring mycophenolic acid pre-dose plasma levels is the most practical approach.

Please note that it is important to take samples at or after 12 h post dose because of the effects of an earlier (6–10 h post-dose) peak of enterohepatically recirculated MPA.

Note: Whole blood samples for mycophenolate assay from external hospitals or General Practitioners must be separated before sending to the laboratory, as levels of mycophenolate in whole blood may change significantly due to breakdown of MPA or the major glucuronide metabolite at ambient and elevated temperatures (Tracey et al., Therapeutic Drug Monitoring 2012; 34: 148–152). Samples should be separated within 12 hours of collection and the plasma stored at 4°C or -20°C prior to posting. Samples should be sent by first class post - or courier if ambient temperatures exceed 30°C.

We would advise referrers not to despatch samples to us on a Friday.
Contact the service providers before sending such samples, on 0(044) 20 3299 3147.
Turnaround: >95% of samples are turned around within 24 h of receipt on weekdays. We aim to issue results by 4 pm on samples received by 1.30 pm and, depending on workload, by 5–6pm for samples received up to 2.30 pm.
Sample: 0.5 mL EDTA plasma or 2 mL EDTA-anticoagulated whole blood just pre-dose (12h / 24 h post-dose for twice / once daily dosing respectively)
Method: Liquid chromatography-tandem mass spectrometry
Principle: Mycophenolic acid is measured in plasma using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (Brown et al., Therapeutic Drug Monitoring 2010; 32: 420–426). The IDM laboratory participates in the International Proficiency Testing Scheme for mycophenolic acid. Measurements of the primary phenolic glucuronide conjugate are also possible using this method but have not been found helpful in patient management.

Immunosuppressive drugs require monitoring because they act within a narrow range of concentrations and show large inter-individual differences in drug handling and efficacy which make standard dosing regimens impractical. Therapy aims to suppress the immune system sufficiently to prevent graft rejection or autoimmune disease but without either acute toxicity (e.g. renal or gastrointestinal damage) or the increased generic risks of infection or malignancy. IDM provides the most valuable method for regulating dosage in these circumstances and because no real time measurement of “immunosuppression” exists. The principle is to adjust dosage on the basis of standardised drug level measurements that can be targeted to a therapeutic range appropriate for the individual patient. Such adjustments must be made in conjunction with clinical information and other laboratory test results. IDM therapeutic ranges may vary with:

  • the indication for drug therapy (reflecting disease or transplant history)
  • time after the operation
  • co-therapy with other immunosuppressive agents.

The customary single blood sample used for monitoring is the trough drug level, determined just prior to dosage and at a constant interval from the time of the previous dose. Measurements at alternative times, e.g. 2 hours post dose (C2), may be useful in certain situations. For ciclosporin in particular, a C2 level might offer an improved estimate of total early drug exposure. However, it may be difficult to obtain accurately if dosage and phlebotomy times vary. Therapeutic ranges are higher for C2 than for trough drug levels because drug concentrations peak at around 2 h post dose. Contact the IDM Laboratory for more information if required.

Immunosuppressive drug concentrations may also be profoundly affected by:

  • co-medication – especially cytochrome P450 inducers and inhibitors for tacrolimus, ciclosporin sirolimus and everolimus (e.g. rifampicin, corticosteroids and antifungal or antiviral agents) and antiviral co-therapy (e.g. ganciclovir, aciclovir); oral antibiotics and changing ciclosporin or tacrolimus levels (or inter-conversion) for mycophenolate;
  • organ function, especially liver function for tacrolimus and ciclosporin, and renal function for mycophenolate;
  • gastrointestinal dysfunction and haemodynamic instability;
  • hypoalbuminaemia and low haematocrit – increasing free drug levels (and often toxicity);
  • genetic variability between individuals e.g. in the expression of cytochrome P450 3A or p-glycoprotein for tacrolimus, ciclosporin or sirolimus, and of UDP-glucuronyltransferase (UDPGT) 1A8/9 for mycophenolate;
  • non-prescription substances such as St John’s wort and grapefruit juice.

In addition to use as an immunosuppressant, everolimus is being used as an antitumour drug and has been licensed for use in treating advanced renal cell carcinoma with the alternate trade name of Afinitor. Currently there is no information available on a suitable therapeutic range for these effects.

The frequency at which IDM is performed generally decreases with time after transplant. It is rarely necessary to monitor levels more than three times weekly e.g. Monday, Wednesday and Friday, because the half-lives of the immunosuppressants exceed 12 h. Consequently, drug levels will not re-equilibrate for 2–3 days after changes in dosage. However, immediately after transplantation, daily monitoring may be required in unstable (especially paediatric) patients but the frequency may decrease to once three or six monthly in long-term stable patients. The frequency of testing should be determined by any changes in likely modulators of drug levels, that is:

  • if immunosuppressive drug dosage is increased or decreased on clinical grounds;
  • if the formulation of the drug is changed e.g. Prograf to Advagraf / Modigraf / Adoport, Neoral to Deximmune, CellCept to Arzip / Myfenax;
  • if acute graft rejection is diagnosed;
  • if any other type of graft dysfunction occurs or is suspected;
  • if drug-related side-effects are detected (e.g. nephro- or neurotoxicity for tacrolimus or ciclosporin, gastrointestinal disturbance for mycophenolate);
  • if co-medication affecting drug levels is introduced, tapered or withdrawn;
  • if liver or renal function additionally deteriorates or improves;
  • if non-adherence is suspected;
  • if diarrhoea or persistent severe gastrointestinal dysfunction occurs.

The examination of drug profiles during a dosage interval may be a valuable adjunct to conventional trough level monitoring. The additional information available from these pharmacokinetic studies may reveal unexpected abnormalities in the rate and extent of drug absorption and disposition.

test-icon Turnaround: within 24hrs.
price-icon Price: Contact Lab
contact-icon Contacts
IDM service: kch-tr.KCHIDMService@nhs.net
ref-range-icon Reference Ranges
Therapeutic Ranges: (males = females)
NB. The range quoted is based on current information and particularly on the data presented by Tredger et al. (Liver Transplantation 2004; 10: 492–502). It will need to be considered in the context of clinical indications and any additional immunosuppressive therapy that is prescribed.

1 – 3.5 mg/L (µg/mL)
  • Stable liver graft recipients on ciclosporin or tacrolimus comedication.
  • Renal, cardiac and other graft recipients.
  • Liver recipients given MPA early post-transplant as monotherapy (+ glucocorticoids), or for supplementary anti-rejection therapy.
  • Treatment of Graft-versus host disease.
  • Treatment of autoimmune disease.
A range of 2 – 5 mg/L may be applicable in thoracic transplantation.