test-icon Sirolimus – LC-MS/MS:

(Assayed daily, Monday to Friday)

Sirolimus (rapamycin, Rapamune) can be used to provide immunosuppression to prevent organ rejection following allograft. Impaired wound healing means it is usually introduced sometime after transplant together with a gradual reduction / withdrawal of calcineurin inhibitor, usually ciclosporin. Whole blood concentrations of sirolimus should be monitored to assist dose optimisation and to minimise side effects / toxicity.

Turnaround: >95% of samples are turned round within 24 h of receipt on weekdays. We aim to issue results by 5 pm on samples received by 1.30 pm and by the following workday morning for samples received up to 3.30 pm
Sample: 2 mL EDTA-anticoagulated whole blood just pre-dose (24 h post-dose for once daily dosing)
Method: Liquid chromatography-tandem mass spectrometry
Principle: Sirolimus is measured in whole blood using a validated in-house liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The IDM laboratory participates in the International Proficiency Testing Scheme for sirolimus.

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.

time-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)

Results may vary with concomitant immunosuppressive therapy and time after and indication for transplantation. Results of < 2 µg/L and > 15 µg/L (ng/mL) may be associated with an increased risk of rejection or side-effects, respectively, and are not recommended.

Similar targets are emerging in heart, kidney and pancreas islet cell transplantation:

  • 8–12 µg/L in post-operative months 1 to 3 (with tacrolimus of 3–6 µg/L or corresponding low-dose ciclosporin therapeutic ranges).
  • 3–8 µg/L after post-operative month 3 (with tacrolimus of 3–6 µg/L or corresponding low-dose ciclosporin therapeutic ranges).
  • Higher levels (up to 20 µg/L) may be used in monotherapy (with glucocorticoids).

NB: Ciclosporin increases sirolimus blood levels and doses of the two agents should be staggered by at least 4 h.