Sirolimus: the evidence for clinical pharmacokinetic monitoring

Clin Pharmacokinet. 2005;44(8):769-86. doi: 10.2165/00003088-200544080-00001.


This review seeks to apply a decision-making algorithm to establish whether clinical pharmacokinetic monitoring (CPM) of sirolimus (rapamycin) in solid organ transplantation is indicated in specific patient populations. The need for CPM of sirolimus, although a regulatory requirement in Europe, has not yet been firmly established in North America and other parts of the world. Sirolimus has demonstrated immunosuppressive efficacy in renal, pancreatic islet cell, liver and heart transplant recipients. The pharmacological response of immunosuppressive therapy with sirolimus cannot be readily evaluated; however, a relationship between trough blood sirolimus concentrations, area under the plasma concentration-time curve (AUC) and the incidence of rejection has been proposed. Furthermore, sirolimus can be measured in whole blood by several assays--high-performance liquid chromatography with detection by tandem mass spectrometry, or with ultraviolet detection, radioreceptor assay or microparticle enzyme immunoassay. Both experimental animal and clinical data suggest that adverse events and their associated severity are correlated with blood concentrations. To prevent rejection and minimise toxicity, a therapeutic range of 4-12 microg/L (measured via chromatographic assays) is recommended when sirolimus is used in conjunction with ciclosporin. If ciclosporin therapy is discontinued, a target trough range of 12-20 microg/L is recommended. Sirolimus pharmacokinetics display large inter- and intrapatient variability, which may change in specific patient populations due to disease states or concurrent immunosuppressants or other interacting drugs. Due to the long half-life of sirolimus, dosage adjustments would ideally be based on trough levels obtained more than 5-7 days after initiation of therapy or dosage change. Once the initial dose titration is complete, monitoring sirolimus trough concentrations weekly for the first month and every 2 weeks for the second month appears to be appropriate. After the first 2 months of dose titration, routine CPM of sirolimus is not necessary in all patients, but may be warranted to achieve target concentrations in certain populations of patients, but the frequency of further monitoring remains to be determined and should be individualised.

Publication types

  • Review

MeSH terms

  • Algorithms
  • Animals
  • Clinical Trials as Topic
  • Decision Making
  • Drug Monitoring
  • Humans
  • Immunosuppressive Agents / pharmacokinetics*
  • Immunosuppressive Agents / therapeutic use
  • Organ Transplantation*
  • Sirolimus / pharmacokinetics*
  • Sirolimus / therapeutic use


  • Immunosuppressive Agents
  • Sirolimus