Clinical pharmacokinetics of sirolimus

Sirolimus (previously known as rapamycin), a macrocyclic lactone, is a pote nt immunosuppressive agent. Sirolimus was recently approved by the US Food and Drug Administration, on the basis of 2 large, double-blind, prospective clinical trials, for use in kidney transplant recipients at a fixed dosage of 2 or 5 mg/day ir, addition to full dosages of cyclosporin and prednison e. However, despite the fixed dosage regimens used in these pivotal trials, pharmacokinetic and clinical data show that sirolimus is a critical-dose d rug requiring therapeutic drug monitoring to minimise drug-related toxiciti es and maximise efficacy. Assays using high performance liquid chromatography coupled to mass spectro metry, although cumbersome, are the gold standard for evaluating other comm only used assays, such as liquid chromatography with ultraviolet detection, radioreceptor assay and microparticle enzyme immunoassay. Sirolimus is available in oral solution and tablet form. It has poor oral a bsorption and distributes widely in tissues, displaying not only a wide int er- and intrapatient variability in drug clearance, but also less than opti mal correlations between whole blood concentrations and drug dose, demograp hic features or patient characteristics. Furthermore, the critical role of the cytochrome P450 3A4 system for sirolimus biotransformation leads to ext ensive drug-drug interactions, among which are increases in cyclosporin con centrations. Thus, sirolimus is now being used to reduce or eliminate expos ure to cyclosporin or corticosteroids. The long elimination half-life of si rolimus necessitates a loading dose but allows once daily administration, w hich is more convenient and thereby could help to improve patient complianc e. This review emphasises the importance of blood concentration monitoring in optimising the use of sirolimus. The excellent correlation between steady-s tate trough concentration (at least 4 days after inception or, or change in , therapy) and area under the concentration-time curve makes the former a s imple and reliable index for monitoring sirolimus exposure. Target trough c oncentration ranges depend on the concomitant immunosuppressive regimen, bu t a range of 5 to 15 mug/L is appropriate if cyclosporin is being used at t rough concentrations of 75 to 150 mug/L. Weekly monitoring is recommended f or the first month and bi-weekly for the next month; thereafter, concentrat ion measurements are necessary only if warranted clinically.