Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus

Background Sirolimus is a novel macrocyclic antibiotic that has an immunosu ppressive mechanism of action distinct from that of cyclosporine and tacrol imus. Objective: The objective of this report is to provide an overview of the cl inical development of sirolimus with emphasis on the mechanism of immunosup pressive activity, prevention of acute renal allograft rejection, clinical pharmacokinetics, concentration-effect relationships, and therapeutic drug monitoring (TDM). Results: Pharmacokinetic studies in adult renal transplant patients have sh own that sirolimus may be characterized as a drug with rapid absorption (t( max) = 1 to 2 hours), low systemic availability (F = 14%), linear dose prop ortionality (2 to 24 mg), extensive partitioning into formed blood elements (B/P = 36), large apparent volume of distribution (1.7 L/kg), prolonged te rminal half-life (62 hours), and large intersubject (CV = 52%) and intrasub ject (CV = 26%) variability in oral-dose clearance. Results from phase III pivotal trials showed that sirolimus (2 or 5 mg/d) reduced acute renal graf t rejection (generally, P < 0.01) without TDM. Although TDM may not be requ ired for a regimen consisting of full-dose cyclosporine and corticosteroids with sirolimus 2 mg/d (4 hours after cyclosporine), it may be warranted in patients (1) with hepatic impairment, (2) who are young children, (3) who are receiving concurrent doses of strong CYP3A/p-glycoprotein inhibitors or inducers, (4) in whom cyclosporine dosing is markedly reduced or discontin ued, and (5) who are at a high risk for rejection. A whole-blood sirolimus therapeutic window of 5 to 15 ng/mL (measured by microparticle enzyme immun oassay) is recommended for patients at standard risk of rejection. The larg e intrapatient variability observed in trough sirolimus concentrations indi cates that dose adjustments should be optimally based on mon than a single trough sample. Because of the time required to reach steady state, sirolimu s dose adjustments would optimally be based on trough levels obtained great er than or equal to 5 to 7 days after a dose change. Conclusions: The effective use of sirolimus in an immunosuppressive regimen for the prevention of acute renal allograft rejection requires an understa nding of the drug's clinical pharmacokinetics, concentration/adverse-effect relationship, concentration-efficacy relationship, and TDM.