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Sirolimus Level

Sirolimus Level

Sirolimus

Sirolimus (rapamycin, Rapamune) is a macrolide antibiotic, isolated from Streptomyces hygroscopicus, that suppresses T-and B-cell proliferation by inhibiting the protein kinase mTOR. It has no effects on calcineurin and, therefore, can be used in addition to cyclosporine or tacrolimus, or as a substitute for these drugs. Adverse effects of sirolimus are concentration-dependent, making therapeutic drug monitoring essential.

Preferred therapeutic ranges may vary by transplant type, protocol, and concomitant medications. Most individuals display optimal response to sirolimus with trough whole blood levels 4 to 20 ng/mL. Some patients may require higher trough levels between 20 and 30 ng/mL.

Useful For

monitoring whole blood sirolimus concentration during therapy, particularly in individuals coadministered cyp3a4 substrates, inhibitors, or inducers adjusting dose to optimize immune suppression while minimizing toxicity evaluating patient compliance.

Clinical Information

Sirolimus is a macrolide antibiotic, isolated from Streptomyces hygroscopicus, with potent effects including suppression of T- and B-cell proliferation and antineoplastic and antifungal activity. It inhibits the protein kinase to arrest the cell cycle; it has no effects on calcineurin and, therefore, can be used in addition to cyclosporine or tacrolimus, or as a substitute in patients intolerant to these drugs. Sirolimus is metabolized by CYP3A4, thus, blood concentrations are affected by drugs that inhibit or induce this enzyme.

The pharmacokinetic interaction between sirolimus and cyclosporine or tacrolimus increases both therapeutic immunosuppression and the toxicity of these agents; lower doses are required with combined use. Adverse effects of sirolimus are generally concentration dependent, making therapeutic drug monitoring essential.

Discussion

To date, there are no reports of sirolimus interacting with nefazodone. Nefazodone inhibits the cytochrome P450 3A4 enzyme system; which can result in nefazodone increasing blood levels of medication that are metabolized by the cytochrome P450 3A4 enzyme system.1-3 Transplant medications metabolized by the cytochrome P450 3A4 enzyme system are: Tacrolimus, cyclosporine, and sirolimus. This can result in supratherapeutic or subtherapeutic transplant drug levels that may result in immunosuppression toxicity or transplant organ rejection when nefazodone is started or discontinued.

This case highlights the importance of monitoring immunosuppression drug levels since the care of transplant patients requires the treatment with many medications that may frequently interact. It is also equally important to educate our patients to inform their transplant staff about any medications that are started or discontinued from any health care provider to prevent drug toxicity or organ rejection.

Sirolimus in renal transplantation

Acute rejection episodes are now as low as 5–20% in the first year after renal transplantation; however, graft half-life has remained almost unchanged in the last decade. This statistic is mainly attributable to the side effects of immune suppression, with loss of allografts due to the chronic allograft nephropathy that is a consequence of calcineurin inhibitor toxicity or hypertension. Patient death due to cardiovascular events, infections and malignancy also contribute to allograft loss.

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