Sirolimus drug monitoring

Taylor, P.J. et al. 2000. Simultaneous quantification of tacrolimus and sirolimus in human blood by high performance liquid chromatography-tandem mass spectrometry. Ther Drug Monitor. 22 608. 

CICLOSPORIN SIROUMUS t bioavailability of sirolimus (30-40% when drug administrations are separated by 4 hours and 100% when administered together) Due to inhibition of P-gp by cidosporin and competition for metabolism by CYP3A4 Be aware of toxic effects of sirolimus and monitor blood levels... 

SIROLIMUS ANTIVIRALS-PROTEASE INHIBITORS t levels with protease inhibitors Inhibition of CYP3A4-mediated metabolism of these immunomod-ulating drugs Monitor clinical effects closely check levels... 

M. Oellerich, V.W. Armstrong, F. Streit, L. Weber, B. Tonshoff, Immunosuppressive drug monitoring of sirolimus and CsA in pediatric patients, Clin. Biochem., 37... 

Kahan BD, Napoli KL, KeEy PA, Podbielski J, Hussein I, Urbauer DL, et al. Therapeutic drug monitoring of sirolimus Correlations with efficacy and toxicity. Clin Transplant 2000 14 97-109. 

Macdonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Therapeutics 2000 22(SupplB) B101-21. 

Kalian BD, Murgia MG, Slaton J, Napoli K. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit 1995 17 672-5. 

Drugs that inhibit the cytochrome P450 isoenzyme CYP3A4 are predicted to raise sirolimus levels. Monitoring is recommended. 

Key words Cyclosporine, Sirolimus, Tacrolimus, Mass spectrometry. Therapeutic drug monitoring... 

Monitoring Monitor whole blood sirolimus concentrations in patients receiving concentration-controlled sirolimus. Monitoring is also necessary in patients likely to have altered drug metabolism, in patients at least 13 years of age who weigh less than 40 kg, in patients with hepatic impairment, and during coadministration of potent CYP3A4 inducers and inhibitors. 

CALCIUM CHANNEL BLOCKERS SIROUMUS Plasma concentrations of sirolimus are t when given with diltiazem. Plasma levels of both drugs are t when verapamil and sirolimus are coadministered Diltiazem and verapamil inhibit intestinal CYP3A4, which is the main site of sirolimus metabolism Watch for side-effects of sirolimus when it is co-administered with diltiazem or verapamil monitor renal and hepatic function. Monitor PR and BP closely when sirolimus is given with verapamil... 

SIROLIMUS CO-TRIMOXAZOLE Exacerbates neutropenia caused by sirolimus Additive effect Monitor blood count closely >- For signs and symptoms of neutropenia, see Clinical Features of Some Adverse Drug Interactions, Immunosuppression and blood dyscrasias... 

M.A. Poquette, G.L. Lensmeyer, T.C. Doran, Effective use ofLC-MS in the routine clinical laboratory for monitoring sirolimus, tacrolimus and CsA, Ther. Drug Monit., 27 (2005) 144. 

Disposition and Pharmacokinetics After oral administration, sirolimus is absorbed rapidly and reaches a peak blood concentration within 1 hour after a single dose in healthy subjects and within 2 hours after multiple oral doses in renal transplant patients. Systemic availability is 15%, and blood concentrations are proportional to doses between 3 and 12 mg/m. A high-fat meal decreases peak blood concentration by 34% sirolimus therefore should be taken consistently either with or without food, and blood levels should be monitored closely. About 40% of sirolimus in plasma is protein bound, especially to albumin. The drug partitions into formed elements of blood, with a blood plasma ratio of 38 in renal transplant patients. Sirolimus is extensively metabolized by CYP3A4 and is transported by P-glycoprotein. Although some of its metabolites are active, sirolimus itself is the major active component in whole blood and contributes >90% of the immunosuppressive effect. The blood tj after multiple doses in stable renal transplant patients is 62 hours. A loading dose of three times the maintenance dose usually provides nearly steady-state concentrations within 1 day. 

There appear to be no reports of an interaction between miconazole and sirolimus. However, a large proportion of miconazole oral gel (both prescription and non-prescription doses) may be swallowed and therefore adequate systemic absorption may occur to produce an interaction. The manufacturers of miconazole oral gel recommend close monitoring and possible dose reduction of sirolimus if both drugs are given. An interaction with intravaginal miconazole would not normally be expected because its systemic absorption is usually very low (less than 2%). 

Drugs that Induce the cydochrome P450 isoenzyme CYP3A4 are predicted to lower sirolimus levels. Close monitoring is recommended. 

These predictions are as yet unconfirmed, but it would certainly be prudent to monitor sirolimus levels closely if these drugs are used concurrently. What should be remembered is that the extent of the inhibitory effects of these drugs is not identical, so that very marked effects like those observed with ketoconazole may not occur, nevertheless the interaction may still be clinically important. Grapefruit juice also inhibits CYP3A4 (potentially raising sirolimus levels), and in this case the manufacturers recommend that concurrent use should be avoided. - ... 

These appear to be the only reports of this interaction, but they are consistent with the way both drugs are known to interact. It would therefore seem prudent to monitor sirolimus levels in any patient in whom phenytoin is started or withdrawn, and to adjust the dose as necessary. 

The manufacturers point out that sirolimus is extensively metabolised by cytochrome P450 isoenzyme CYP3A4 and cleared by P-glycoprotein, so drugs such as the protease inhibitors, which inhibit their activity may raise sirolimus levels. Close monitoring with dose adjustments are recommended during the concurrent use of sirolimus and nelfinavir, or any other protease inhibitor. 

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