sirolimus; rapamycin (Rapamune)
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Indications
- oral immunosuppressive agent for prophylaxis of organ transplantation rejection
- recommended for use with cyclosporine & glucocorticoids
- used as eluate in coronary stents to reduce restenosis[3]
- tuberous sclerosis - renal angiomyolipomas
- facial angiolipomas (topical)
Dosage
- loading dose of 6 mg PO (15 mg/kg)
- maintenance: 2 mg PO QD (1 mg/kg/day)
- should be taken 4 hours after cyclosporine
- mix with 60 mL of water or orange juice only
Solution: (oral)
topical 1%
Storage
- in refrigerator protected from light
- stable at room temperature for 30 days
Pharmacokinetics
- bioavailability
- approximately 14%
- high fat meal increases bioavailability 34%
- 92% bound to serum protein
- serum levels 9 ng/mL with 2 mg/day
- metabolized by cyt P450 3A4 & P-glycoprotein
- terminal elimination 1/2life is 62 hours
Adverse effects
- dyslipidemia, hypercholesterolemia
- nephrotoxicity
- increased serum creatinine
- proteinuria[10]
- Herpes simplex infections with doses > 5 mg/day
- hypertension
- rash
- increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus[6]
- BK virus associated nephropathy in renal transplant patients
- new-onset diabetes mellitus[10]
- anemia, leukopenia[10]
Drug interactions
*
- cyclosporine increases sirolimus levels (2 fold)
- diltiazem increases bioavailability of sirolimus
- ketoconazole increases sirolimus levels (4-fold)
- rifampin increases sirolimus clearance
- other agents that may increase sacrolimus levels
- any drug that inhibits cyt P450 3A4 may increase levels of sirolimus
- grapefruit juice inhibits metabolism of sirolimus
- any drug that induces cyt P450 3A4 may diminish levels of sirolimus
- vaccines:
- sirolimus inhibits response to vaccines
- live virus vaccines should not be used with sirolimus
* agents that may be administered without dose-adjustment of sirolimus:
- drug interaction(s) of methotrexate with biological response modifier
- drug interaction(s) of antibiotics with warfarin
Mechanism of action
- blocks activation of ribosomal S6 kinase, ribosomal protein S6 phosphorylation & recruitment of mRNAs containing polypyrimidine into polysomes.
- inhibits T-lymphocyte activation & proliferation
- binds to FK506-binding proteins FKBP1A (FKBP12), FKBP1B, FKBP2, FKBP3, & FKBP10
- inhibits target of rapamycin regulatory kinase & suppresses T-cell proliferation
- induces G1 arrest[1] through interferences with activation of S6 kinase & G1-kinases
- rapamycin-bound FKBP1A binds FRAP1 & inhibits mTOR (mTOR inhibitor)
- antimitotic properties[4]
Notes
- produced by Streptomyces hygroscopicus
- increases longevity in mice probaby via inhibition of mTOR[5]
More general terms
- mTOR inhibitor; target of rapamycin inhibitor
- heterocyclic compound, 3 rings
- lactone
- antifungal agent
- prokaryote-specific molecule
Additional terms
- cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
- FK506-binding protein 1A (12 kD FK506-binding protein, immunophilin FKBP12, FKBP1A)
- FK506-binding protein 2 (13 kD FK506-binding protein, FKBP2)
- FK506-binding protein 3, 25 kD FK506-binding protein or rapamycin-selective 25 kD immunophilin
- sirolimus in blood
- tacrolimus; FK506; fujimycin (Prograf, Advagraf, Envarsus XR)
References
- ↑ 1.0 1.1 Lavin MF, Khanna KK, Beamish H, Spring K, Watters D, Shiloh Y. Relationship of the ataxia-telangiectasia protein ATM to phosphoinositide 3-kinase. Trends Biochem Sci. 1995 Oct;20(10):382-3. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8533147 (G1 arrest)
- ↑ Kaiser Permanente Pharmacy update
- ↑ 3.0 3.1 Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 4.0 4.1 Journal Watch 23(14):110, 2003 Lemos PA et al Early outcome after sirolimus-eluting stent implantation in patients with acute coronary syndromes: insights from the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. J Am Coll Cardiol 41:2093, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12798587
- ↑ 5.0 5.1 Miller T Proceedings of the 38th Annual Meeting of the American Aging Association: Integrative Biology: Hormones, Signaling, and Aging. May 29-June 1, 2009, Scottsdale, AZ
Harrison DE et al Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009 Jul 8 http://dx.doi.org/10.1038/nature08221 - ↑ 6.0 6.1 FDA MedWatch http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm165731.htm
- ↑ FDA Medwatch http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm171828.htm
- ↑ FDA Medwatch Rapamune (sirolimus): Drug Monitoring Recommendations http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm197059.htm
- ↑ Deprecated Reference
- ↑ 10.0 10.1 10.2 10.3 Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
Database
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5281079
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=65448
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5284616
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3001038
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=644278
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5040
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=444776
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=313006
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=478951