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sirolimus; rapamycin (Rapamune)

Indications: - oral immunosuppressive agent for prophylaxis of organ transplantation rejection - renal graft rejection - cardiac transplantation - recommended for use with cyclosporine & glucocorticoids - used as eluate in coronary stents to reduce restenosis [3] - tuberous sclerosis - renal angiomyolipomas - facial angiolipomas (topical) Dosage: 1) loading dose of 6 mg PO (15 mg/kg) 2) maintenance: 2 mg PO QD (1 mg/kg/day) 3) should be taken 4 hours after cyclosporine 4) mix with 60 mL of water or orange juice only Solution: (oral) - 1 mg/mL (60 & 120 mL, or 1,2, 5 unit-of-use pouches) topical 1% Storage: - in refrigerator protected from light - stable at room temperature for 30 days Pharmacokinetics: 1) bioavailability a) approximately 14% b) high fat meal increases bioavailability 34% 2) 92% bound to serum protein 3) serum levels 9 ng/mL with 2 mg/day 4) metabolized by cyt P450 3A4 & P-glycoprotein 5) terminal elimination 1/2life is 62 hours Adverse effects: 1) dyslipidemia, hypercholesterolemia 2) nephrotoxicity - increased serum creatinine - proteinuria [10] 3) Herpes simplex infections with doses > 5 mg/day 4) hypertension 5) rash 6) increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus [6] 7) BK virus associated nephropathy in renal transplant patients 8) new-onset diabetes mellitus [10] 9) anemia, leukopenia [10] Drug interactions:* 1) cyclosporine increases sirolimus levels (2 fold) 2) diltiazem increases bioavailability of sirolimus 3) ketoconazole increases sirolimus levels (4-fold) 4) rifampin increases sirolimus clearance 5) other agents that may increase sacrolimus levels - calcium channel blockers, macrolides (clarithromycin), GI prokinetic agents (cisapride), bromocryptine, cimetidine, danazol, HIV protease inhibitors 6) any drug that inhibits cyt P450 3A4 may increase levels of sirolimus -> grapefruit juice inhibits metabolism of sirolimus 7) any drug that induces cyt P450 3A4 may diminish levels of sirolimus 8) vaccines: a) sirolimus inhibits response to vaccines b) live virus vaccines should not be used with sirolimus * agents that may be administered without dose-adjustment of sirolimus: - acyclovir, digoxin, glyburide, nifedipine, norgestrel/ ethinyl estradiol, prednisolone & Bactrim Mechanism of action: 1) blocks activation of ribosomal S6 kinase, ribosomal protein S6 phosphorylation & recruitment of mRNAs containing polypyrimidine into polysomes. 2) inhibits T-lymphocyte activation & proliferation 3) binds to FK506-binding proteins FKBP1A (FKBP12), FKBP1B, FKBP2, FKBP3, & FKBP10 a) inhibits target of rapamycin regulatory kinase & suppresses T-cell proliferation b) induces G1 arrest [1] through interferences with activation of S6 kinase & G1-kinases c) rapamycin-bound FKBP1A binds FRAP1 & inhibits mTOR (mTOR inhibitor) 4) antimitotic properties [4] Notes: - produced by Streptomyces hygroscopicus - increases longevity in mice probaby via inhibition of mTOR [5]

Interactions

drug interactions drug adverse effects of immunosuppressive agents monitor with immunosuppressive agents

Related

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)

General

antifungal agent heterocyclic compound, 3 rings lactone mTOR inhibitor; target of rapamycin inhibitor prokaryote-specific molecule

Properties

SIZE: MW = 915 G/M INHIBITS: FKBP12-rapamycin complex-associated protein

Database Correlations

PUBCHEM correlations

References

  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: 8533147 (G1 arrest)
  2. Kaiser Permanente Pharmacy update
  3. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  4. 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: 12798587
  5. 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. FDA MedWatch http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm165731.htm
  7. FDA Medwatch http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm171828.htm
  8. FDA Medwatch Rapamune (sirolimus): Drug Monitoring Recommendations http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm197059.htm
  9. Deprecated Reference
  10. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015