Sirolimus

From Anvita Health Wiki

Contents 1 Indications 2 Dosage 3 Storage 4 Pharmacokinetics 5 Adverse-effects 6 Drug-interactions 7 Mechanism-of-action 8 Notes 9 More General Terms 10 Additional Terms 11 Internet Database 12 References

Indications

• oral immunosuppressive agent for prophylaxis of organ rejection
• recommended for use with cyclosporine & glucocorticoids
• used as eluate in coronary stents to reduce restenosis [3]

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)

• 1 mg/mL (60 & 120 mL, or 1,2, 5 unit-of-use pouches)

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

• hypercholesterolemia
• increased serum creatinine
• 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
  
• drug adverse effects of immunosuppressive agents

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

• calcium channel blockers, macrolides, GI prokinetic agents (i.e. cisapride), bromocryptine, cimetidine, danazol, HIV protease inhibitors

• 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:

• acyclovir, digoxin, glyburide, nifedipine, norgestrel/ ethinyl estradiol, prednisolone & Bactrim
  
• 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

• antimitotic properties [4]

Notes

• produced by Streptomyces hygroscopicus
• increases longevity in mice probaby via inhibition of mTOR [5]

More General Terms

• antineoplastic agent (chemotherapeutic agent)
• heterocyclic compound, 3 rings
• lactone
• immunosuppressive agent
• 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 (Prograf)

Internet Database

PubChem: 5281079
PubChem: 65448
PubChem: 5284616
PubChem: 3001038
PubChem: 644278
PubChem: 5040
PubChem: 444776
PubChem: 313006
PubChem: 478951

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: [1] (G1 arrest)
2. Kaiser Permanente Pharmacy update
3. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: [2] (subscription needed) [3]
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: [4]
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 [5]
6. FDA MedWatch [6]
7. FDA Medwatch [7]
8. FDA Medwatch Rapamune (sirolimus): Drug Monitoring Recommendations [8]

sirolimus; rapamycin (Rapamune)