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Sirolimus
drug data and news
Sirolimus drug data, resources, and news articles (when available). Onconews.org provides news on cancer research. This section, which includes profiles on medicines that may or not be cancer-related is in beta form. If things run smoothly we will be releasing a new format late in the summer of 2006.
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| Generic name | Sirolimus | ||
| Brand Names/Synonyms | Antibiotic Ay 22989; Rapamune; Rapamycin; Rapamycin / Sirolimus; Rapamycin, ≪ 98% by Tlc; Sirolimus; Sirolimus [Usan:Ban:Inn] | ||
| Indication | For the treatmnet of post operative pain | ||
| Sponsored links | Description | Not Available | |
| Pharmacology | Sirolimus, a macrocyclic lactone produced by Streptomyces hygroscopicus, is an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that Sirolimus be used in a regimen with cyclosporine and corticosteroids. | ||
| Mechanism Of Action | Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin IL-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, Sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The Sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle. | ||
| Sirolimus News (When available) |
Study Suggests Drug-Eluting Stent Type and Vessel Size are ... 16 May 2006 Xtent CUSTOM I Trial Shows Zero Restenosis, Favorable Late Loss ... 16 May 2006 Two Million Patients Treated With the CYPHER(R) Sirolimus-Eluting ... Apr 26, 2006 Cordis Corporation Submits Pre-Market Approval Submission for ... May 11, 2006 Two Million Patients Treated With the CYPHER(R) Sirolimus-Eluting ... Apr 26, 2006 Cordis seeks FDA OK for stent indication May 11, 2006 ACC/AHA update secondary-prevention guidelines May 15, 2006 Stanford expert presents new options in the treatment of CAD May 5, 2006 Fungus drug hope May 14, 2006 COMUNICADO: Boston Scientific to Release Latest Clinical Trial ... May 9, 2006 Johnson & Johnson, Boston Scientific Win One Court Decision Each ... May 11, 2006 Court rules for both Cordis and Boston Scientific May 12, 2006 Court Upholds Two Jury Decisions In Patent Case Between Cordis And ... May 11, 2006 Drug-eluting and Bare-metal Stents Have Similar Long-Term Safety ... May 12, 2006 ASD - AGM STATEMENT May 10, 2006 WHO sounds warning bells for diabetics Apr 30, 2006 District Court Issues Two Decisions Regarding Patent Litigation ... May 12, 2006 J&J Cordis Unit Seeks FDA OK For Cypher Coronary Stent May 11, 2006 Dr. Julio Palmaz, Inventor of Stent Widely Used in Coronary and ... May 8, 2006 Dr. Julio Palmaz, Inventor of Stent Widely Used in Coronary and ... May 8, 2006 Currency, Generic Competition Mars Johnson & Johnson's First ... Apr 18, 2006 SurModics Reports Second Quarter 2006 Results; Record Revenue and ... Apr 19, 2006 (PRN) - SEPTA Market Street Elevated Reconstruction Project ... Apr 26, 2006 Johnson & Johnson Reports 2006 First-Quarter EPS Rose 17.0% on ... Apr 18, 2006 Prograf Now Approved for Prophylaxis Use in Heart Transplantation ... Apr 21, 2006 | ||
| Dosage Forms | SOLUTION | ||
| Drug_Category | Immunosuppressive Agents; Antifungals; Antibiotics; Anti-bacterial Agents; Unclassified Therapeutic Agents (92:00.00); ATC:L04AA10 | ||
| Absorption | Not Available | ||
| Interactions |
-->Interactions for Sirolimus: Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below. Cyclosporine capsules MODIFIED: Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp. Because of the effect of cyclosporine capsules (MODIFIED), it is recommended that sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Studies assessing the effect of concomitant administration of cyclosporine capsules (MODIFIED) with sirolimus oral solution and with sirolimus tablets are summarized below. Rapamune Oral Solution: In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus either simultaneously or 4 hours after a 300 mg dose of NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean Cmax and AUC of sirolimus were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were increased by 37% and 80%, respectively, compared with administration of sirolimus alone. In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus alone, 2 hours before, and 2 hours after a 300 mg dose of NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean Cmax and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone. Mean cyclosporineCmax and AUC were not significantly affected when sirolimus was given simultaneously or when administered 4 hours after NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after NeoralÒ in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration. Rapamune Tablets: In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus (Rapamune Tablets) either simultaneously or 4 hours after a 300-mg dose of NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, meanCmax and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimusCmax and AUC were both increased by only 33% compared with administration of sirolimus alone. Cyclosporine oral solution: In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m2/day was administered simultaneously with SandimmuneÒ Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (%CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following SandimmuneÒ Oral Solution (cyclosporine oral solution) administration. However, the %CV was higher (range 85.9% - 165%) than those from previous studies. SandimmuneÒ Oral Solution (cyclosporine oral solution) is not bioequivalent to NeoralÒ Oral Solution (cyclosporine oral solution MODIFIED), and should not be used interchangeably. Although there is no published data comparing SandimmuneÒ Oral Solution (cyclosporine oral solution) to SangCyaÒ Oral Solution (cyclosporine oral solution [MODIFIED]), they should not be used interchangeably. Likewise, SandimmuneÒ Soft Gelatin Capsules (cyclosporine capsules) are not bioequivalent to NeoralÒ Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) and should not be used interchangeably. Diltiazem: Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus Cmax,tmax,and AUCwere increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. Erythromycin: Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus Cmax and AUC were increased 4.4- and 4.2-fold respectively and tmax was increased by 0.4 hr. ErythromycinCmax and AUC were increased 1.6- and 1.7-fold, respectively, andtmax was increased by 0.3 hr. Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of RapamuneÒ Oral Solution, as reflected by increases in sirolimus Cmax,tmax,and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminalt1/2 of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations. Rifampin: Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended. Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20-mg dose of sirolimus oral solution, greatly increased sirolimus oral-dose clearance by 5.5-fold (range = 2.8 to 10), which represents mean decreases in AUC andCmax of about 82% and 71%, respectively. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered. Verapamil: Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady state to 26 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. SirolimusCmax and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change intmax. The Cmax and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and tmax was decreased by 1.2 hr. Drugs which may be coadministered without dose adjustment Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. A synopsis of the type of study performed for each drug is provided. Sirolimus and these drugs may be coadministered without dose adjustments. Acyclovir: Acyclovir, 200 mg, was administered once daily for 3 days followed by a single 10-mg dose of sirolimus oral solution on day 3 in 20 adult healthy volunteers. Atorvastatin: Atorvastatin, 20 mg, was given daily for 10 days to 23 healthy volunteers, followed by a combined regimen of sirolimus oral solution, 2 mg, and atorvastatin, 20 mg, for 5 days. Digoxin: Digoxin, 0.25 mg, was administered daily for 8 days and a single 10-mg dose of sirolimus oral solution was given on day 8 to 24 healthy volunteers. Glyburide: A single 5-mg dose of glyburide and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Sirolimus did not affect the hypoglycemic action of glyburide. Nifedipine: A single 60-mg dose of nifedipine and a single 10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Norgestrel/ethinyl estradiol (Lo/OvralÒ ): Sirolimus oral solution, 2 mg, was given daily for 7 days to 21 healthy female volunteers on norgestrel/ethinyl estradiol. Prednisolone: Pharmacokinetic information was obtained from 42 stable renal transplant patients receiving daily doses of prednisone (5-20 mg/day) and either single or multiple doses of sirolimus oral solution (0.5-5 mg/m2 q 12h). Sulfamethoxazole/trimethoprim (BactrimÒ ): A single oral dose of sulfamethoxazole (400 mg)/trimethoprim (80 mg) was given to 15 renal transplant patients receiving daily oral doses of sirolimus (8 to 25 mg/m2). Other drug interactions Co-administration of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) is not recommended. Sirolimus is extensively metabolized by the CYP3A4 isoenzyme in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-gp drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. Therefore, absorption and the subsequent elimination of systemically absorbed sirolimus may be influenced by drugs that affect these proteins. Strong inhibitors of CYP3A4 and P-gp significantly decrease the metabolism of sirolimus and increase sirolimus concentrations, while strong inducers of CYP3A4 and P-gp significantly increase the metabolism of sirolimus and decrease sirolimus concentrations. In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered. Sirolimus is a substrate for the multidrug efflux pump, P-gp in the small intestine. Therefore, absorption of sirolimus may be influenced by drugs that affect P-gp. Aside from those mentioned above, other drugs that increase sirolimus blood concentrations include (but are not limited to): Calcium channel blockers: nicardipine. Antifungal agents: clotrimazole, fluconazole. Antibiotics: troleandomycin. Gastrointestinal prokinetic agents: cisapride, metoclopramide. Other drugs: bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., ritonavir, indinavir). Aside from those mentioned above, other drugs that decrease sirolimus concentrations include (but are not limited to): Anticonvulsants: carbamazepine, phenobarbital, phenytoin. Antibiotics: rifapentine. Care should be exercised when drugs or other substances that are metabolized by CYP3A4 are administered concomitantly with Rapamune. Grapefruit juice reduces CYP3A4-mediated metabolism of Rapamune and must not be used for dilution (see DOSAGE AND ADMINISTRATION). Herbal Preparations St. Johnís Wort (hypericum perforatum) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. Johnís Wort in patients receiving Rapamune could result in reduced sirolimus concentrations. Vaccination Immunosuppressants may affect response to vaccination. Therefore, during treatment with Rapamune, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid. Drug-Laboratory Test Interactions There are no studies on the interactions of sirolimus in commonly employed clinical laboratory tests. | ||
| Toxicity | Not Available | ||
| Organisms Affected | Enteric bacteria and other eubacteria | ||
| Chemical IUPAC Name | Not Available | ||
| Chemical Formula | C51H79NO13 | ||
| Molecular Weight | 914.172 g/mol | ||
| Smiles String | CC1CCC2CC(C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)C1(O2)O)C(C)CC4CCC(C(C4)OC)O)C)C)O)OC)C)C)C)OC | ||
| Melting Point | Not Available | ||
| Water Solubility | Not Available | ||
| State | Solid | ||
| LogP/Hphobicity | 5.773 | ||
| Isoelectric Point | Not Available | ||
| Biotransformation | Not Available | ||
| Half Life | 57-63 hours | ||
| Protein Binding [%] | 92% | ||
| RxList Link | RXlist | ||
| Sponsored links | |||
| Drug Reference |
http://www.drugs.com/cons/Sirolimus.html http://www.rxlist.com/cgi/generic2/sirolimus.htm | ||
| Drug Type | Approved Drug | ||
| Accession No | APRD00178 | ||
| CAS Registry Number | 53123-88-9 | ||
| KEGG Compound ID | C07909 | ||
| PubChem ID | SID:207443 | ||
| PharmGKB ID | PA451365 | ||
| SwissProt ID | Not Available | ||
| GenBank ID | Not Available | ||
| Drug ID Number [DIN] | 2243237 |
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