|
Antiinfectives
General Rx
Renal Rx
Transplant Rx
Pkinetics
Educational
KidneyWorks
Clinical Tools
|
WARNINGS
- Dyslipidemia (ñ total cholesterol and triglycerides) requiring treatment with lipid-lowering drugs is a frequent side effect of sirolimus therapy.
- Combined with CSA and steroids, sirolimus significantly reduces GFR (and ñ Scr) compared to placebo or azathioprine.
- The administration of sirolimus to liver transplant recipients in the immediate post-transplant period may be associated with increased risk of hepatic artery thrombosis.
|
Sirolimus (Rapamune®) is an immunosuppressive agent previously known as rapamycin. It has been under development for more than 20 years before it gained FDA approval on September 15th 1999. Sirolimus is a macrocyclic lactone [ C51H79N1O13 ; MWt = 914.2 ] produced by Streptomyces hygroscopicus found in the soil of Easter Island. Structurally, sirolimus resembles tacrolimus and binds to the same intracellular binding protein or immunophilin known as FKBP-12. However, sirolimus has a novel mechanism of action. Whereas tacrolimus and cyclosporine block lymphokine (e.g., IL2) gene transcription , sirolimus acts later to blocks IL2-dependent T lymphocyte proliferation and the stimulation caused by cross-linkage of CD28, possibly by blocking activation of a kinase referred to as mammalian target of rapamycin or "mTOR", a serine-threonine kinase that is important for cell cycle progression. Therefore, sirolimus is believed to act in synergy with cyclosporine (or tacrolimus) in suppressing the immune system.
Sirolimus is a white to off-white powder that is insoluble in water but freely soluble in benryl alcohol, chloroform, and other organic solvents. The commercially available oral solution of sirolimus (Rapamune) contains 1 mg/mL of sirolimus, about 2% ethanol, and the following inactive ingredients: Phosal 50 PG (phosphatidylcholine, propylene glycol, monodiglycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and Polysorbate 80, NF.
Sirolimus inhibits the activation and proliferation of T lymphocyte in response to stimulation by antigens and cytokines (IL-2, IL-4, and IL-15). This inhibition is believed to be mediated by a mechanism that is distinct from that of tacrolimus, cyclosporine (CSA), or other immunosuppressants. Sirolimus also inhibits antibody production.
In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12). The sirolimus:FKBP-12 complex, which has no effect on calcineurin activity, 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 of the cell cycle from the G1 to the S phase .
In some animal studies, sirolimus induced tolerization; the immunosuppressive effect lasted up to 6 months after discontinuation of therapy. Whether sirolimus can induce significant tolerization in humans is yet to be established.
Sirolimus is FDA approved as an adjunctive agent (in combination with CSA + steroids) for the prevention of acute renal allograft rejection. In clinical trials, sirolimus (+ CSA + steroids) reduced the incidence of biopsy-proven acute rejection by about 40% during the 1st 6 months of therapy compared placebo.
Two phase III trials evaluating the efficacy of sirolimus have provided data indicating that sirolimus is safe and effective. The Rapamune U.S. Multicenter Study included 719 renal transplant recipients who were randomized to receive either sirolimus (2 mg/day or 5 mg/day) or azathioprine (2 to 3 mg/kg/day). All patients also received cyclosporine and prednisone. Both sirolimus regimens were found to be significantly more effective than azathioprine at reducing the incidence of acute rejection. Graft and patient survival were similar in all treatment groups.2
| The Rapamune U.S. Multicenter Study |
| |
Sirolimus 2 mg
(n = 284) |
Sirolimus 5 mg
(n = 274) |
Azathioprine
(n = 161) |
p |
| Incidence of acute rejection, graft loss, and death at 6 months |
18.7% |
16.8% |
32.3% |
<0.05 |
| Acute rejection at 6 months |
16.5% |
11.3% |
29.2% |
<0.05 |
| Graft survival at 12 months |
94.7% |
92.7% |
94.0% |
NS |
| Patient survival at 12 months |
97.1% |
96.0% |
98.1% |
NS |
In the Rapamune Global Study, conducted in Australia, Canada, Europe, and the United States, 576 renal transplant recipients were stratified to receive either sirolimus (2 mg/day or 5 mg/day) or placebo. All patients also received cyclosporine and prednisone. As in the U.S. study, sirolimus was found to be superior to placebo at reducing the incidence of acute rejection within the first 6 months following transplant. Graft and patient survival were similar in all treatment groups.2
| The Rapamune Global Study |
| |
Sirolimus 2 mg
(n = 227) |
Sirolimus 5 mg
(n = 219) |
Placebo
(n = 130) |
p |
| Incidence of acute rejection, graft loss, and death at 6 months |
30% | 25.6% |
47.7% | <0.05 |
| Acute rejection at 6 months |
24.7% | 19.2% |
41.5% | <0.05 |
| Graft survival at 12 months |
89.9% | 90.9% |
87.7% | NS |
| Patient survival at 12 months |
96.5% | 95.0% |
94.6% | NS |
- Oral absorption: rapid (time-to-peak concentration = 2 hrs). Fatty meals significantly reduce the rate and extent of absorption. Sirolimus should be taken consistently with or without food.
Oral bioavailability: approximately 14%
- Distribution: Vd = 12 ± 7.52 L/kg; blood/plasma = 36 ± 17.9; plasma protein (mainly albumin) = 92%.
- Metabolism: Sirolimus is a substrate for both cytochrome P450 3A4 and P-glycoprotein (a large membrane protein that acts as a drug pump, usually transporting drugs out of the cell). Sirolimus is extensively metabolized in the liver by O-demethylation and/or hydroxylation. Sirolimus is the major component in human whole blood and contributes greater than 90% of the immunosuppressive activity.
Liver disease significantly increases sirolimus bioavailability, reduces its clearance, and prolongs its elimination half-life
- Excretion: mainly in feces.
The terminal elimination half life (t½) is 72 hrs in males and 61 hrs in females.
- Sirolimus trough concentrations (whole blood; steady-state; ng/mL) was 8.59 ± 4.01 for the 2 mg/day dose and 17.3 ± 7.4 for 5 mg/day dose.
- A loading dose of 3 times the maintenance dose will provide near steady state concentrations within 1 day.
|
Sirolimus PK parameters (mean ± SD)
in renal transplant recipients given daily doses of sirolimus for 1, 3, or 6 months in combination with cyclosporine (Neoral) and corticosteroidsa |
|
| n | Dose | Cmax,ssb
(ng/mL) | tmax,ss
(hr) |
AUCt,ssb
(ng.hr/mL) | CL/F/Wtc
(mL/hr/kg) |
| 19 | 2 mg | 12.2 ± 6.2 | 3.01 ± 2.40 | 158 ± 70 | 182 ± 72 |
| 23 | 5 mg | 37.4 ± 21 | 1.84 ± 1.30 | 396 ± 193 | 221 ± 143 |
a: Sirolimus administered four hours after cyclosporine (Neoral).
b: These parameters are dose normalized for the statistical comparison.
c: CL/F/WT = oral dose clearance. |
- The administration of sirolimus to liver transplant recipients in the immediate post-transplant period may be associated with increased risk of hepatic artery thrombosis.
- Hyperlipidemia is a major complication of sirolimus therapy. Patients should be closely monitored and treated as necessary. Patients treated with a statin should be made aware of and monitored for rhabdomyolysis. However, so far there has no reports of any clinically significant interactions between sirolimus and the statins.
- The combination of CSA + sirolimus is apparently more nephrotoxic than CSA alone. This is attributed to a kinetic interaction between the two immunosuppressants leading to a marked elevations in the blood level of CSA. However, no such interaction occurs when sirolimus is combined with tacrolimus and the two agents may be administered at the same time.
- Antimicrobial Prophylaxis against PCP (for 12 months) and CMV (for at least 3 months) is essential.
- Women of child-bearing potential should use effective contraception prior to, during, and for at least 3 months after the termination of sirolimus therapy.
- It is recommended that blood sirolimus levels be monitored in these patients:
- Patients ³13 yr old weighing <40 kg
- Patients with significant liver disease
- Patients receiving drugs that either inhibit the CyP450 3A4 or the P-glycoprotein (e.g., diltiazem, ketoconazole, fluconazole, verapamil, Synercid, etc) or induce it (rifampin, phenytoin, carbamazepine, etc).
- Patients whose CSA dose has been reduced or discontinued.
- Patients receiving sirolimus plus low-dose tacrolimus.
- Patients who are at high risk for acute rejection.
- Sirolimus (Rapamune®) is available only for oral administration.
- 1-mg tablets (white, triangular-shaped; NDC # 0008-1031-05, bottle of 100 tablets; NDC # 0008-1031-10, Redipak® cartons of 100 tablets, 10 blister cards of 10 tablets each).
- The oral solution (1 mg/mL) is available as multi-dose, amber glass bottles or as single-unit laminated aluminum pouches:
| Product | NDC # |
|
| 60-mL glass bottle | 0008-1030-04 |
| 150-mL glass bottle | 0008-1030-14 |
|
| 30 1-mL unit pouches | 0008-1030-03 |
| 30 2-mL unit pouches | 0008-1030-07 |
| 30 5-mL unit pouches | 0008-1030-08 |
|
- The bottles are supplied with an oral syringe adapter for fitting into the neck of the bottle together with disposable oral syringes and caps for daily use.
- Sirolimus should be taken consistently either with or without food.
- Sirolimus should be taken 4 hrs after the CSA dose. However, if sirolimus is combined with tacrolimus (instead of CSA), the two drugs may be taken at the same time.
- The correct amount of sirolimus solution should be added to 60-mL of water or orange juice in a glass or plastic container, stirred vigorously and drunk at once. The container should be refilled with 120 mL of water, stirred vigorously, and taken at once. Only water or orange juice should be used. Also, no paper or Styrofoam cups should be used.
- Grapefruit juice should be avoided since it can significantly alter sirolimus kinetics.
- Adult loading dose = 6 mg ( = 3 x the maintenance dose). A loading dose is recommended because of the drugs long half-life; without a loading dose it may take ³ 2 wks to reach steady state.
- Adult maintenance dose = 2 mg/day
- Children maintenance dose ³ 13 yrs old: 1 mg/m2/day; maximum 2 mg/day
- Children loading dose = 3 x the maintenance dose; maximum 6 mg.
- Increased risk for infections and lymphoma.
- Impaired wound healing.
- Metabolic: hypercholesterolemia and hypertriglyceridemia (~50% of pts).
- CVS: hypertension
- Hematologic: thrombocytopenia and to a lesser extent anemia.
- Skeletal: arthralgia
- Skin: acne and rash
- Respiratory: increased risk of interstitial pneumonitis {NEJM 2000; 343 (24):1815}, and upper respiratory tract infections
- CNS: insomnia and tremor
- CSA ® ñ sirolimus Cmax and AUC probably due to the combined effects of the competitive inhibition of CYP450 3A4 plus the inhibition of the P-glycoprotein in the wall of the small intestine.
- Inhibitors of CYP450 like ketoconazole and diltiazem ®ñ sirolimus Cmax and AUC
- Inducers of CYP450 like rifampin ®òsirolimus Cmax and AUC
- No significant interactions were observed with acyclovir, digoxin, glyburide, prednisolone, oral contraceptives, and co-trimoxazole
- Kelly et al. Sirolimus: a potent new potent immunosuppressive agent. Pharmacotherapy '97; 17(6): 1148-56
- Vasquez, E. Sirolimus: a new agent for prevention of renal allograft rejection. AJHP2000;57(5): 437-448
- McAlister et al. Sirolimus-tacrolimus combination immunosuppression. Lancet 2000 Jan 29;355(9201):376-7
- Rapamune Prescribing Information. Wyeth-Ayerst Pharmaceutical.
|
