Medication Review
`Medication Review
`
`Kim Bremer, Department Editor
`
`Sirolimus: Mammalian Target of Rapamycin Inhibitor to Prevent
`Kidney Rejection
`Patricia A. Cowan
`
`Vanrenterghem, & Neylan, 1999). In phase III clinical tri-
`als, cyclosporine, corticosteroids, and either sirolimus (2
`or 5 mg/day doses), azathriopine, or placebo were admin-
`istered to 1, 296 kidney transplant recipients. The inci-
`dence of acute rejection of the transplanted kidney was
`significantly lower among patients receiving sirolimus as
`part of their immunosuppressant regimen compared to
`those receiving azathriopine or placebo (Food and Drug
`Administration, 20 0 0 ) .
`Although tacrolimus and sirolimus bind to the same
`immunophilin, their mechanism of action differs. The
`combination of tacrolimus and sirolimus is synergistic in
`pre-clinical models permitting the use of lower dosages of
`tacrolimus that may reduce or eliminate some of the
`adverse effects of tacrolimus. McAlister and colleagues
`( 2000) reported only one episode of rejection, attributed to
`noncompliance, in 32 liver, kidney, and kidney-pancreas
`transplant recipients receiving a combination of sirolimus,
`low dose tacrolimus, and low dose steroid with early with-
`drawal for immunosuppression. Currently, studies are
`being conducted to determine the effect of tacrolimus-
`sirolimus combinations on kidney transplant graft func-
`tion, patient and graft survival, and adverse effects.
`Although current immunosuppressive regimens based
`upon cyclosporine or tacrolimus are very effective at
`reducing the incidence of acute rejection and preventing
`loss of the transplanted kidney from acute rejection, these
`drugs are known to compromise renal function.
`Subsequently, investigations comparing sirolimus versus
`cyclosporine as a base therapy for immunosuppression
`have been undertaken with similar outcomes in patient
`survival, kidney graft survival, and incidence of rejection
`being reported (Groth et al., 1999; Kreis et al., 20 0 0 ) .
`Compared to recipients receiving cyclosporine, the
`sirolimus group exhibited lower serum creatinine levels
`and better glomerular filtration rates in the early post-
`transplant period (1-2 months posttransplant), with signif-
`icant differences sustained at 12 months posttransplant
`(Kreis et al., 20 0 0 ) .
`
`The Medication Review section of the Nephrology Nursing
`J o u r n a l presents information on medications administered to
`individuals with nephrologic disorders. Readers wishing to
`contribute to this column should contact Kim Bremer, department
`e d i t o r, for assistance. For specific guidelines, see any February issue
`of the Nephrology Nursing Journal. The opinions and assertions
`contained herein are the private views of the contributors and do not
`necessarily reflect the views of the American Nephrology Nurses’
`A s s o c i a t i o n .
`
`Kay E. HelzerLifelong administration of multiple immunosuppres-
`
`sants is usually required to maintain function of a
`transplanted kidney. Selection of immunosuppres-
`sant agents has been geared toward preventing acute
`rejection and minimizing drug-induced side effects. In
`recent years, a number of new immunosuppressant agents
`have been approved for the prevention of acute rejection
`resulting in improved graft and patient survival, as well as
`improved function of the transplanted kidney. The oppor-
`tunity to individualize immunosuppressant regimens
`based upon patient demographics and immunologic ch a r-
`acteristics has expanded with the recent approval of
`sirolimus for prevention of acute rejection in renal trans-
`plant recipients.
`
`Mechanism of Ac t i o n
`The mechanism of action of sirolimus is distinct from
`that of other commonly used immunosuppressants.
`Sirolimus and its O-alkylated analogue SDZ RAD bind to
`immunophilins known as FK 506 binding proteins
`( FKBP), specifically FKBP 12. These sirolimus-FKBP
`complexes then bind to mammalian target of rapamycin,
`an intracellular enzyme that modulates lymphocyte cellu-
`lar division and proliferation (Sehgal, 1998; Va s q u e z ,
`2000). While calcineurin inhibitors, like cyclosporine and
`tacrolimus, interfere with T-cell activation by blocking the
`production of interleukin-2 (IL-2), sirolimus predominant-
`ly inhibits T-cell proliferation by blocking T-cell respon-
`siveness to IL-2. However, sirolimus does not block the
`IL-2 signals that lead to T-cell apoptosis, a process
`believed to be essential in the development of allograft tol-
`erance. Additionally, sirolimus decreases immunoglobulin
`production by B-cells
`(American Society of
`Transplantation, 2000).
`
`Clinical Tr i a l s
`The safety and efficacy of sirolimus in combination
`with cyclosporine to prevent acute rejection of a trans-
`planted kidney has been established in randomized, mul-
`ticentered clinical studies. Combination immunosuppres-
`sant therapy of sirolimus, cyclosporine (at full or reduced
`dose), and steroids resulted in a lower incidence of biopsy
`proven rejection in kidney transplant recipients compared
`to transplant recipients who received cyclosporine,
`steroids, and placebo
`(Khan,
`Julian, Pe s c o v i t z ,
`
`Patricia A. Cowan, PhD, RN, is a faculty member in the College of
`Nursing at the University of Tennessee Health Science Center, Memphis, TN.
`
`Kay E. Helzer, BSN, CNN, is a transplant coordinator at Samaritan
`Transplant Services in Phoenix, AZ.
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`Drug Interactions/Co n t r a i n d i c a t i o n s
`Like tacrolimus and cyclosporine, sirolimus is metabo-
`lized by
`the cytochrome P450 3A4
`isoenzyme.
`Concomitant administration of cyclosporine (modified)
`and sirolimus in stable renal transplant recipients resulted
`in markedly increased sirolimus peak and trough blood
`concentrations (Kaplan, Me i e r - K r i e s che, Napoli, &
`Kahan, 1998) prompting a recommendation that sirolimus
`be administered 4 hours after cyclosporine (modified)
`when used in combination. Co-administration of sirolimus
`and ketoconazole is not recommended as ketoconazole
`increases sirolimus blood concentration levels. A similar
`relationship was observed when sirolimus was adminis-
`tered with diltiazem. Rifampin has been demonstrated to
`lower sirolimus exposure. Agents that alter cyclosporine
`levels may also alter sirolimus levels. Increased sirolimus
`levels may result with concomitant administration of
`nicardipine, verapamil, danazol, clarithromycin, ery-
`thromycin, allopurinol, metoclopromide, fluconazole,
`itraconzole, and grapefruit juice. Reduced sirolimus levels
`may occur with concomitant administration of carba-
`mazepine, phenobarbital, phenytoin, mafcillin, octreotide,
`and ticlopidine. No clinically significant drug interactions
`have been reported with the use of sirolimus and acy-
`clovir, digoxin, glyburide, nifedipine, norgestrel, ethinyl
`estradiol, and trimethoprim-sulfamethoxazole (Ke l l y ,
`Gruber, Behbod, & Kahan, 1997; Vasquez, 2000).
`
`Do s a g e
`Label recommendations for sirolimus are a 6 mg load-
`ing dose as soon as possible after transplantation (24 - 48
`hours posttransplant) followed by a daily maintenance
`dose of 2 mg daily by mouth. In children 13 years or older
`who weigh less than 40 kg, the initial dose is 3 mg/m2 w i t h
`a recommended maintenance dose of 1 mg/m2/ d a y
`(Wyeth-Ayerst, 1999). The safety and efficacy of sirolimus
`in children less than 13 years of age has not been estab-
`lished. Precise guidelines for therapeutic drug monitoring
`of sirolimus are being developed. High performance liq-
`uid chromatography (HPLC-UV) and HPLC-mass spec-
`troscopy are the preferred assays for determining
`sirolimus blood concentrations. Recently, concentrated-
`controlled dosing for sirolimus was recommended (Kahan
`et al., 2000). Five to seven days after initiating sirolimus,
`serum trough levels should be obtained using the HPLC -
`UV assay. Blood for sirolimus trough levels should be
`drawn 22 - 24 hours after the previous dose, preferably
`before 10 am, so it is important to instruct the patient to
`hold the next dose of sirolimus until the sample is
`obtained. A sirolimus trough level should be ch e cked 5-7
`days after a dose change. Once the patient is stabilized,
`sirolimus levels only need to be drawn every 2-3 months.
`The dose should be adjusted based on the trough levels.
`When used in combination with other immunosuppres-
`sant agents, a target trough level of 5-15 ng/ml is recom-
`mended. In studies where sirolimus was employed as a
`base agent for immunosuppression, the average mainte-
`nance dose of sirolimus ranged from 6 to 9 mg/day with
`sirolimus target trough levels of 30 ng/ml during the first
`2 month posttransplant and 15 ng/ml thereafter (Groth et
`al., 1999; Kreis et al., 20 0 0 ) .
`
`Co s t
`The approximate cost of sirolimus is $328 . 80 for 30
`p o u ches with each pouch containing 2 mg/ml. Cost varies
`depending upon dose ordered. Overall immunosuppres-
`sion cost will depend upon whether sirolimus is employed
`as an adjunct immunosuppressant with either tacrolimus
`or cyclosporine as base therapy, whether reduced doses of
`the base immunosuppressant can be used, or whether
`sirolimus is employed as the base immunosuppressant
`a g e n t .
`
`Di a l y z a b i l i t y
`The effect of dialysis on sirolimus levels has not been
`established. The lipophilic nature of sirolimus makes it
`unlikely to be effectively removed with dialysis (Va s q u e z ,
`2000). Sirolimus is primarily bound to red blood cells with
`approximately 3% free in plasma, so negligible amounts
`may be removed with plasmapheresis.
`
`Common Ad verse Reactions
`Sirolimus therapy is associated with adverse reactions
`that are different from those for other immunosuppressive
`therapies. Key adverse reactions observed in sirolimus
`plus cyclosporine-treated patients are increased blood
`lipids, including triglycerides and cholesterol, and reduced
`platelet and white blood cell counts. The increased triglyc-
`erides and cholesterol can be treated successfully with the
`use of lipid and/or cholesterol-lowering drugs. The
`reduced platelet and white blood cell counts normally
`respond to a reduction in sirolimus dose. Other adverse
`reactions include hypertension, rash, acne, arthralgia,
`diarrhea, and hypokalemia. These reactions are dose
`related (Kelly, 1999 ) .
`
`Nursing Co n s i d e r a t i o n s
`that African-
`suggested
`Preliminary evidence
`Americans exhibit a reduced rate and extent of sirolimus
`absorption. When sirolimus was used in combination with
`low dose cyclosporine, African-Americans exhibited a
`higher rate of rejection than Caucasians; thus African-
`Americans receiving sirolimus and cyclosporine combina-
`tion immunosuppressant therapy may need to be main-
`tained at higher levels than Caucasian transplant recipi-
`ents (American Society of Transplantation, 2000).
`It is recommended that sirolimus be administered 4
`hours after the morning dose of cyclosporine to minimize
`potential toxicities. Dosing with respect to food should be
`consistent to minimize variability in oral absorption.
`Sirolimus is available in a bottle or pouch. A table form of
`sirolimus was recently approved by the Food and Drug
`Administration. The prescribed amount of sirolimus
`should be mixed in a glass or plastic container with at least
`two ounces (1/4 cup, 60 ml) of water or orange juice.
`Grapefruit and Seville orange juice should not be used as
`it increases the bioavailability of the medication. When
`using the pouch, squeeze the entire contents of the pouch
`into the glass or plastic container.
`Sirolimus should be stored protected from light and
`refrigerated at 2-8o C (36 - 46o F). Once the bottle is
`opened, the contents should be used within 1 month. If
`necessary, patients may store both pouches and bottles at
`
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`K., & MacDonald, A.S. (2000). Sirolimus-tacrolimus combi-
`nation immunosuppression. L a n c e t, 3 5 5, 376 - 377.
`Sehgal, S.N. (1998). Rapamune® (RAPA, rapamycin, sirolimus):
`Me chanism of action immunosuppressive effect result from
`b l o ckade of signal transduction and inhibition of cell cycle
`progression. Clinical Bioch e m i s t r y, 31(5), 335 - 340 .
`Vasquez, E.M. (2000). Sirolimus: A new agent for prevention of
`renal allograft rejection. American Journal of Health Sy s t e m
`Pharmacy, 57(5), 437- 448, 449 - 451.
`Wyeth-Ayerst. (1999). Rapamune® solution package insert.
`Philadelphia: Au t h o r.
`
`room temperature up to 25o C (77o F) for several days, but
`no longer than 30 days. Sirolimus oral solution provided
`in bottles may develop a slight haze when refrigerated.
`E a ch amber syringe used to draw up the dose of sirolimus
`should be discarded after each use (Wyeth-Ayerst, 1999).
`
`S u m m a r y
`Current immunosuppressive therapies are effective but
`can be associated with significant adverse reactions.
`Sirolimus works differently from the immunosuppressants
`currently available, and except for increased lipid levels,
`the adverse reaction profile of sirolimus does not appear
`to overlap to any great extent with that associated with
`cyclosporine or tacrolimus. While additional research is
`needed, the initial clinical data in kidney recipients sug-
`gest that sirolimus, in combination with cyclosporine or
`tacrolimus, might have the potential to reduce the fre-
`quency of rejection episodes, permit reductions in
`cyclosporine or tacrolimus dosage, and permit steroid
`withdrawal (Kelly, 1999 ) .
`
`References
`American Society of Transplantation (2000, January). TOR inhi -
`bition: A new pathway to immunosuppre s s i o n. St. Pe t e r s b u r g ,
`FL: Au t h o r.
`Food and Drug Administration. (2000, June). NDA 21 - 08 3
`S i rolimus
`Rapamune® [On-line]. Available
`at:
`h t t p : / /w w w. f d a . g o v / o h r m s / d o ck e t s / a c / 99 / s l i d e s / 3529 s l a / s
`l d 014.htm
`Groth, C.G., Backman, L., Morales, J.M., Calne, R., Kreis, H.,
`Lang, P., Touranine, J.L., Clasesson, K., Campistol, J.M.,
`Durand, D., Wramner, L., Brattstrom, C., & Charpentier, B.
`( 1999). Sirolimus (Rapamycin)-based therapy in human
`renal transplantation. Sirolimus Renal Study Group.
`Transplantation, 67(7), 1036 - 1042 .
`Kelly, P.A. (1999). New immunosuppressant recently approved
`by the FDA. Stadtlanders Lifetimes, 3, 26 - 27.
`Kelly, P.A., Gruber, S.A., Behbod, F., & Kahan, B.D. (1997 ) .
`Sirolimus: A new, potent immunosuppressive agent.
`P h a r m a c o t h e ra p y, 17(6), 1148 - 156 .
`Kahan, B.D. (1998). Rapamycin: Personal algorithms for use
`based on 250 treated renal allograft recipients. Tra n s p l a n t
`P ro c e e d i n g s, 30(5), 2185 - 2188 .
`Kahan, B.D., Julian, B.A., Pescovitz, M.D., Vanrenterghem, Y., &
`Neylan, J. (1999). Sirolimus reduces the incidence of acute
`rejection episodes despite lower cyclosporine doses in
`Caucasian recipients of mismatched primary renal allo-
`grafts: A phase II trial. Rapamune Study Group.
`Tra n s p l a n t a t i o n, 68( 10), 1526 - 1532.
`Kahan, B.D., Napoli, K.L., Kelly, P.A., Podbielski, J., Hussein, I.,
`Urbauer, D.L., Katz, S.H., & van Buren, C.T. (20 0 0 ) .
`Therapeutic drug monitoring of sirolimus: Co r r e l a t i o n s
`with efficacy and toxicity. Clinical Tra n s p l a n t a t i o n, 14, 97- 109 .
`Kaplan, B,. Me i e r - K r i e s che, H.U., Napilo, K.L,. & Kahan, B.D.
`( 1999). Correlation between pretransplant test dose of
`cyclosporine pharmacokinetics and posttransplant sirolimus
`blood levels. The Drug Monitor, 31(1), 44 - 49 .
`Kreis, H., Cisterne, J.M., Land, W., Wramner, L., Squifflet, J.P. ,
`Abramowicz, D., Campistol, J.M., Morales, J.M., Grinyo,
`J.M., Mourad, G., Berthoux, F.C., Brattstrom, C.,
`L e b r a n chu, Y., & Vialtel, P. (2000). Sirolimus in association
`with mycophenolate mofetil induction for the prevention of
`acute graft rejection
`in renal allograft recipients.
`Transplantation, 69(7), 1252 - 1260 .
`McAlister, V.C., Gao, Z., Peltekian, K., Domingues, J., Mahalati,
`
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