Wym

Kidney or liver transplant 1

A10 thero signs or symptoms of rejection? (TeuM'SCr for kidney transpant; tLFTs for liver transplant)

hHrIhh r

Empiric treatment r

Labs resolved?

NO-1

No induction thorapy

Heart transplant —► Biopsy

Heart transplant —► Biopsy

Reject ior?

Moderate to severe resoled?

1 No

Steretds or ATG

Reject on resolved?

FIGURE 55-2. Example protocol of immunosuppressive medication use in organ transplantation. Center-specific protocols may use rabbit antithymocyte immunoglobulin (RATG), an interleukin 2 receptor antagonist (IL-2RA), or no induction therapy. In any situation, patients receive IV methyl-prednisone prior to, during, or immediately following the transplant operation. The patient then will begin the maintenance immunosuppressive regimen. The center-specific protocol will specify which calcineurin inhibitor (cyclosporine or tacrolimus) is used in combination with mycophenolate mofetil or sirolimus with or without steroids. Patients then are monitored for signs and symptoms of rejection. If rejection is suspected, a biopsy can be done for definitive diagnosis, or the patient may be treated empirically for rejection. Empirical treatment generally involves administration of corticosteroids. If signs and symptoms of rejection are resolved with empirical therapy, the patient will continue to be monitored according to the center-specific protocol. If rejection is confirmed by biopsy, treatment may be based on the severity of rejection. High-dose corticosteroids are used most frequently for mild to moderate rejection. RATG can be used for moderate to severe rejections or steroid-resistant rejections. Severe rejection episodes that are not resolved with steroids or RATG are treated with OKT-3. (BUN, blood urea nitrogen; CI, calcineurin inhibitor; CSA, cyclosporine; IL2RA, interleukin 2 receptor antagonist; LFT, liver function test; MPA, mycophenolic acid; OKT-3, moronomab-CD3; SCr, serum creatinine; SRL, sirolimus; TAC, tacrolimus.) (From Schonder KS, Johnson HJ. Solid Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1466.)

The usual oral adult dose of cyclosporine ranges from 3 to 7 mg/kg/day in two divided doses.9 The appropriate selection of the starting dose usually depends on the organ type, the patient's pre-existing disease states, and other concomitant immunosuppressive agents utilized. Cyclosporine microemulsion is available as 25 mg and 100 mg individually blister packed capsules and an oral solution. An IV formulation is also available. When converting a patient from oral to IV, the dosage should be reduced to approximately one-third of the oral dose.9

Cyclosporine whole blood trough concentrations have traditionally been obtained to help monitor for efficacy and safety. Therapeutic trough levels (C0) may range from 50 to 400 ng/mL (50-400 mcg/L or 42-333 nmol/L). Target levels should be individualized for each patient, usually depending on the organ transplanted, patient's condition, method of assay (high-performance liquid chromatography [HPLC], monoclonal, polyclonal), and time since transplantation. Newer studies suggest that monitoring of concentrations at 2 hours postdose (C2) correlates better with toxicity and efficacy when compared to C0.25

Tacrolimus

Tacrolimus (also known as FK506) is the second calcineurin inhibitor and was approved by the FDA in 1997. Even though cyclosporine and tacrolimus both belong to the same general medication class, there are several differences between the two. First, looking at efficacy, some studies suggest that tacrolimus-based regimens are associated with improved short-term survival when compared with cyclosporine-based regimens.26 However, newer data suggest that there is no significant difference in acute

rejection rates between cyclosporine and tacrolimus. In recent years, tacrolimus has become the workhorse calcineurin inhibitor in many transplant centers, due in large

part to a more favorable adverse reaction profile.

Oral starting doses of tacrolimus range from 0.1 to 0.2 mg/kg/day in two divided doses. Tacrolimus is available in 0.5-, 1-, and 5-mg capsules and as an injectable.9 The IV formulation is usually avoided due to the risk of anaphylaxis because of its castor oil component and nephrotoxicity. Tacrolimus C0whole blood levels should be monitored (12 hours after the last administered dose) and maintained between 5 and 15 ng/mL (5-15 mcg/L), again depending on the transplanted organ, patient's condition, and time since transplant.9

Adverse Drug Reactions

^ One of the major drawbacks of the calcineurin inhibitors is their ability to cause acute and chronic nephrotoxicity. Acute nephrotoxicity has been correlated with high doses and is usually reversible. Chronic calcineurin inhibitor toxicity, however, is typically irreversible and is linked to chronic drug exposure. Table 55-4 expands upon the more common calcineurin inhibitor-induced adverse events.

Comparative Efficacy—Calcineurin Inhibitors

Several studies have assessed the clinical efficacy of cyclosporine versus tacrolimus. Most of the studies have shown similar long-term patient and allograft survival. Some renal transplant studies have demonstrated improved renal function in the tacrolimus treated patients. The most significant difference between the two agents appears to be

their adverse drug reaction profiles. Antiproliferatives

These agents are generally considered to be adjuvant to the calcineurin inhibitors or possibly sirolimus. The medications included in this class are azathioprine and the MPA derivatives.

Azathioprine

Azathioprine was originally approved by the FDA in 1968 as an adjunct immunosuppressant for use in renal transplant recipients. It is available in oral and IV dosage forms.9 Prior to the advent of cyclosporine, the combination of azathioprine and corticosteroids was the mainstay of immunosuppressive therapy. Over the past 10 years, the use of azathioprine has declined markedly, due in large part to the success of the

MPA derivatives which are more specific inhibitors of T-cell proliferation. Azathioprine is a prodrug for 6-mercaptopurine (6-MP), a purine analog. 6-MP acts as an antimetabolite and inhibits DNA replication with a resultant reduction in T-cell proliferation.9 The typical oral dose of azathioprine for organ transplantation is 3 to 5 mg/ kg once a day. The maintenance dose is usually reduced to 1 to 2 mg/kg/day within a few weeks post-transplant. Dose reductions due to severely impaired renal function may be necessary since 6-MP and its metabolites are renally eliminated.9 Trough concentrations of 6-MP are not monitored; however, most clinicians often monitor for signs of myelosuppression and liver dysfunction. Myelosuppression (mainly leukopenia and thrombocytopenia) is a frequent, dose-dependent and dose-limiting complication (greater than 50% ofpatients) that often prompts dose reductions.9 Other common adverse events include hepatotoxicity (2-10%) and GI disease (10-15%; mostly nausea and vomiting). Importantly, pancreatitis and venoocclusive disease of the liver occurs in less than 1% of patients following chronic azathioprine therapy.9

Mycophenolic Acid Derivatives

Mycophenolate mofetil was approved by the FDA in 1995 and enteric-coated MPA

in 2004. Both agents are considered to be adjunctive immunosuppressants. Both mycophenolate mofetil and enteric-coated MPA are prodrugs for MPA. MPA acts by inhibiting inosine monophosphate dehydrogenase, a vital enzyme in the de novo pathway of purine synthesis. Inhibition of this enzyme prevents the proliferation of most cells that are dependent upon the de novo pathway for purine synthesis including T cells.8,9,28-30

Mycophenolate mofetil is available in 250 mg and 500 mg capsules, an oral suspension (100 mg/mL; in cherry syrup) and as an injectable.9 Usual doses of mycophenolate mofetil range from 1,000 to 3,000 mg/day in two to four divided doses. The conversion between oral and IV mycophenolate mofetil is 1:1. Enteric-coated MPA is available in 180-mg and 360-mg tablets. The appropriate equimolar conversion between mycophenolate mofetil and enteric-coated MPA is 1,000 mg of my-

28 31

cophenolate mofetil to 720 mg of enteric-coated-MPA. ' The recommended start-

ing dose of enteric-coated MPA is 720 mg given twice daily. It appears that conversion of mycophenolate mofetil to enteric-coated MPA is safe, but more studies are needed to determine the exact role of enteric-coated MPA in the immunosuppressive armamentarium. MPA trough concentrations can be monitored; however, they are not routinely recommended.

Table 55-4 Management of Common Adverse Effects of Calcineurin Inhibitors

M oil Likely Adwrsr tvent Offending CI

Monitoring Parameters

Therapeutic Managcmenl OpUons tfefJuwo«kily I ¡Chr'r

Hypo tension' Cyclosporins

HypHtptdcfliidf Cyclosporins

HypeiE]fc«nii/ Tacrolimus

Tacrolimus

Lhine output

Btopiy prawn O-mdured nOpilrOÍÜKiCitJ'

Bleed puttuii' Huil rate

Faslmg lipid panel

Blood g4ueose (Hasting and norifastingi Hflfnogtobln A,

Fine hand nemof Menral smusttvsng«

floduccooosclii poMitKS

Modify legimem Ctdd d change 1o non CI containing regime

Imlidflc1 patlwM speciTic juihypci tensive theiapy Reduce cyclosporine dose Of posible) Clw^lroaicydwÉtt ría uaoinuiiofSlícfcnuí

IrnliaK? patlenl spetifc chatosteral lowering therapy

Reduce cyclosporine dose Of posible]

t+Tflrty^ triHft (jr. kJígJOíine [0 UOClirtluS Ot SilOlnflij*

Diet mcxlilicdhoni Reduce («loflimusdoie [rfpo*Ji)ie] Reduce steroids p iMtiwi ü laking Hwri sod a poíüUle) Irp '¡i^L1 paLkiH spctifc glucose kwc.i^ [ht?upy flniulln or oul\ lhefapy}

Cihange (ron* »ooimus to í yckHoonne of siioJimtij

Reduce lacro^irmr1. dose tí poisilHej dunjtfiMihHkntiitityclofioilKciilekilil

HGrn,Heicgk: EM**

nepatolooi icy filhci ftetlrotybe EiUhm lmh,Hir<i

Hisuftltl ilopetla

Taootinui

Gingival Cpfcuporoe

Hypetplasii

Plahiïuts

Hemoglobin

HfliHtoOH

Sympiomç of ¿nernls

Liver function ¡«Is

K (uiually 11 \'<> Usually -l) P04 (usually1)

Patient torn plains û< emeiilw Mil UMivcn or m,ik>- |HHern hair growth

P-ariem «jmplainsof encettiw hair k'r.l

P-aricTKl complains oi emessive gum growth RCiOtninNHViitioriS ItV.'qïy from the patient's dcrnMst

RtduttCI (lûit (if pOMlHct ModHi* rotjimfiri ijctJ or (iHKfiiaiUiVGCûAUlnlrq amvxiçih hematologic dit is high toi j'i meds e^cei* stetcifct

Redure Cl dose (IF piKiltfe}

Mcxliiy reqiiwn l.kld i> f liano? m non Cl ronMimrvj regimenù Trï.'Jl flFClidVtS.' iiTflilLjnoefi.ç.. Vf-1 rL-ptaccnifrifl) Rcduce Cl dose (ïï possible;

Modif-y regimïn [add lx change Ho nanti OtKIUWng regimefi) Reducu tjtlcKfxif mk> dose lif pOsaWe) Cc&nwfk haïr removal

Change fiom cyclospoiinelo taaoftnus or slnohiKE Redute taciolimui dose Ci posstite)

Hair ^wjth Uealmentt (je, minoadi, firusterkie—maies only)

Change from TacrdlmustocyrfciSfiQrlneor sliollmits

Rcduce cys lospor ine dow Of possible)

Oal siatgery (gum lesec tien)

Change from cyclosporinelo tactolimusor sjiotnujs

BUN,bltnd uiea niliotjea tUHcafclLHii ihanneH MockprifLcakinsurin fthMor; CMJ. central nemous syslemt HTM, hyperh:nym, K potassium, P/ifi. magnriui*cK),(ii*iifJw.

'T. k ri ilin lut is jto OSWXiiKd wil 11 h "i MtlSkJi i jT*J typttftpMffllit, IHH (0 i rnui h klvw? m (TU CCtfïipjrrtl (0 CïtlOSpOtinC VycVwporiirwl * W a^WC iatwj with hflpe([jl)t(:«?iiaandi!N5 toxicities hui K) s mix h lt>^ef ent^m f-ompjied Tacrolimus fiomBefi I, S.fl.

The most common adverse events associated with these agents are GI

(18-54%; diarrhea, nausea, vomiting, and gastritis) and myelosuppression 8,12,28-30

(20-40%) ' ' Despite being enteric-coated, enteric-coated MPA has produced

the same degree of GI adverse events as mycophenolate mofetil. However, recent data suggest that there is a benefit in converting patients with documented mycophenolate-induced GI disease from mycophenolate mofetil to enteric-coated MPA.

Comparative Efficacy—Antiproliferatives

Due to the results of several studies, the MPA derivatives have replaced azathioprine as the antiproliferative agent of choice in most organ transplant centers. The MPA derivatives are generally considered to provide a more specific immunosuppressive effect compared to azathioprine. Mycophenolate mofetil and enteric-coated mycophenolate acid have similar safety and efficacy data in renal transplant recipients. The decision to choose one agent over another is a purely practitioner-dependent preference.

Target of Rapamycin Inhibitors

Sirolimus

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some

European countries. Sirolimus is a macrolide antibiotic that has no affect on cal-

8 33 34

cineurin phosphatase. ' ' Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either aza-

thioprine or mycophenolate mofetil. Sirolimus can also be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or

O/f other adverse events.J At this time, the most exciting data for sirolimus point to its ability to prevent long-term allograft dysfunction when used as a substitute for the

calcineurin inhibitors in renal transplant recipients. , ,

Sirolimus inhibits T-cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2

9 33

Sirolimus is available in a 1-mg and 2-mg tablet and a 1 mg/mL oral solution. The current FDA approved dosing regimen for sirolimus is a 6 mg loading dose followed by a 2 mg/day maintenance dose.9 It was recommended that this agent does not require therapeutic drug monitoring. However, most centers do check trough concen-

trations and adjust doses to reach goal concentrations. Most clinicians who use sir-olimus utilize a loading dose of 5 to 15 mg/day for 1 to 3 days to more rapidly achieve

adequate immunosuppression. , , Maintenance doses of sirolimus usually range from 1 to 10 mg/day given once daily. Sirolimus blood C0 levels should be obtained and maintained between 5 and 20 ng/mL, depending on the institution-specific pro-

tocols. Switching between immunoassays may produce different results that may be clinically significant. Of note, sirolimus has a half-life of approximately 62 hours, which means that it will not reach steady state after dosage changes for several days.9

The most common adverse events reported with sirolimus are leukopenia (20%), thrombocytopenia (13-30%), andhyperlipidemia (.38-57%).9,3 Other adverse effects include delayed wound healing, anemia, diarrhea, arthralgias, rash, hypergly-cemia, pneumonitis, and mouth ulcers. Sirolimus has a FDA black-box warning in newly transplanted liver and lung recipients.9 In liver transplant recipients, use of sir-olimus immediately after transplant is associated with an increased risk of hepatic artery thrombosis, graft loss, and death. In lung transplant recipients, bronchial anastomotic dehiscence, including some fatal cases, has been noted in patients treated with sirolimus, tacrolimus, and corticosteroids.

Corticosteroids

Traditional triple-therapy immunosuppressive regimens have consisted of a calcineurin inhibitor, an antiproliferative or ToR inhibitor, and corticosteroids. In recent years, many protocols have focused on corticosteroid sparing or avoidance. Avoidance or sparing of corticosteroids has been supported in the literature, although more studies are needed to help better characterize which patients should follow these proto-cols.38-41 A typical taper includes a bolus of IV methylprednisolone 100 to 500 mg at the time of transplant, then tapered over 5 to 7 days to a maintenance low dose of prednisone 5 to 10 mg/day. Although most centers still use low dose steroids for im-munologically high risk patients, a number of programs have developed an immun-

osuppression protocol that completely avoids or withdraws corticosteroids at some

point post-transplantation. " At most transplant centers, therapeutic drug monitoring of corticosteroids is not employed. Corticosteroids are associated with a variety of acute and chronic toxicities. The most common adverse events have been summarized in Table 55-5.9

® Corticosteroids have various effects on immune and inflammatory response systems, although their exact mechanism of immunosuppression is not fully understood. It is generally believed that at high doses, the agents are directly lymphotoxic and at lower doses, the corticosteroids act by inhibiting the production of various cytokines that are necessary to amplify the immune response.1

The most commonly used corticosteroids are methylprednisolone (IV and oral) and prednisone (oral), although prednisolone and dexamethasone have also been shown to be effective for organ transplantation. Corticosteroid doses vary by center-specific protocols, organ type, and patient characteristics.

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