Clinical Use of Immunosuppressants

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176 Clinical Use of Immunosuppressants

Advances in molecular biology and immunology have provided for greater understanding of the mechanisms involved in allograft rejection. Many of the key pathways of organ rejection are targeted by today’s growing armamentarium of immunosuppressive drugs, and a vast array of immunosuppressive combinations has dramatically decreased the incidence of acute allograft rejection. However, very little ground has been gained with respect to the impact of chronic allograft rejection on long-term allograft survival. Furthermore, with long-term use, the relative nonselectivity of current immunosuppressants can lead to development of malignancies and opportunistic infections. As we continue to explore different combinations of immunosuppressants and new immunosuppressive pathways, our comprehension of the immune system will grow, and we can help patients come closer to true allograft acceptance.

image Basic Principles of Immunosuppression

Optimal immunosuppression as it relates to transplantation is defined as the level of drug therapy that achieves graft acceptance with least suppression of systemic immunity. By optimizing immunosuppressive therapy, systemic toxicity (i.e., infection and malignancy) and other side effects can be minimized, albeit not entirely eliminated. Because monitoring of blood levels and titration of immunosuppression on this basis is possible with only a few agents in practice, oversuppression or undersuppression almost invariably becomes apparent only in retrospect. Recently, monitoring CD3+ cell counts has provided an alternative means of measuring the degree of immunosuppression.

Current immunosuppression protocols typically use multiple drugs, each directed at a discrete site in the T-cell activation cascade.1 Most immunosuppressive regimens combine drugs, often with differing modes of action and toxicities, allowing lower doses of each drug. Transplantation immunosuppression can be (1) pharmacologic, consisting of drugs such as corticosteroids, cytokine suppressive agents, and cell cycle inhibitors, or (2) biological, consisting of monoclonal and polyclonal antilymphocyte antibodies and anticytokine receptor antibodies.2

The combination of cyclosporine or tacrolimus with a corticosteroid forms the backbone of most maintenance immunosuppressive regimens being used today. An antiproliferative agent also may be added. In general, the early postoperative period calls for the greatest degree of immunosuppression. As time goes on, many patients can maintain graft function with smaller doses of immunosuppressive agents.

If acute cellular rejection occurs, it is common to treat it with a brief course of high doses of corticosteroids, antilymphocyte antibodies, or both. Generally, high doses of a corticosteroid are used initially to reverse the acute attack on the allograft. Antilymphocyte antibody therapy with monoclonal or polyclonal antibodies is used for more severe rejection or if corticosteroid therapy fails.

Induction therapy, also called prophylactic therapy, refers to the use of antilymphocyte antibodies immediately after transplantation. This practice is based on the theory that early incapacitation of the immune system may reduce the likelihood of subsequent rejection. Claimed benefits are delayed onset of acute rejection, fewer episodes of rejection, and no significant increase in infectious complications.3,4 The related concept of sequential therapy was introduced in response to the significant renal toxicity of cyclosporine observed in recipients of liver, heart, and kidney transplants. The practice is to use antibody therapy for the first 1 to 2 weeks after transplantation—the period in which renal injury is most likely to occur from a variety of insults. Cyclosporine therapy is not used during this period but is started later. The impact of this strategy on long-term renal function is much less clear.

This early intensification of immunosuppression is not universally accepted. Some experts voice concern because of the well-known association between antilymphocyte antibody therapy (and immunosuppression in general) and infection and malignancy.5,6 Others describe no benefit, greater expense,7 or the successful use of regimens that avoid induction altogether.8 Intermediate strategies involve the use of induction only in high-risk patients or the use of just one dose of an antilymphocyte agent, followed by early evaluation of renal function.

Although some patients can tolerate complete withdrawal of immunosuppressive therapy without exhibiting rejection,3 it is best done as a protocol-based strategy with patients under strict supervision. The current general approach is to minimize long-term immunosuppression. Various withdrawal protocols target individual components of the immunosuppressive regimen (e.g., corticosteroids, calcineurin inhibitors) in an attempt to decrease serious complications of immunosuppression—namely, infection, malignancy, and renal dysfunction.

image Overview of Transplantation Immunobiology

Antigen specificity is determined by an antigen-binding unit on the surface of the T cell called the T-cell receptor (TCR). The specificity and diversity of the TCR binding site result from variations in its amino acid composition among different T cells. The gene sequence coding for the TCR rearranges during development in the thymus such that each T cell has a different TCR binding specificity. The result is a complex system that enables lymphocytes to discriminate between “self” and “nonself” or foreign antigens.

Once inside tissues or the circulation of the body, foreign antigens are presented to lymphocytes by antigen-presenting cells (APCs), epitomized by dendritic cells. APCs phagocytose foreign proteins and cleave them enzymatically into small peptides that are 8 to 12 amino acids in length. These peptides are loaded onto a class of specialized carrier molecules known as major histocompatibility complex (MHC) molecules. The MHC molecule carries the peptide fragment to the cell surface, where it is displayed to T cells in the host’s lymphoid organs. Thus, there are three essential requirements for the adaptive immune response known as rejection: (1) the presence of an antigen fragment or protein (a ligand) at the cell surface of the APC, (2) a receptor that recognizes the ligand, and (3) activation of T cells.

The migration pattern of the antigen also is a critical factor. The only mobile antigens in solid organ transplantation are “passenger leukocytes” of donor bone marrow origin that are present in the graft. After transplantation of the solid organ, these white blood cells migrate promptly and preferentially to host lymphoid organs.911 These organs or organized heterotopic lymphoid collections provide the unique architectural structure and cellular milieu wherein factors necessary for progression from an immunogenic environment to a tolerogenic environment are present in abundance. These factors include cytokines, other molecules, cell-cell proximity, and homing mechanisms that ensure an efficient response to the antigen.12 In the lymphoid organs, dendritic cells and other APCs that have captured and processed the antigen present the peptide fragment of the antigen to antigen-specific TCRs in the context of their upregulated host MHC peptide.

The efferent (effector) phase begins with the secretion of interleukin (IL)-2, or T-cell growth factor) and interferon alpha (IFN-α) by activated lymphocytes. The antigen-specific immune activation and clonal expansion is aborted unless there is upregulation by the APCs of “accessory” cell-bound (co-stimulatory) molecules that sustain accelerated production of IL-2 and foster the secretion of numerous other cytokines (e.g., IL-1, IL-6, IL-9, IL-10, IFNs, tumor necrosis factor alpha and beta [TNF-α, TNF-β]) and growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor [GM-CSF]).13 The sequential nature of the response amplification has been obscured by use of the term co-stimulatory to describe the accessory molecules, implying that the afferent and early effector phases are simultaneous.

The TCR is a cell-surface molecule that associates with accessory molecules including CD3, and either CD4 or CD8. The TCR-CD3 complex interacts with the peptide fragment carried by the MHC molecule of the APC. This complex is stabilized by the CD4 or CD8 molecule of the T cell. This interaction produces the signal that initiates activation of the T cell, leading to proliferation of a T-cell clone that recognizes the particular antigen fragments of the foreign protein. The basis for MHC-restricted antigen recognition requires antigen presentation by APCs bearing an MHC molecule specific to the host.

Antigen-directed proliferation of T-cell clones is absolutely essential for an effective immune response. The response is driven by a positive feedback loop. T cells that recognize antigen make the potent growth factor, IL-2, and simultaneously become responsive to IL-2 by expressing the IL-2 receptor. This dual synthesis allows the cells to stimulate their own proliferation, as well as the proliferation of other T cells. Lymphocytes recirculate at a rate of 1% to 2% per hour, migrating through all tissues of the body. Specialized cell-surface “homing” molecules on T lymphocytes mediate attachment to targeted alien tissues, with a special avidity for the endothelial cells of an allograft’s vessels.

During an ongoing immune response, proliferating T cells recruit many other cell types and immune mechanisms into action. Cytokines and chemokines can attract and activate other leukocytes. For example, cytokines produced by CD4-positive helper T cells attract macrophages and CD8-bearing cytotoxic lymphocytes into rejecting allografts.14 These cytokines also trigger macrophage activation and CD8+ T-lymphocyte cell maturation. The resulting multicellular tissue infiltration has traditionally been referred to as a delayed-type hypersensitivity response. Cytokines released by helper T cells also are responsible for the activation of B cells and thus, indirectly, for the majority of antibody production. Cytokines also upregulate expression of both MHC molecules on tissues and adhesion molecules on endothelium. These events aid in the entry and accumulation of leukocytes. Finally, cytokines activate distant organ responses such as the hepatic acute-phase response, production of phagocytes in the bone marrow, and the hypothalamic-pituitary axis, producing the systemic signs of inflammation.

Once the antigen is consumed or removed, the process down-regulates. If antigen removal is incomplete, continuously sensitized (“memory”) T cells remain and contribute to a stronger secondary response on rechallenge with the same antigen. However, in some instances, if the antigen cannot be eliminated, the immune response can become exhausted and T cells deleted by mechanisms that are not fully understood but include Fas ligand-mediated apoptosis. Exhaustion-deletion in the first weeks or months after transplantation is never complete, but it can be maintained in a stable state by small numbers of persistent donor leukocytes.

Molecular insights regarding IL-2 gene transcription and the structure of the IL-2 receptor (IL-2R) have led to IL-2R-targeted therapy. As molecular knowledge has advanced, investigators have gained greater understanding of the workings of many immunosuppressants. New strategies guided by this knowledge have resulted in attempts to develop site-directed immunosuppression. Virtually every known step of the immune process can be targeted, and many new drugs are now in various stages of evolution.

image Specific Agents


Corticosteroids are extensively used in brief courses at high doses for the reversal of acute rejection episodes. These drugs are also used extensively in clinical immunosuppressive protocols for both induction and maintenance phases.15 Five glucocorticosteroids are commonly used in transplantation: hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone.

Because hydrocortisone has the greatest mineralocorticoid activity per unit of glucocorticoid activity, its routine application in transplantation is relatively limited. The other four agents have more glucocorticoid activity in proportion to their mineralocorticoid activity.

Prednisone has an oral bioavailability of about 80%, and it is metabolized in the liver to its active form, prednisolone. Oral prednisolone has a bioavailability of 100%. The serum half-life of both prednisone and methylprednisolone is 2 to 3 hours.16 The oral bioavailability of dexamethasone is 61%, and this drug has a half-life of 2 hours.17 However, the clinical activity of corticosteroids (i.e., suppression of cytokine production) persists for 24 hours or longer. In other words, the half-life for biological activity is much longer than the circulating half-life.

There is no universally accepted fixed dosing regimen for corticosteroids. Rather, the dose is often dictated by local protocols. A preoperative dose of 250 to 1000 mg of methylprednisolone may be given, followed by 20 to 200 mg/d during the first week. Acute rejection may be treated with 1 to 3 large doses—250 to 1000 mg of methylprednisolone—or by a regimen starting at 200 mg/d of oral prednisone and tapering to baseline maintenance doses over 3 to 6 days. There is evidence that doses lower than those traditionally used can be equally effective. In combination regimens, steroid doses often can be reduced to 5 or 10 mg/d or less and perhaps given every other day.

Corticosteroids have broad effects on many cell types. These agents interfere with the production of IL-1 and IL-2, blocking the early steps of T-cell activation. Other pharmacologic effects related to immune function include:

Prednisone and prednisolone have much less mineralocorticoid effect than the naturally occurring glucocorticoids do; however, sodium retention, edema, hypertension, potassium loss, and hypokalemic alkalosis can be seen with prolonged use of these drugs. Suppression of the pituitary-adrenal axis can be seen with all corticosteroids, but the magnitude of this effect varies among patients. Acute adrenal insufficiency can develop unexpectedly if patients are stressed, even as long as 12 months after corticosteroids are withdrawn.

The adverse effects of corticosteroids are numerous and cause considerable morbidity. An increased incidence of serious infections is well documented. Impaired fibroblast growth and collagen synthesis contribute to poor wound healing. Hence, surgical wounds and anastomoses are at increased risk for dehiscence, and gastrointestinal ulcers tend to heal slowly, leading to increased risks of perforation and rebleeding. Spontaneous ulceration of the gastrointestinal tract occurs in approximately 2% of patients taking steroids. Because signs of inflammation are suppressed, the diagnosis of intraabdominal infection and peritonitis can be significantly delayed, sometimes with disastrous consequences.

Corticosteroids impair glucose tolerance, often dramatically. For patients receiving large doses of corticosteroids, it often is best to use sliding-scale insulin regimens to ensure adequate control of blood sugar levels. Some patients require long-term therapy with oral hypoglycemic agents or insulin to maintain adequate glucose control.

Central nervous system effects such as euphoria and mood swings are well known. These adverse effects are generally dose dependent and are seen most frequently early in the postoperative period or with therapy for acute rejection episodes when higher doses of steroids are used. Central nervous system effects are usually self-limited and do not require treatment.

Long-term use of corticosteroids can cause bone demineralization and lead to osteoporosis. Atherosclerosis may be accelerated. Prolonged administration of glucocorticoids is associated with increased incidence of cataracts and elevated intraocular pressure (glaucoma). Soft-tissue and dermal changes (e.g., fat redistribution, skin atrophy, “moon face,” striae) produce the characteristic cushingoid appearance.

To minimize development of adverse sequelae, most immunosuppressive protocols attempt to reduce the dose of corticosteroids over time to physiologic levels (equivalent to 5 mg/d or less of prednisone). However, corticosteroid doses must be reduced carefully to minimize side effects while maintaining adequate immunosuppression to prevent acute rejection of the allograft.

Cytokine Inhibitors

Before the introduction of cyclosporine, immunosuppression protocols relied heavily on corticosteroids and cytotoxic drugs. These regimens had the disadvantage of producing broad suppression of the immune and inflammatory cascades. Cyclosporine introduced a new era of immunosuppression because it provided potent, relatively specific, and noncytotoxic suppression of T-cell activation.


Cyclosporine is a lipophilic cyclic polypeptide with 11 amino acids and a molecular weight of 1202. On entering the T cell, cyclosporine binds to cyclophilin, a cytoplasmic immunophilin protein. The cyclosporine-cyclophilin complex inhibits the activity of calcineurin, which in turn inhibits transcription of several genes including those encoding IL-2, IL-3, IL-4, GM-CSF, IFN-γ, and TNF-α. One key action that results from blockade of calcineurin is inhibition of signaling via nuclear factor of activated T cells (NF-AT), which regulates activation of the IL-2 gene; this effect ultimately prevents synthesis of IL-2.18 Inhibition of the synthesis of IL-2, a potent T-cell growth factor, is the crucial activity of cyclosporine.

Cyclosporine is insoluble in water and therefore must be dissolved in an organic solvent. There currently exist two formulations: cyclosporine (Sandimmune [Novartis Pharmaceuticals, East Hanover, New Jersey]) and cyclosporine for microemulsion (cyclosporine, modified; Neoral [Novartis Pharmaceuticals] and Gengraf [Abbott Laboratories, North Chicago, Illinois]). The microemulsion formulation substantially increases cyclosporine absorption; the overall time to peak cyclosporine concentration is reduced, the peak concentration is higher, and the area under the curve (AUC) is increased. The lipophilicity of the conventional cyclosporine formulation is responsible for its variable bioavailability

Oral bioavailability is about 30%, but there is much individual variability (range 10%-60%). Absorption in the small intestine decreases with bowel dysfunction or reduced bile flow.19 The volume of distribution of cyclosporine is large and variable. The drug is metabolized in the liver via cytochrome P450 (CYP) 3A4 enzymes. It also is a substrate for the P-glycoprotein efflux pump. The mean terminal half-life with normal liver function is 19 hours. The microemulsion formulation of cyclosporine has superior pharmacokinetics, does not require bile excretion for its bioavailability, and is better dispersed and absorbed compared to conventional cyclosporine. The relative bioavailability of the microemulsion formulation is approximately 60%.20 The total AUC is increased by 30% compared with the conventional formulation.21

At least 17 cyclosporine metabolites have been identified, and a few of them are immunosuppressive, although considerably less so than the parent compound. The half-life of cyclosporine increases with hepatic failure and is changed significantly by coadministration of a large number of other drugs that can increase or decrease serum levels by induction or competitive inhibition of P450 (Table 176-1).22 For all these reasons, it is essential that cyclosporine levels be monitored regularly and dosage adjusted accordingly.

TABLE 176-1 Drugs That Alter Cyclosporine and Tacrolimus Concentrations

Increase Decrease
Diltiazem Rifampin
Nicardipine Carbamazepine
Verapamil Phenobarbital
Fluconazole Phenytoin
Itraconazole Ticlopidine
Ketoconazole Nafcillin
Methylprednisolone (in large doses)  
Protease inhibitors  

Monitoring cyclosporine levels is not straightforward. Different results are obtained when cyclosporine concentrations in blood or plasma are determined by radioimmunoassay or by high-pressure liquid chromatography (HPLC). Neither method is clearly superior, and there are no universally accepted blood levels; target levels vary widely from center to center. Desired levels in serum or plasma as measured by radioimmunoassay23 are 150 to 250 ng/mL at the time of transplantation, tapering to 50 to 100 ng/mL after 3 to 6 months. If the drug is measured in whole blood by HPLC, desired levels are 100 to 300 ng/mL initially, tapering to 80 to 200 ng/mL.

Recent literature suggests that AUC values and peak concentrations measured 2 hours after dosing (C2) are more sensitive predictors of cyclosporine effects and may be better parameters to guide therapeutic monitoring of the microemulsion formulation of cyclosporine. Decreased bioavailability of cyclosporine has been correlated with acute rejection.24 The first 4 hours after administration of a dose of cyclosporine represents the period of greatest variability in cyclosporine absorption.25 Limited sampling techniques consisting of 2 to 5 blood samples drawn within the first 4 hours after cyclosporine administration are used to determine the AUC. AUC values greater than 4400 µg/L/h correlate well with a low incidence of allograft rejection.24,26 One study compared the correlation between the trough concentration, C2, and the occurrence of rejection and concluded that trough concentrations lack predictive value; however, acute rejection did not occur in patients with C2 values above 1200 µg/L.27 Because of the convenience of a single blood sample compared with the multiple blood samples necessary for AUC measurements, C2 monitoring is becoming a preferred way to adjust cyclosporine dosing. C2 levels should range between 1.5 and 2.0 µg/mL for the first few months after transplantation and should be reduced to 0.8 µg/mL after 6 to 12 months of therapy.26,28

The typical daily intravenous (IV) dose of cyclosporine is 4 to 5 mg/kg. This amount can be given in two divided doses, each being delivered over 2 to 6 hours. Alternatively, some prefer to use a slow continuous infusion over 24 hours. The changeover to oral dosing usually requires a dose 3 times higher, or about 12 to 15 mg/kg/d. Oral cyclosporine should be administered every 12 hours. After 1 to 2 weeks, the dosage can be slowly tapered once equilibration within body fat stores occurs. In many patients, the dose is tapered to as low as 3 mg/kg/d by 6 months after transplantation. Liver transplant recipients who have a T tube which diverts some bile flow require higher oral doses because of decreased absorption. Pediatric patients eliminate cyclosporine faster than adults, and they require larger doses, typically about 5 to 6 mg/kg/d IV and 14 to 18 mg/kg/d orally. Some pediatric patients require doses up to 50% to 100% larger than adult doses.

Several adverse effects can occur early after initiation of cyclosporine therapy. Acute nephrotoxicity and hypertension are major problems. The mechanisms responsible for these adverse effects are controversial.29,30 Nephrotoxicity may be the result of cyclosporine-induced afferent arteriolar vasoconstriction that results in part from an imbalance between the production of prostaglandin E2, a vasodilator, and that of thromboxane A2, a vasoconstrictor.31,32 Other possible factors include endothelin-1-induced vasoconstriction and impaired nitric oxide production.33 Cyclosporine-induced nephrotoxicity is transient and reversible with a decrease in dosage or discontinuation of the drug.34 The incidence of nephrotoxicity varies from approximately 25% to 38%.35

Neurotoxicity associated with cyclosporine ranges from minor toxicity, manifesting as tremors, to severe complications such as seizures or encephalopathy.36 Tremors caused by cyclosporine are common (prevalence 10%-55%) and may improve over time without a change in therapy. The causal association between seizures and encephalopathy is often unclear.36 Several reports have detailed a rare syndrome characterized by confusion and cortical blindness in both liver and bone marrow transplantation patients. Hypomagnesemia and hypocholesterolemia are believed to be risk factors for cyclosporine-induced neurotoxicity.29

Hypertension occurs frequently and usually begins within weeks after commencement of cyclosporine therapy. The incidence of hypertension varies widely in different patient populations, ranging from 10% to 80%.35 It is hypothesized37 that hypertension is caused by cyclosporine-induced vasoconstriction in the renal or systemic circulation or both, perhaps as a result of antagonism of endothelium-derived relaxation factors or increased synthesis of endothelin-1, a vasoconstrictor. Hypertension responds to sodium restriction and is best managed with diuretics or calcium channel blockers.30

Cyclosporine is diabetogenic, although analysis of this effect is confounded by the frequent concomitant use of steroids with cyclosporine. Other metabolic effects of cyclosporine include hypochloremic alkalosis and changes in serum concentrations of potassium, magnesium, prolactin, and testosterone. Hepatotoxicity, manifested by cholestatic jaundice, is common,29 but intrahepatic cholestasis often resolves if the dose of cyclosporine is reduced. Connective tissue side effects of cyclosporine are common and can be distressing to the patient because of the cosmetic manifestations. These changes include hirsutism (seen within 2-4 weeks in 20%-45% of patients receiving cyclosporine), gingival hyperplasia (in 4%-16% of patients), and coarsening of facial features.38 Long-term administration of cyclosporine is associated with irreversible nephrotoxicity. The incidence of this serious side effect is estimated to be 15% to 40%.39 The pathologic lesion resembles nephrosclerosis.40


Tacrolimus (FK-506; Prograf [Fujisawa Healthcare, Deerfield, Illinois]) is a macrolide antibiotic with immunosuppressive activity produced by the fungus Streptomyces tsukubaensis. It is approved by the U.S. Food and Drug Administration (FDA) for heart, liver, and kidney transplant recipients. It is also used extensively in small bowel, pancreas, and lung transplantation. The molecular structure of tacrolimus is unrelated to that of cyclosporine, and the two drugs have different cytosolic binding sites.41,42 Tacrolimus binds to the immunophilin called FK-binding protein-12 (FKBP12).43 Like the cyclosporine-cyclophilin complex, the tacrolimus-FKBP12 complex binds to and inhibits the activity of calcineurin. As is the case with cyclosporine, inhibition of calcineurin by tacrolimus blocks transcription of several genes including those encoding IL-2, IL-3, IL-4, GM-CSF, IFN-γ, and TNF-α. The effect of tacrolimus on TNF-β expression differs from that induced by cyclosporine. Tacrolimus-mediated inhibition of TNF-β expression may play a role in reducing chronic rejection,43 although no clinical difference has been noted between the two drugs. Like cyclosporine, inhibition of calcineurin disrupts signaling via NF-AT, ultimately inhibiting synthesis of the potent T-cell growth factor, IL-2; this is the key pharmacologic effect of tacrolimus. The immunosuppressive effects of tacrolimus also may involve other pathways that activate T cells.44

Tacrolimus is highly lipophilic and must be dissolved in an organic solvent. Oral bioavailability is highly variable and poor, reportedly ranging from 6% to 56%, with a mean of 25%.45 The gastrointestinal absorption of tacrolimus, compared with that of cyclosporine, is less dependent on bile flow.46 Tacrolimus is extensively bound to erythrocytes because of the high concentration of FKBP12 found in the red blood cells. Like cyclosporine, tacrolimus is metabolized in the liver via the cytochrome P450 enzyme system, primarily by CYP3A4, although other enzymes have been reported to be involved as well.47 Tacrolimus metabolism, like that of cyclosporine, can be significantly altered by liver dysfunction or coadministration of other drugs that induce or competitively inhibit P450; these effects can decrease or increase circulating levels of tacrolimus (see Table 176-1). Tacrolimus is a substrate for the P-glycoprotein efflux pump. The mean terminal half-life of tacrolimus is 12 hours. At least 15 metabolites of tacrolimus have been identified43; some of these have as much as 10% of the immunosuppressive activity of the parent compound.47

Therapeutic monitoring of circulating tacrolimus concentrations is essential for preventing toxicity while maintaining adequate immunosuppression. Plasma and whole-blood trough concentrations correlate with AUC as well as clinical outcomes and toxicities.48 Because of the extensive binding of tacrolimus to erythrocytes, whole-blood tacrolimus concentrations are 10 to 30 times higher than the corresponding plasma concentrations.47 The most commonly used tacrolimus assay is the microparticulate enzyme immunoassay, although HPLC and enzyme-linked immunosorbent assays are also readily available.49 The therapeutic range for tacrolimus levels in whole blood is 5 to 20 ng/mL. Plasma tacrolimus levels should be maintained between 0.5 and 2 ng/mL.

The typical IV dose of tacrolimus is 0.05 to 0.1 mg/kg/d. The drug should be administered as a slow continuous infusion over 24 hours. Oral doses are generally 3 to 4 times higher than IV doses and range from 0.1 to 0.2 mg/kg/d, administered in 2 divided doses every 12 hours. Maintenance doses of tacrolimus range from 0.0125 to 0.5 mg/kg/d owing to variability among patients with respect to absorption of the drug and requirements for immunosuppression.47 No decrease in tacrolimus dose is needed when the T tube is clamped after liver transplantation. Because tacrolimus clearance is faster in pediatric patients, larger doses may be required in children compared with adults.47 Pediatric IV doses range from 0.03 to 0.05 mg/kg/d, and pediatric oral doses range from 0.15 to 0.3 mg/kg/d in divided doses.

Tacrolimus has a potential advantage over cyclosporine because of its ability to reverse ongoing acute rejection.5053

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