39

Steroid withdrawal is the complete discontinuation of prednisone, typically a few

months post-transplant. In the era of cyclosporine (Sandimmune)- and azathioprinebased regimens, withdrawal was associated with a high rate of acute rejection and

late graft loss. With the introduction of newer agents, steroid avoidance or

withdrawal has been viewed with renewed interest. Steroid withdrawal has been

successful in at least 50% of kidney transplant recipients—resulting in reductions in

blood pressure and lipid levels. Some protocols withdraw corticosteroids within the

first few days to weeks after the initial transplantation period, whereas others

withdraw them in 3 to 6 months or later after transplantation. The rate of success

depends not only on the immunosuppressives used but on the population (high risk vs.

low risk) and timing of withdrawal. Most success takes place in low-risk patients

receiving antibody induction, such as rATG, with tacrolimus and mycophenolate with

short-term steroids (≤1 week). African-Americans, pediatric patients, patients who

have retransplants, highly sensitized patients, patients with a high serum creatinine

(>2.5 mg/dL), and those who have had a recent rejection episode are more difficult

to withdraw from steroids. This is particularly true early (<3 months) after

transplantation. Withdrawal in these cases is associated with a higher rate of

rejection. Later withdrawal may be attempted, but the benefits in terms of side effect

profile may not be as great. Not all studies have demonstrated significance

differences in side effect profiles between steroid withdrawal and continuation.

Long-term outcomes are also limited using this approach. Low-risk populations are

candidates for steroid avoidance or early withdrawal. First-time transplantation,

living-donor, well-matched transplantation, older age, and stable graft function

without rejection are factors associated with a positive benefit to steroid

withdrawal.

39

D.T. would be considered a low-risk patient because of her low immunologic

activity evidenced by first time transplant, a living donor, low PRA, older age, and

ethnicity. Therefore, a steroid avoidance protocol, such as the one indicated here,

would be appropriate. As with other transplant recipients, she must be closely

monitored for rejection and adverse effects.

Cyclosporine

CASE 34-4

QUESTION 1: B.B. is a 27-year-old, 55-kg African-American man who received a deceased donor kidney

transplant. Within 12 hours of the transplantation, his immunosuppression consisted of modified cyclosporine

(Neoral) 300 mg PO BID, MMF 1.5 g PO BID, and prednisone. He was taking other medicines for

hypertension and infection prophylaxis. What pharmacokinetic and monitoring parameters and adverse effects

should be considered with using cyclosporine?

Cyclosporine pharmacokinetic parameters exhibit significant intrapatient and

interpatient variability. A number of factors are known to influence its

pharmacokinetic behavior and outcomes. These include age, ethnicity, transplant

type, underlying disease, time after transplantation, GI metabolism and motility;

biliary and liver function; metabolism, body weight, cholesterol, albumin, red blood

cell mass; and drug interactions and formulation.

40 For example, children, AfricanAmericans, and patients with cystic fibrosis tend to have reduced absorption,

increased clearance of cyclosporine, or both. Patients who are obese or who have

decreased liver function will have reduced clearance. Oral absorption of

cyclosporine, which has been characterized as slow, incomplete, and highly variable,

is the parameter that is most significantly affected. Absorption can depend on the type

of transplant, time after transplantation, presence of food and its composition,

intestinal function (e.g., diarrhea, ileus), small bowel length, and presence or absence

of external bile drainage. Bioavailability ranges from less than 5% to 90%.

41

In most

transplant recipients, cyclosporine absorption increases over time.

p. 730

p. 731

Because the original cyclosporine (Sandimmune) absorption was so poor and

erratic, the IV route was used for the first few days after transplantation, particularly

after liver transplantation. Cyclosporine can be given IV as a continuous infusion (2–

3 mg/kg/day) or intermittently (2.5 mg/kg/day) over 2 to 6 hours divided into two

equal doses. Sandimmune is used in very few patients today.

Neoral and Sandimmune are not bioequivalent and, therefore, not interchangeable.

Neoral produces a higher maximum concentration (Cmax

), shorter time to Cmax

(Tmax

), and higher area under the concentration–time curve (AUC) than Sandimmune.

It has significantly less intrasubject and intersubject pharmacokinetic variability, and

a better correlation exists between single doses and trough concentrations and AUC

than Sandimmune. The bioavailability of Neoral is approximately 20% higher than

that of Sandimmune. Several other generic capsules and liquid formulations are now

available for both.

Cyclosporine is extensively distributed into red blood cells; whereas in plasma it

is highly bound to lipoproteins. It is extensively metabolized by both the gut and liver

cytochrome P-450 3A4 enzymes and transported by P-glycoprotein. The average

half-life is about 15 to 20 hours. Cyclosporine is an inhibitor of CYP3A4 and Pgp, so

it can interact with other drugs.

41

Cyclosporine can cause a number of adverse effects, of which nephrotoxicity is the

most frequent and worrisome. Other major effects include hypertension,

hyperlipidemia, tremors, headaches, seizures, paresthesias, hypomagnesemia,

hypokalemia or hyperkalemia, hyperuricemia, hyperglycemia, gout, gingival

hyperplasia, hirsutism, hemolytic–uremic syndrome, and hepatotoxicity. If these

occur, they generally respond to a reduction in dose or concentration although some

cases require discontinuation of cyclosporine.

42

Cyclosporine concentrations are monitored to prevent toxicity, optimize efficacy,

and assess patient compliance to the prescribed regimen. Most institutions monitor

trough cyclosporine levels. During the early postoperative period, cyclosporine

levels are often measured daily, keeping in mind that these may not reflect steadystate concentrations, and that dosage changes should be made every few days. The

target trough therapeutic concentration of cyclosporine during the first 2 months posttransplant is 150 to 300 ng/mL with most whole blood assays. About 1 to 6 months

after transplantation, the cyclosporine trough concentration target is lowered to 150

to 250 ng/mL. After 6 months, the targeted cyclosporine trough concentration is

lowered even further to 50 to 150 ng/mL. These ranges differ among institutions and

depend on the transplant type, time after transplantation, and other agents used. The

range is reduced over time, given that less immunosuppression is required after

transplantation and that the pharmacokinetics change over time. A few programs may

monitor C2 levels, obtained 2 hours after a dose or determine AUC; however, these

are more cumbersome. A number of assay methods are used to measure cyclosporine

concentrations, and most institutions use the method that is most familiar to their

transplant physicians.

43

As in all cases, pharmacokinetic and drug level data must be interpreted in

conjunction with the patient’s clinical condition. In addition, deference always must

be given to trends established by multiple cyclosporine levels rather than reacting to

a single level. Single levels may be erroneous because of variability in dose

administration, incorrect sampling time or techniques, or assay error.

B.B. was started on Neoral 10 mg/kg/day given in two divided doses. Because he

is African-American, he may require even higher doses, because the of the increased

gut metabolism of cyclosporine in this population. His trough concentration will be

monitored closely and adjusted if necessary. Once B.B. is home, cyclosporine

monitoring is necessary less frequently and eventually only every 1 to 2 months. He

should be watched closely for signs of rejection and toxicity.

CASE 34-4, QUESTION 2: B.B. developed GI intolerance, nausea, vomiting, and diarrhea, to both

mycophenolate products (mycophenolate mofetil and mycophenolic acid sodium) and cannot take either one

anymore. A decision is made to use an mTOR inhibitor, sirolimus or everolimus instead. What would be

important pharmacokinetic considerations, an appropriate regimen, and monitoring parameters for this agent?

mTOR Inhibitors

Sirolimus, and more recently everolimus, could be used as a substitute for other

immunosuppressives. Experience and literature is more extensive with sirolimus.

16

.

Sirolimus can be used in the immediate post-transplant period although impaired

wound healing and lymphocele development in kidney transplantation have limited

its use in the early period. In the case of liver transplantation, its use is

contraindicated in the early post-transplantation period because of hepatic artery

thrombosis. Sirolimus can be added later, as is the practice in many centers, as

replacement for or minimization of cyclosporine, tacrolimus, steroids, or

mycophenolate. In addition, sirolimus may be used as a substitute for these agents in

patients predisposed to or with evidence of malignancy.

44 Early experience

advocated an initial loading dose followed by a once-daily maintenance dose;

however, because of its adverse effect profile, not all centers use loading doses. The

starting maintenance dose is 2 to 5 mg. The typical loading dose is 6 mg followed by

2 mg every day. In high-risk patients, such as African-Americans, a 15-mg loading

dose and 5-mg daily dose is recommended along with cyclosporine. Other centers

have used loading doses of 10 to 15 mg, followed by 5 to 10 mg/day for the first

week with target troughs of 10 to 15 ng/mL for the first month and 5 to 10 ng/mL

thereafter when used with tacrolimus. Sirolimus is often given 4 hours after the

morning dose of cyclosporine. If administered at the same time as cyclosporine,

sirolimus concentrations are on average 40% higher.

45

As with other immunosuppressives, sirolimus is associated with a number of side

effects, including impaired wound healing, lymphedema, oral ulcerations,

hypercholesterolemia, hypertriglyceridemia, diarrhea, arthralgias, epistaxis, rash,

acne, leukopenia, thrombocytopenia, nausea and vomiting, lymphocele, hypokalemia,

anemia, hypertension, pneumonitis, reproductive endocrine disorders, and infection.

Dose-related hypertriglyceridemia, as well as hypercholesterolemia, occurs within

the first few weeks of therapy and is sufficiently significant to require intervention

with lipid-lowering agents, although it may respond to dosage reduction to some

degree. Leucopenia and thrombocytopenia are also dose related. Sirolimus is

associated with the development of proteinuria in kidney transplant recipients. The

exact mechanism is unknown, but many transplant centers are now routinely

monitoring for proteinuria in patients on sirolimus therapy and generally avoid its use

in patients with preexisting proteinuria. Unfortunately, adverse effects are often the

reason for discontinuing this agent in many patients.