Cyclosporine and Tacrolimus

The calcineurin inhibitors are administered as part of immunosuppressive

regimens in kidney, liver, heart, lung, and bone marrow transplant recipients.
They are also used in autoimmune disorders such as psoriasis and multiple
sclerosis.

The pathophysiologic mechanism for AKI is renal afferent arteriole

vasoconstriction and ATN. AKI often occurs within the first 6 to 12 months of
treatment and can be reversible with dose reduction or drug discontinuation.

Risk factors include high dose, elevated trough blood concentrations, increased
age, and concomitant therapy with other nephrotoxic drugs.

Cyclosporine and tacrolimus are extensively metabolized by the liver through the
cytochrome P450 3A pathway; drugs that inhibit their metabolism (eg,
erythromycin, clarithromycin, fluconazole, ketoconazole, verapamil, diltiazem,
nicardipine) can increase blood concentrations of cyclosporine and tacrolimus and
precipitate AKI.

Pharmacogenetic variability in drug absorption and metabolism can also alter

blood concentrations.

Careful monitoring of cyclosporine or tacrolimus trough concentrations and

maintaining them in the target range can reduce the occurrence of AKI; however,
AKI can still occur with therapeutic or even low blood concentrations.

Calcium channel blockers may have a renoprotective effect through dilation of the
afferent arterioles and are often used preferentially as antihypertensive agents in
kidney transplant recipients. However, the calcineurin inhibitor dose would need
to be reduced to avoid high blood concentrations because of reduced metabolism.

It is often difficult to differentiate AKI from acute organ rejection in kidney

transplant recipients because the conditions may present with similar symptoms
and physical examination findings. However, fever and graft tenderness are more
likely to occur with rejection, whereas neurotoxicity is more likely to occur with
cyclosporine or tacrolimus toxicity.

Kidney biopsy is often needed to confirm the diagnosis of rejection.

Immunosuppressive regimens utilize multiple medications working on different

targets of the immune system. There are generally three stages of medical
immunosuppression: (a) induction therapy, (b) maintenance therapy, and (c)
treatment of rejection.

The CNIs, cyclosporine and tacrolimus, are considered the cornerstone of modern
immunosuppressive protocols. The CNIs work by complexing with cytoplasmic
proteins (cyclosporine with cyclophilin and tacrolimus with FK binding

protein-12).These complexes inhibit calcineurin phosphatase, which results in

reduced IL-2 gene transcription and a reduction in IL-2 synthesis. This diminishes
T-cell activation.

Cyclosporine Cyclosporine USP was first approved in 1983, but was associated
with a variable oral absorption. The development of a newer formulation,
cyclosporine microemulsion USP (ie, modified), introduced in 1994, allowed for
more consistent drug exposure due to a more reliable pharmacokinetic profile.1
Cyclosporine modified is the formulation of choice for most transplant centers
utilizing cyclosporine. The two formulations are not interchangeable.

The usual oral adult dose of cyclosporine ranges from 3 to 7 mg/kg/day in two
divided doses. Appropriate selection of the starting dose depends on the organ
type, the patient’s comorbidities, and other concomitant immunosuppressive
agents utilized.

Cyclosporine modified is available as 25 mg and 100 mg capsules and an oral

solution. An IV formulation of conventional cyclosporine is also available. When
converting a patient from oral to IV, the dosage should be reduced to
approximately one- third of the total daily oral dose.7 Cyclosporine whole-blood
trough concentrations (C0) have traditionally been obtained to help monitor for
efficacy and safety. Therapeutic C0 may range from 50 to 400 ng/mL (mcg/L;

42–333 nmol/L).

Target levels should be individualized for each Tacrolimus was approved in 1997.
Oral starting doses range from 0.1 to 0.2 mg/kg/day in two divided doses.

Tacrolimus is available in 0.5 mg, 1 mg, and 5 mg capsules and as an injectable.7

Two once-daily tacrolimus formulations are also available. Once-daily
formulations are not bioequivalent and should not be substituted in clinical
practice; however, these differences in their compositions are unlikely to have any
major therapeutic benefit. Tacrolimus C0 should be monitored and maintained
between 5 and 15 ng/mL (mcg/L; 6 and 19 nmol/L), again depending on the
transplanted organ, patient’s condition, and time since transplant.
The tacrolimus IV formulation is usually avoided due to the risk of anaphylaxis,
because of its castor oil component, and nephrotoxicity.6 Doses for IV
administration are recommended to start at 0.01 mg/kg/day. In an effort to avoid
IV tacrolimus, many transplant centers utilize sublingual (SL) tacrolimus in

their patients unable to receive the medication by mouth.

Adverse Drug Reactions One of the major disadvantages of the CNIs is their
ability to cause nephrotoxicity. Acute nephrotoxicity has been correlated with high
doses and is usually reversible. Chronic CNI toxicity, however, is typically

irreversible and linked to chronic drug exposure. expands on the more common
CNI–associated adverse events.Comparative Efficacy Even though cyclosporine
and tacrolimus are both CNIs, there are several differences between the two. A
meta-analysis comparing cyclosporine to tacrolimus