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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.
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.
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
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.
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.
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