**Question:** Sirolimus is more likely than cyclosporine to cause which of the following adverse effects?

**Core Concept:** Sirolimus and cyclosporine are immunosuppressive drugs used in organ transplantation to prevent rejection. Both drugs act by inhibiting the activity of calcineurin, a key enzyme involved in the activation of T-cells. However, they differ in their pharmacokinetics and side effect profiles.

**Why the Correct Answer is Right:** Sirolimus has a more complex pharmacokinetic profile, with a lower maximum plasma concentration, a narrow therapeutic index, and a longer half-life compared to cyclosporine. This results in a higher steady-state plasma concentration and a higher incidence of some side effects.

**Why Each Wrong Option is Incorrect:**

A. **Nephrotoxicity:** Both drugs can cause nephrotoxicity, but the difference in their pharmacokinetic profiles does not explain this difference in incidence.
B. **Neurotoxicity:** This side effect is more commonly associated with cyclosporine, not sirolimus.
C. **Increased risk of malignancy:** Although immunosuppressive therapy increases the risk of malignancy, the difference in the incidence is not solely attributed to the drug's pharmacokinetic properties.
D. **Nephrotoxicity:** This side effect is more commonly associated with cyclosporine, not sirolimus.

**Clinical Pearl:** The higher steady-state plasma concentration of sirolimus results in a higher incidence of some side effects, such as thrombocytopenia, hyperlipidemia, and stomatitis. Clinicians should consider these differences when selecting the most appropriate immunosuppressive agent for each patient based on their individual characteristics and the specific clinical situation.

**Correct Answer:** D. **Nephrotoxicity:** This side effect is more commonly associated with cyclosporine, not sirolimus.