Summary

Rapamycin (sirolimus) and diltiazem have a clinically significant drug interaction where diltiazem inhibits CYP3A4 metabolism, leading to increased rapamycin blood levels. This interaction requires careful monitoring and potential dose adjustments to prevent rapamycin toxicity while maintaining therapeutic efficacy.

Introduction

Rapamycin (sirolimus) is an immunosuppressive medication primarily used to prevent organ transplant rejection and treat certain cancers. It belongs to the mTOR inhibitor class and is metabolized extensively by the CYP3A4 enzyme system. Diltiazem is a calcium channel blocker commonly prescribed for hypertension, angina, and certain arrhythmias. As a moderate CYP3A4 inhibitor, diltiazem can significantly affect the metabolism of drugs that are CYP3A4 substrates, including rapamycin.

Mechanism of Interaction

The interaction between rapamycin and diltiazem occurs through inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme system. Rapamycin is extensively metabolized by CYP3A4 in the liver and intestinal wall. Diltiazem acts as a competitive inhibitor of CYP3A4, reducing the enzyme's ability to metabolize rapamycin. This inhibition leads to decreased clearance and increased bioavailability of rapamycin, resulting in elevated plasma concentrations that can persist for several days after diltiazem initiation due to rapamycin's long half-life.

Risks and Symptoms

The primary clinical risk of this interaction is rapamycin toxicity due to elevated blood levels. Potential adverse effects include increased susceptibility to infections and malignancies due to over-immunosuppression, delayed wound healing, hyperlipidemia, thrombocytopenia, and nephrotoxicity. In transplant patients, while higher rapamycin levels may reduce rejection risk, they significantly increase the risk of serious infections and other dose-related toxicities. The interaction can increase rapamycin levels by 60-90%, making dose adjustments essential for patient safety.

Management and Precautions

When co-administering rapamycin and diltiazem, reduce the rapamycin dose by approximately 30-50% and monitor rapamycin trough levels closely, especially during the first 2-4 weeks. Target therapeutic ranges should be maintained while avoiding toxicity. Monitor for signs of over-immunosuppression including infections, delayed healing, and laboratory abnormalities such as thrombocytopenia or elevated lipids. If diltiazem is discontinued, rapamycin levels will decrease, requiring dose increases and continued monitoring. Consider alternative antihypertensive agents with minimal CYP3A4 interaction if clinically appropriate. Regular communication between cardiology and transplant teams is essential for optimal patient management.

Rapamycin interactions with food and lifestyle

Rapamycin should be taken consistently either with or without food, as food can significantly affect absorption. High-fat meals can increase rapamycin blood levels by up to 35%, while the timing and fat content of meals can cause variable drug absorption. Grapefruit juice should be avoided as it can increase rapamycin blood levels and potentially lead to increased side effects. Patients should maintain consistent dietary habits and timing of meals when taking rapamycin to ensure stable drug levels.

Diltiazem interactions with food and lifestyle

Grapefruit and grapefruit juice should be avoided while taking diltiazem as they can significantly increase blood levels of the medication, potentially leading to dangerous drops in blood pressure and heart rate. Alcohol consumption should be limited or avoided as it can enhance the blood pressure-lowering effects of diltiazem and increase the risk of dizziness, fainting, and falls. Patients should also be cautious when standing up quickly or engaging in activities requiring alertness, as diltiazem can cause dizziness and lightheadedness, especially when starting treatment or increasing the dose.