Rapamycin (Sirolimus) and Atorvastatin Interaction: Risks, Monitoring, and Dose Adjustments

Does atorvastatin change sirolimus levels? What the Rapamune label says

In its clinical pharmacology drug-interaction section, the Rapamune label states that clinically significant pharmacokinetic drug-drug interactions were not observed in studies of the drugs it lists, and that sirolimus and these drugs may be co-administered without dose adjustments. Atorvastatin is on that list, alongside acyclovir, digoxin, glyburide, nifedipine, norgestrel/ethinyl estradiol, prednisolone and sulfamethoxazole/trimethoprim [1].

The label covers Rapamune tablets and oral solution [1].

Shared metabolic pathways

Sirolimus is a substrate of both CYP3A4 and P-glycoprotein. It is extensively metabolized in the intestinal wall and liver by CYP3A4, with P-gp counter-transporting drug back into the gut lumen [1]. Atorvastatin is also a CYP3A4 substrate, and the Lipitor label lists OATP1B1/1B3 and BCRP as transporters involved [2]. Both drugs are CYP3A4 substrates, but the Rapamune label reports no clinically significant pharmacokinetic interaction between sirolimus and atorvastatin [1].

For sirolimus, the label's practical concern is drugs that push its own blood levels up or down. Its caution list for weak or moderate modulators includes diltiazem, verapamil, fluconazole, clotrimazole, nicardipine, metoclopramide and several HIV and hepatitis C protease inhibitors, which can increase sirolimus concentrations, and carbamazepine, phenobarbital, phenytoin, rifapentine and St. John's wort, which can decrease them [1]. Atorvastatin is not on that caution list; it is on the no-adjustment list [1].

The pairs that do carry warnings

The sirolimus label says to avoid strong CYP3A4 and P-gp inducers and inhibitors, naming rifampin and rifabutin as inducers and ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin and clarithromycin as inhibitors [1]. The atorvastatin label attaches dose limits to some of those same drugs: with clarithromycin or itraconazole, atorvastatin should not exceed 20 mg daily; with nelfinavir, 40 mg. It does not recommend atorvastatin at all with cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir [2].

Cyclosporine matters for transplant patients. The Rapamune label says cyclosporine increases sirolimus concentrations and that, to diminish this interaction, Rapamune is taken 4 hours after cyclosporine [1]. Separately, cyclosporine at 5.2 mg/kg/day raised the area under the curve of a 10 mg atorvastatin dose 8.69-fold and peak concentration 10.66-fold, and the atorvastatin label calls that combination not recommended [2].

Why atorvastatin is in the picture at all

Sirolimus raises blood lipids. In the label's renal transplant studies, hypercholesterolemia occurred in 43 to 46% of sirolimus-treated patients and hypertriglyceridemia in 45 to 57%, against 23% for each on placebo [1]. Up to 90% of patients in the sirolimus trials needed lipid-lowering treatment with agents such as statins or fibrates, and despite that up to 50% still had fasting serum cholesterol above 240 mg/dL and triglycerides above target [1]. The label advises monitoring for hyperlipidemia and starting interventions such as diet, exercise and lipid-lowering drugs if it is detected [1]. These lipid rates come from renal transplant studies, not studies of weekly low-dose rapamycin [1].

What to watch for on each label

The atorvastatin label's main safety concern is myopathy and rhabdomyolysis, with risk factors of age 65 or older, uncontrolled hypothyroidism, renal impairment, interacting drugs and higher dose. The label says patients should promptly report unexplained muscle pain, tenderness or weakness, particularly with malaise or fever, and calls for discontinuation if markedly elevated CK levels occur or myopathy is diagnosed or suspected [2]. In the TNT trial, CK of 10 times the upper limit of normal or higher occurred in 0.3% of patients on 80 mg versus 0.1% on 10 mg [2]. Persistent transaminase elevations above 3 times the upper limit occurred in about 0.7% of atorvastatin patients overall, and by dose in 0.2% (10 mg), 0.2% (20 mg), 0.6% (40 mg) and 2.3% (80 mg) [2].

On the sirolimus side, hypertriglyceridemia and hypercholesterolemia are both among the adverse reactions occurring in 30% or more of renal transplant patients [1].

Grapefruit, cannabidiol and St. John's wort

Grapefruit appears on both labels. The sirolimus label states that grapefruit juice inhibits CYP3A4-mediated metabolism of sirolimus and must not be taken with Rapamune or used to dilute it [1]. The atorvastatin label takes a threshold approach: avoid more than 1.2 liters of grapefruit juice daily. In its study, 240 mL daily raised the area under the curve of a single 40 mg dose 1.37-fold [2].

Two other interactions appear on the sirolimus label. Cannabidiol can raise sirolimus blood levels, and the label says to monitor closely and consider a Rapamune dose reduction when the two are used together [1]. St. John's wort is on the list of agents that can decrease sirolimus concentrations [1].

Low-dose weekly rapamycin for longevity

Sirolimus has no FDA-approved indication for aging, longevity or healthspan; the labeled uses are renal transplant rejection prophylaxis and lymphangioleiomyomatosis [1]. The 48-week PEARL trial (NCT04488601) randomized healthy, normative-aging adults to placebo or 5 mg or 10 mg compounded rapamycin once weekly. Adverse and serious adverse events were similar across groups, visceral adiposity did not change significantly (p=0.942), and the authors concluded the regimen was relatively safe over 48 weeks, with efficacy not established [3]. Compounded drugs are not FDA-approved, and FDA does not verify their safety, effectiveness or quality before they are marketed [4]. The PEARL abstract does not report an analysis of atorvastatin co-use [3]. HealthRX.com offers rapamycin by prescription.