Rapamycin (Sirolimus) and Gabapentin Interaction: What Clinicians and Patients Need to Know

Do sirolimus and gabapentin interact directly?

No study testing the two drugs together was found. They use different elimination routes, and gabapentin showed no meaningful inhibition of the major CYP enzymes in vitro, so a CYP-mediated effect on sirolimus is not expected.

Sirolimus is a substrate of both CYP3A4 and P-glycoprotein, and the label says inducers and inhibitors of those pathways can lower or raise its blood concentrations [1]. It is extensively metabolized in the intestinal wall and liver, about 91% of radioactivity is recovered in feces, and mean terminal half-life is about 62 hours in stable renal transplant patients [1].

Gabapentin is a prescription anticonvulsant that FDA first approved in 1993 [2]. The Neurontin label says it is not appreciably metabolized in humans, is eliminated unchanged by the kidneys, and has clearance proportional to creatinine clearance.

Sirolimus exposure depends on liver and gut metabolism rather than on the kidney. Hepatic impairment raises sirolimus AUC by 43% in mild, 94% in moderate and 189% in severe impairment, and the label reduces the maintenance dose accordingly [1]. Sirolimus levels are also affected by CYP3A4 and P-gp modulators, and the label warns of a decline in renal function with long-term combination of cyclosporine and Rapamune [1].

Why kidney function matters for gabapentin

The Neurontin label sets lower maximum daily gabapentin doses as creatinine clearance falls. It gives a supplemental dose after hemodialysis and says older adults should have doses chosen by creatinine clearance, because clearance is reduced in older age and in kidney impairment.

On the sirolimus side, the label's kidney warning is tied to a specific partner drug: a decline in renal function with long-term combination of cyclosporine and Rapamune [1]. Increased creatinine is also one of the most common adverse reactions in renal transplant patients on Rapamune (39% to 40% versus 38% on placebo), but everyone in those trials was also on cyclosporine and corticosteroids, so the figures do not isolate sirolimus [1].

When both drugs are in a regimen, a change in creatinine clearance changes the appropriate gabapentin dose. Sirolimus levels instead track hepatic function and the drugs that inhibit or induce CYP3A4 and P-glycoprotein [1].

Dizziness, sleepiness and breathing

Both drugs list dizziness. The Neurontin label reports somnolence and dizziness in its postherpetic neuralgia trials, and dizziness appears among the Rapamune adverse reactions reported in 20% or more of patients in the lymphangioleiomyomatosis study [1].

The breathing warning belongs to gabapentin. FDA's 2019 safety communication covers gabapentin and pregabalin in people with respiratory risk factors: opioid pain medicines or other CNS depressants, lung conditions such as COPD, and older age. FDA required new respiratory depression warnings in the labels [3]. It lists confusion, unusual dizziness, extreme sleepiness, slowed or shallow breathing, unresponsiveness and bluish skin as signs that need immediate medical attention [3]. Sirolimus is not named in that communication.

What actually changes sirolimus levels

The Rapamune label says to avoid strong CYP3A4 and P-glycoprotein inducers such as rifampin and rifabutin, and strong inhibitors such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin and clarithromycin [1]. It advises caution with weaker modulators. Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, HIV and hepatitis C protease inhibitors, metoclopramide, nicardipine, troleandomycin and verapamil may raise sirolimus concentrations. Carbamazepine, phenobarbital, phenytoin, rifapentine and St. John's wort may lower them [1]. Cannabidiol can raise sirolimus levels [1].

The label says grapefruit juice inhibits CYP3A4-mediated metabolism of sirolimus and must not be taken with or used to dilute Rapamune. It also says cyclosporine increases sirolimus concentrations and that Rapamune should be taken 4 hours after cyclosporine [1].

Transplant doses and weekly longevity doses

The Rapamune label covers prevention of organ rejection in renal transplant patients aged 13 and older and treatment of lymphangioleiomyomatosis [1]. It has no approved indication for aging or longevity, and its adverse reaction rates come from transplant and LAM dosing, not from the low intermittent doses used off-label [1].

In the 48-week PEARL trial, healthy adults took placebo or 5 mg or 10 mg of compounded rapamycin once weekly. Visceral adiposity did not change, adverse and serious adverse events were similar across groups, and no lifespan outcome was measured [4]. Compounded rapamycin is not FDA-approved, and FDA does not verify the safety, effectiveness or quality of compounded drugs before they are marketed [5].