Cannabidiol inhibition of CYP3A4 raising tacrolimus levels

Transplantmedium

A 64-year-old man with a history of ESRD due to ADPKD status post kidney transplant 1 year ago presents for routine follow-up. His immediate post-transplant course was uncomplicated, and he was discharged after 5 days. Three weeks after discharge, he was admitted with community-acquired pneumonia, and an induced sputum culture was positive for Streptococcus pneumoniae. He had an episode of mild acute rejection 2 months after transplant that was managed successfully with high-dose corticosteroids. He has also had several instances of supratherapeutic tacrolimus trough levels and chronic diarrhea, which required decreased dosing of tacrolimus and mycophenolate, respectively. Current medications include tacrolimus, mycophenolate, and prednisone. Of note, he has a history of cannabis use, which he discontinued immediately prior to transplant (confirmed by blood testing). At this visit, he admits that 2 weeks after transplant, he resumed smoking marijuana and taking oral cannabidiol (CBD) 1–2 times per week. His peak eGFR following transplantation was 79 mL/min/1.73 m², and his current eGFR is 62 mL/min/1.73 m². Which of the following events is MOST LIKELY attributable to this patient's use of cannabis products?

  1. A.Acute rejection
  2. B.Supratherapeutic tacrolimus troughCorrect
  3. C.Chronic diarrhea
  4. D.Pneumococcal pneumonia

Explanation

The most likely adverse event attributable to cannabis use in this patient is supratherapeutic tacrolimus trough levels. Cannabis refers to the products of the Cannabis sativa plant, such as the flowers or buds, which are commonly referred to as marijuana. Cannabis can be consumed by inhalation or ingestion and is the most widely used illicit substance (by federal statute) in the United States. Extensively touted for medicinal and intoxicating properties, cannabis is being legalized in an increasing number of states. Cannabis contains numerous components that may be biologically important, but the 2 dominant components are tetrahydrocannabinol (THC), which produces psychoactive effects, and CBD, which is reported to have analgesic and anxiolytic properties. CBD is almost ubiquitously available and is marketed to treat pain, insomnia, and many other somatic complaints. A pharmaceutical CBD preparation has been approved for the treatment of intractable seizures in patients with Lennox-Gastaut syndrome. CBD inhibits the function of cytochrome P450 3A4 (CYP3A4), which is responsible for the metabolism of multiple medications including tacrolimus, resulting in supratherapeutic drug levels and toxicity. The use of CBD is widespread and increasing, so it is inevitable that practicing nephrologists will encounter questions about its use and its effect on the kidneys. Outcomes data are scant and short term, but to date, 1-year mortality and graft survival appear no different between cannabis users and nonusers. There are no data associating cannabis use with allograft rejection. Similarly, there are no data associating cannabis use with pneumococcal pneumonia or worsened mycophenolate-associated gastrointestinal symptoms. Inhalational use of cannabis has been linked to fungal pneumonia in transplant recipients and other immunocompromised patients. The Centers for Disease Control and Prevention recommends that solid organ transplant recipients refrain from smoking marijuana.

Why each option

A.
No data link cannabis use to allograft rejection, and one-year graft survival appears similar in cannabis users and nonusers.
B.
Correct. Cannabidiol inhibits CYP3A4, the main pathway of tacrolimus metabolism, explaining recurrent supratherapeutic troughs requiring dose reduction.
C.
Diarrhea in this patient is attributable to mycophenolate, and no data show cannabis worsens mycophenolate-associated gastrointestinal toxicity.
D.
Cannabis has not been linked to pneumococcal pneumonia; inhaled marijuana is associated with fungal, not pneumococcal, infection in transplant recipients.

Reference: Leino AD, Am J Transplant 2019 (evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus)

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