Can you guess what happened?

Florian Lemaitre

Assistant Professor, School of Medicine
Clinical Pharmacologist
Rennes University Hospital, France

On September the 21st, a cool wind blew on the rooftop of Rome’s The Hives hotel located near the Basilica Santa Maria Maggiore. Eight brave attendees of the2021 IATDMCT annual general meeting woke up early and enjoyed a warm Italian coffee. While the clock showed 7:30 AM, the sun was already up in the sky and the audience was proposed a series of enigmas formulated as clinical cases regarding drug-drug interactions in the era of immunosuppressive drugs. As 680 members of the IATDMCT (with the notable exception of these eight attendees), do not know the answers of these riddles, our compass’s Editor-in-chief, Natalia Riva, suggested we call on the reader’s expertise to solve these drug monitoring puzzles.

So, in the following cases, can you guess what happened?

Case#1

Male of 44 years old, benefited from a kidney transplantation on July the 2nd. His weight is 62 kg and his height 175 cm. He had a rheumatoid purpura and received dialysis from 2019 onwards before being transplanted.

His immunosuppressive treatment was initially: Basiliximab, Tacrolimus 6 mg BID, Mycophenolate Mofetil 1000 mg BID and Prednisone 20 mg OD. The other treatments are Lansoprazole 30mg OD in the evening, Amlodipine 5 mg BID, Irbesartan 300mg OD in the evening, Bisoprolol fumarate 2.5 mg in the morning and 3.75 mg in the evening and Sulfamethoxazole/Trimethoprim 400mg/80mg OD.

His clinical course was initially adequate with creatinine nadir at 111 μM on day-13. He was discharged on day-20 and on day-36, his tacrolimus TDM revealed a trough concentration of 42.6 ng/mL. The creatinine peaked at 516 μM on day-42. The tacrolimus was stopped and then the dosage was adapted to a final 0.5 mg BID (see figure 1).

Trying to explain what led to this large overexposure in tacrolimus, the team questioned the patient. He has no hepatic disorders, no pharmacological treatment modifications, no changes in diet (notably no grapefruit intake) and no digestive disorders. The patient was a cannabis smoker (he reported anxiety) but stopped his consumption recently due to clinician’s advice.

Can you guess what happened?

Figure 1. Tacrolimus trough concentrations and creatinine levels for Case 1. Tacrolimus daily dosage are presented in orange / dark red.

Case #2

Female of 41 years is a kidney transplant recipient since May 2021. She received rATG because of high-risk immunization. A few weeks after her transplantation, she was hospitalized for a pyelonephritis. She presented with fever (39°C). Her renal function rapidly deteriorated (her creatinine was stable at 120 μM and increased to 195 μM in a few days).

At admission, her treatment was Tacrolimus 6 mg in the morning and 5 mg in the evening, Amlodipine 10 mg OD, Ganciclovir 450 mg OD, Atorvastatine 10 mg OD, Mycophenolate mofetil 1000 mg BID, Prednisone 10 mg OD. Tacrolimus trough concentration at the time of hospital admission was 23.2 ng/mL (trough concentration at last visit was 8.4 ng/mL and was stable). The Tacrolimus dosage has been stable for the last three weeks and the blood sample was taken adequately just before the drug intake. Liver parameters are normal and the patient does not have any digestive disorders. Of note, no new treatment has been introduced recently and the patient has not self-medicated herself.

The clinician struggles to explain this tacrolimus overexposure.

Can you guess what happened?

Case #3

A kidney transplant male recipient treated with Tacrolimus 5 mg BID (with actual trough concentrations around 8 ng/mL), Mycophenolate mofetil 1000 mg BID, Prednisone 10mg OD. The patient has developed a cytomegalovirus infection three months after the end of his prophylaxis treatment with ganciclovir. He then received another treatment course of intravenous ganciclovir for 21 days but, finally, the infection was only partly controlled with Foscarnet (the viral load is stable around 3 Log copies/mL but does not decrease anymore). The renal function is worsening with a 50 μM increase in the creatinine level during the Foscarnet treatment. Suddenly the Tacrolimus concentrations surges at 20.3ng/mL. When you reach out to the nurse in charge of the patient, she tells you that the patient is now receiving some off-label drug but she can’t remember the name.

Can you guess what happened?

ANSWERS

Case#1

The patients took cannabidiol (CBD), which is labelled as an anticonvulsivant drug but also available as a natural product freely accessible in some countries. CBD is a CYP3A4, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 inhibitor. Leino and colleagues reported the case of a transplant recipient treated with 20 mg/kg/d of CBD in whom tacrolimus dosage had to be reduced from 5 mg BID to 1 mg BID in order to maintain trough concentrations to their previous level (1). As CBD is also a potential inhibitor of UGT2B7, and while the acyl-glucuronide metabolism is a minor pathway, mycophenolic acid exposure might also be impacted. In fact, few “natural” products can interfere with tacrolimus metabolism and transport. We can cite grapefruit and some other citruses (pomelos, limes and Sevilla oranges) as well as some green tea extracts, schisandra berries and turmeric (2) herbs, and dietary supplements is usually the consequence of a physical, chemical or physiologic relationship between a drug and a product consumed as food, nutritional supplement or over-the-counter medicinal plant. The current educational review aims at reminding to the prescribing physicians that the most clinically relevant drug-food interactions may not be strictly limited to those with grapefruit juice and with the Saint John’s Wort herbal extract and may be responsible for changes in drug plasma concentrations, which in turn decrease efficacy or led to sometimes life-threatening toxicity. Common situations handled in clinical practice such as aging, concomitant medications, transplant recipients, patients with cancer, malnutrition, HIV infection and those receiving enteral or parenteral feeding may be at increased risk of drug-food or drug-herb interactions. Medications with narrow therapeutic index or potential life-threatening toxicity, e.g., the non-steroidal anti-inflammatory drugs, opioid analgesics, cardiovascular medications, warfarin, anticancer drugs and immunosuppressants may be at risk of significant drug-food interactions to occur. Despite the fact that considerable effort has been achieved to increase patient’ and doctor’s information and ability to anticipate their occurrence and consequences in clinical practice, a thorough and detailed health history and dietary recall are essential for identifying potential problems in order to optimize patient prescriptions and drug dosing on an individual basis as well as to increase the treatment risk/benefit ratio.

Due to the large availability of CBD without a prescription, pharmacologists and pharmacists should be aware of the risk of drug-drug interaction with this product.

Case #2

In this case, it was not about drug-drug interaction but rather disease-drug interaction. The sole explanation to the surge in the tacrolimus concentration in this patient was the role of inflammation. It is now accepted that inflammation can downregulate CYP activity. Pro-inflammatory cytokines, by activating Nf-kB pathway prevent the heterodimerization of nuclear retinoid x receptor (RXR)-β and can, therefore, decrease drug-metabolizing enzymes and transporters genes transcription. Other mechanisms include induction of the CYP- dependent proteasome by nitric oxide and epigenetic changes. Little has been reported on tacrolimus accumulation in a context of inflammatory state except from a case-report from Bonneville and colleagues (3). At the IATDMCT AGM in Rome, our team also presented preliminary data in kidney transplantation suggesting influence of inflammation on tacrolimus pharmacokinetics (Oral session: immunosuppressants, communication 283). A comprehensive review on the impact of inflammation on metabolism and transport of drugs has also been recently published by Stanke-Labesque and colleagues (4). Inflammation modulates important drug-metabolizing enzymes and transporters (DMETs). Keeping an eye on inflammatory markers when performing therapeutic drug monitoring and drug dosage adjustment should become second nature for pharmacologists.

Case #3

The patient has been given off-label letermovir which is a human cytomegalovirus (CMV) terminase inhibitor indicated for CMV infection prophylaxis and disease in allogeneic hematopoietic stem cell transplantation. The drug has already been used off-label in case of secondary prophylaxis in kidney transplant patients (5). Letermovir has been shown to be a CYP3A4 and CYP2C8 inhibitor. McCrea and colleagues conducted a drug-drug interaction study in 14 healthy volunteers comparing tacrolimus exposure alone (administered as a single dose) and when given with letermovir (administered as multiple doses). In this study, tacrolimus area under the curve increased by a 2.4 factor due to letermovir inhibition on its metabolism (6) MK-8228. Letermovir also increased cyclosporine and sirolimus but not mycophenolic acid exposure. While the drug has not yet entered the solid organ transplantation field, pharmacologists should pay attention to its drug-interaction potential.

References:
1. Leino AD, Emoto C, Fukuda T, Privitera M, Vinks AA, Alloway RR. Evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus. Am J Transplant. 2019 Oct;19(10):2944–8.
2. Mouly S, Lloret-Linares C, Sellier P-O, Sene D, Bergmann J-F. Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John’s Wort? Pharmacol Res. 2017 Apr;118:82– 92.
3. Bonneville E, Gautier-Veyret E, Ihl C, Hilleret M-N, Baudrant M, Fonrose X, et al. Unexpected overdose blood concentration of tacrolimus: Keep in mind the role of inflammation. Br J Clin Pharmacol. 2020 Sep;86(9):1888– 91.
4. Stanke-Labesque F, Gautier-Veyret E, Chhun S, Guilhaumou R, French Society of Pharmacology and Therapeutics. Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment. Pharmacol Ther. 2020 Nov;215:107627.
5. Rho E, Näf B, Müller TF, Wüthrich RP, Schachter T, von Moos S. Use of letermovir-valganciclovir combination as a step-down treatment after foscarnet for ganciclovir-resistant CMV infection in kidney transplant recipients. Clin Transplant. 2021 Jun 28;e14401.
6. McCrea JB, Macha S, Adedoyin A, Marshall W, Menzel K, Cho CR,et al. Pharmacokinetic Drug-Drug Interactions Between Letermovir and the Immunosuppressants Cyclosporine, Tacrolimus, Sirolimus, and Mycophenolate Mofetil. J Clin Pharmacol. 2019 Oct;59(10):1331–9.