Key words : Fungal infection, Immunosuppression, Kidney function, Renal transplant

Introduction
Fluconazole is commonly prescribed against fungal infections in kidney transplant patients.¹ However, this prescription is challenging because of potentially marked and unpredictable drug-drug interactions. Thus, a deeper understanding of the clinical characteristics of this drug-drug interaction may allow physicians to have better therapeutic management as to when and how to adjust the dosage of tacrolimus when combined with fluconazole in this vulnerable population. Here, we report a case of tacrolimus and fluconazole drug-drug interaction in a stable kidney transplant patient.

Case Report
A 20-year-old female patient had been receiving tacrolimus, mycophenolate, and prednisone as concomitant chronic transplant medication for immunosuppression since 2012 after kidney transplant. Tacrolimus trough blood concentration was monitored routinely posttransplant. The chronic therapeutic range target was between 4 and 12 ng/mL.² The patient’s tacrolimus trough blood concentration ranged between 5.8 and 8 ng/mL with dose of 8 mg/day of tacrolimus. On day 58 posttransplant, fluconazole was initiated for Candida albicans infection. Tacrolimus blood concentration increased under fluconazole treatment by 125% (18.4 ng/mL) on day 79 and by 212% (25.4 ng/mL) on day 84 posttransplant. On day 92, tacrolimus trough blood concentration returned to the therapeutic range (5.6 ng/mL), with decrease of tacrolimus daily dose by 50% (to 4 mg). After fluconazole withdrawal, the patient was returned to the initial tacrolimus daily dose (8 mg), which was necessary to maintain a tacrolimus trough blood concentration in the therapeutic range.

Discussion
Cytochrome 450 (CYP3A4/5) in the liver and in the intestine is responsible for the metabolism of tacrolimus. However, fluconazole is known as an inhibitor of CYP3A4.³ Thus, drug-drug interactions between fluconazole and tacrolimus are likely to involve CYP3A4.

Fluconazole coadministration with tacrolimus shows a significant clinical effect on tacrolimus trough blood concentrations in kidney transplant patients. Maintaining a tacrolimus trough blood concentration in the therapeutic range is crucial for these patients; therefore, physicians should be aware of fluconazole prescriptions to make necessary tacrolimus dose adjustments and to provide closer tacrolimus monitoring.

References:

1. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of Candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 15;62(4):e1-e50. doi:10.1093/cid/civ933
   CrossRef - PubMed
2. Lemaitre F, Monchaud C, Woillard JB, Picard N, Marquet P. Synthèse des recommandations de l’International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) sur le suivi thérapeutique pharmacologique du tacrolimus. Therapies. 2020;75(6), 681-685. doi:10.1016/j.therap.2020.06.004
   CrossRef - PubMed
3. He J, Yu Y, Yin C, et al. Clinically significant drug-drug interaction between tacrolimus and fluconazole in stable renal transplant recipient and literature review. J Clin Pharm Ther. 2020;45(2):264-269. doi:10.1111/jcpt.13075
   CrossRef - PubMed