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26 September 2017 : Original article  

Pharmacokinetic Interaction Between Tacrolimus and Fentanyl in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

Fumiaki Kitazawa1ABCDEF, Shin-ichi Fuchida2ABDE, Yoko Kado1BE, Kumi Ueda1E, Takatoshi Kokufu1DE, Akira Okano2D, Mayumi Hatsuse2D, Satoshi Murakami2D, Yuko Nakayama3DEF, Kohji Takara3ACDEF, Chihiro Shimazaki2DEF

DOI: 10.12659/AOT.904505

Ann Transplant 2017; 22:575-580

Abstract

BACKGROUND: Tacrolimus and fentanyl are well-known cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic range. However, the pharmacokinetic interaction between tacrolimus and fentanyl is unclear. The aim of this study was to determine whether drug interaction exists between tacrolimus and fentanyl.

MATERIAL AND METHODS: A retrospective study was performed in 6 patients who had received allogeneic hematopoietic stem cell transplantation between April 2010 and March 2015. The patients received continuous intravenous infusion of fentanyl with concomitant use of tacrolimus, and the blood concentrations of tacrolimus were evaluated using fluorescence polarization immunoassay.

RESULTS: The clearance (CL) of tacrolimus decreased significantly from 1.28 to 0.68 mL/min/kg with concomitant use of fentanyl. The CL changed with time and dose of fentanyl administration. In addition, the CL of tacrolimus was reverted by stopping fentanyl infusion. Horn’s drug interaction probability scale indicated a probable category or possible category, suggesting a drug interaction between tacrolimus and fentanyl. No patient showed a difference in hepatic or renal function before and after fentanyl administration. No additional administration of other CYP3A4 inhibitors was observed, suggesting that the drug interaction was mediated by CYP3A4.

CONCLUSIONS: The influence of fentanyl on the pharmacokinetics of tacrolimus was demonstrated to be of clinical importance. It is proposed that the dose of tacrolimus be reduced by 40% when used in combination with fentanyl.

Keywords: Cytochrome P-450 CYP3A, Drug Interactions, Fentanyl, Metabolic Clearance Rate, Tacrolimus

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Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358