Effect of obesity on pharmacokinetics of transdermal fentanyl: Single-center retrospective study and animal study

Satoshi Mizuno; Shintaro Gake; Makiko Takabayashi; Yuriko Ito; Hiroko Sanada; Natsumi Sugimoto; Akari Maeda; Takuto Tamamura; Kazuki Sawamoto; Yusuke Hara; Yoshiko Ohi; Chiaki Tsuji; Yukiko Shiomoto; Yukio Kato; Arimi Fujita; Tsutomu Shimada; Ken-Ichi Miyamoto; Yoshimichi Sai

doi:10.1016/j.dmpk.2024.101035

Effect of obesity on pharmacokinetics of transdermal fentanyl: Single-center retrospective study and animal study

Drug Metab Pharmacokinet. 2024 Nov 5:60:101035. doi: 10.1016/j.dmpk.2024.101035. Online ahead of print.

Authors

Satoshi Mizuno¹, Shintaro Gake¹, Makiko Takabayashi², Yuriko Ito², Hiroko Sanada¹, Natsumi Sugimoto¹, Akari Maeda¹, Takuto Tamamura¹, Kazuki Sawamoto², Yusuke Hara², Yoshiko Ohi², Chiaki Tsuji², Yukiko Shiomoto², Yukio Kato³, Arimi Fujita⁴, Tsutomu Shimada⁵, Ken-Ichi Miyamoto², Yoshimichi Sai⁶

Affiliations

¹ Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
² Department of Hospital Pharmacy, University Hospital, Kanazawa University, Kanazawa, Japan.
³ Department of Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kanazawa, Japan.
⁴ Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan; Department of Hospital Pharmacy, University Hospital, Kanazawa University, Kanazawa, Japan.
⁵ Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan; Department of Hospital Pharmacy, University Hospital, Kanazawa University, Kanazawa, Japan; Department of Clinical Pharmacy and Healthcare Science, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Science, Kanazawa University, Kanazawa, Japan.
⁶ Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan; Department of Hospital Pharmacy, University Hospital, Kanazawa University, Kanazawa, Japan; AI Hospital/Macro Signal Dynamics Research and Development Center, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: sai-ys@staff.kanazawa-u.ac.jp.

PMID: 39693856
DOI: 10.1016/j.dmpk.2024.101035

Abstract

A retrospective study and an animal study were conducted to investigate factors affecting the transdermal fentanyl dose to achieve adequate pain relief in patients switched from other opioids. In the retrospective study, patient factors were included as gender, age, body mass index (BMI), and serum albumin concentration. In obese (BMI ≥25) patients, the post-titration dose of transdermal fentanyl was significantly lower than in normal (BMI 18.5-25) patients despite the initial dose was the same. To support this unexpected finding, fentanyl was administered intravenously and transdermally to Zucker (fa/fa) rats as an obese model and Zucker (+/+) rats as a control. No difference in systemic clearance (CL_tot) after intravenous administration was observed between the two groups. However, transdermal bioavailability (F) and fentanyl release ratio from the formulation (F_a) were significantly increased in Zucker (fa/fa) rats compared to Zucker (+/+) rats. Skin availability (F_skin), calculated as F divided by F_a, was also significantly increased. These results indicated that obesity should be considered as a factor in the titration of transdermal fentanyl dose.

Keywords: Obesity; Opioid switching; Pain relief; Transdermal fentanyl; Zucker rats.