Model‐Based Tacrolimus Dosing Using the Population Pharmacokinetic Analysis Under the Nirmatrelvir/Ritonavir Therapy
14 affiliations
- 1Department of Pharmacy Kobe University Hospital Kobe Japan
- 2Department of Clinical Pharmacology and Therapeutics Kyoto University Hospital Kyoto Japan
- 3Department of Pharmacy Hirosaki University Hospital Hirosaki Japan
- 4Department of Pharmaceutical Sciences Tohoku University Hospital Sendai Japan
- 5Department of Pharmacy Yamagata University Hospital Yamagata Japan
- 6Department of Pharmacy University of Yamanashi Hospital Chuo Japan
- 7Division of Pharmacy Chiba University Hospital Chiba Japan
- 8Department of Pharmacy University of Tsukuba Hospital Tsukuba Japan
- 9Department of Pharmacy Gifu University Hospital Gifu Japan
- 10Department of Hospital Pharmacy Nagoya University Hospital Nagoya Japan
- 11Department of Pharmacy Kyushu University Hospital Fukuoka Japan
- 12Department of Pharmacy Kagoshima University Hospital Kagoshima Japan
- 13Department of Pharmacy University of the Ryukyus Hospital Ginowan Japan
- 14Laboratory of Clinical Pharmacy Showa Pharmaceutical University Machida Japan
Abstract
Nirmatrelvir/ritonavir is an antiviral agent used against severe acute respiratory syndrome coronavirus 2 infection and inhibits cytochrome P450 3A and P‐glycoprotein. The concomitant use of nirmatrelvir/ritonavir markedly increases tacrolimus blood concentrations. Although temporary discontinuation or dose reduction of tacrolimus at the start of nirmatrelvir/ritonavir therapy is recommended in the package insert of this drug, little information is available on tacrolimus dosage adjustment when restarting. In this study, tacrolimus blood concentrations before and after nirmatrelvir/ritonavir co‐administration were collected from national university hospitals across Japan, and population pharmacokinetic analysis was performed to develop an optimal dosing strategy for tacrolimus. In total, 83 tacrolimus blood concentrations from 15 patients were used in the analysis. First, the individual pharmacokinetic parameters of tacrolimus before the intake of nirmatrelvir/ritonavir were estimated by post hoc Bayesian analysis using previously reported population pharmacokinetic parameters based on a two‐compartment model. The change in the relative bioavailability and clearance of tacrolimus after nirmatrelvir/ritonavir administration was estimated by population pharmacokinetic modeling. Consequently, tacrolimus clearance was considered almost completely inhibited, and relative bioavailability increased 7.99‐fold with the co‐administration of nirmatrelvir/ritonavir. The optimal dosing strategy based on the simulation was to withhold tacrolimus during nirmatrelvir/ritonavir therapy and to restart tacrolimus at 10% of the baseline dose on day 1, followed by 20% on day 3% and 50% on day 6, and increased to 100% on day 9 after discontinuation of nirmatrelvir/ritonavir, respectively. The proposed strategy will contribute to a safe and effective tacrolimus therapy when used in combination with nirmatrelvir/ritonavir.
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BibTeX
@article{itohara2026modelbased,
title = {{Model‐Based Tacrolimus Dosing Using the Population Pharmacokinetic Analysis Under the Nirmatrelvir/Ritonavir Therapy}},
author = {Kotaro Itohara and Yoshiki Katada and Takahiro Hatayama and Toshiaki Igarashi and Jiro Ogura and Tomoki Fukushima and Shingo Yamazaki and Masato Homma and Takashi Niwa and Yoshiaki Kato and Nanae Yamamoto and Hideyuki Terazono and Hideo Shiohira and Tomohiro Terada and Ikuko Yano},
journal = {CPT: Pharmacometrics \& Systems Pharmacology},
year = {2026},
month = sep,
doi = {10.1002/psp4.70341},
url = {https://doi.org/10.1002/psp4.70341},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Model‐Based Tacrolimus Dosing Using the Population Pharmacokinetic Analysis Under the Nirmatrelvir/Ritonavir Therapy
AU - Kotaro Itohara
AU - Yoshiki Katada
AU - Takahiro Hatayama
AU - Toshiaki Igarashi
AU - Jiro Ogura
AU - Tomoki Fukushima
AU - Shingo Yamazaki
AU - Masato Homma
AU - Takashi Niwa
AU - Yoshiaki Kato
AU - Nanae Yamamoto
AU - Hideyuki Terazono
AU - Hideo Shiohira
AU - Tomohiro Terada
AU - Ikuko Yano
PY - 2026
DA - 2026/09/06
JO - CPT: Pharmacometrics & Systems Pharmacology
DO - 10.1002/psp4.70341
UR - https://doi.org/10.1002/psp4.70341
AB - Nirmatrelvir/ritonavir is an antiviral agent used against severe acute respiratory syndrome coronavirus 2 infection and inhibits cytochrome P450 3A and P‐glycoprotein. The concomitant use of nirmatrelvir/ritonavir markedly increases tacrolimus blood concentrations. Although temporary discontinuation or dose reduction of tacrolimus at the start of nirmatrelvir/ritonavir therapy is recommended in the package insert of this drug, little information is available on tacrolimus dosage adjustment when restarting. In this study, tacrolimus blood concentrations before and after nirmatrelvir/ritonavir co‐administration were collected from national university hospitals across Japan, and population pharmacokinetic analysis was performed to develop an optimal dosing strategy for tacrolimus. In total, 83 tacrolimus blood concentrations from 15 patients were used in the analysis. First, the individual pharmacokinetic parameters of tacrolimus before the intake of nirmatrelvir/ritonavir were estimated by post hoc Bayesian analysis using previously reported population pharmacokinetic parameters based on a two‐compartment model. The change in the relative bioavailability and clearance of tacrolimus after nirmatrelvir/ritonavir administration was estimated by population pharmacokinetic modeling. Consequently, tacrolimus clearance was considered almost completely inhibited, and relative bioavailability increased 7.99‐fold with the co‐administration of nirmatrelvir/ritonavir. The optimal dosing strategy based on the simulation was to withhold tacrolimus during nirmatrelvir/ritonavir therapy and to restart tacrolimus at 10% of the baseline dose on day 1, followed by 20% on day 3% and 50% on day 6, and increased to 100% on day 9 after discontinuation of nirmatrelvir/ritonavir, respectively. The proposed strategy will contribute to a safe and effective tacrolimus therapy when used in combination with nirmatrelvir/ritonavir.
SN - 2163-8306
ER -