A model-based pharmacokinetic assessment of drug-drug interaction between tacrolimus and nirmatrelvir/ritonavir in a kidney transplant patient with COVID-19
© 2023 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics..
We experienced a patient with a remarkable and prolonged increase in tacrolimus blood concentrations when nirmatrelvir/ritonavir was concomitantly used. The inhibitory intensity and duration of nirmatrelvir/ritonavir on tacrolimus pharmacokinetics were examined using a model-based analysis. A renal transplant patient taking oral tacrolimus continuously was treated with nirmatrelvir/ritonavir for 5 days. The baseline tacrolimus trough blood concentration was 4.2 ng/mL. Tacrolimus was discontinued on Day 6 after the concomitant administration of nirmatrelvir/ritonavir, and the trough concentration increased to 96.4 ng/mL on Day 7. The model-based analysis showed that tacrolimus clearance decreased to 35% and bioavailability increased by 18.7-fold after the coadministration of nirmatrelvir/ritonavir, compared with before the coadministration. Therefore, nirmatrelvir/ritonavir drastically decreased both the apparent clearance and apparent volume of distribution. Simulated tacrolimus concentrations could be best fitted to the observed concentrations when the inhibitory effects of nirmatrelvir/ritonavir were modeled to disappear over about 10 days by first-order elimination. In conclusion, nirmatrelvir/ritonavir greatly increases tacrolimus concentrations by not only reducing clearance, but also increasing bioavailability. Interactions between nirmatrelvir/ritonavir and low-bioavailability drugs which are substrates for CYP3A and P-glycoprotein, such as tacrolimus, are harmful, and concomitant use of these medicines should be avoided.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:53 |
|---|---|
| Enthalten in: |
Drug metabolism and pharmacokinetics - 53(2023) vom: 18. Dez., Seite 100529 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Tomida, Takeshi [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 16.12.2023 Date Revised 16.12.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.dmpk.2023.100529 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM364165758 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM364165758 | ||
| 003 | DE-627 | ||
| 005 | 20231227133143.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.dmpk.2023.100529 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1230.xml |
| 035 | |a (DE-627)NLM364165758 | ||
| 035 | |a (NLM)37924724 | ||
| 035 | |a (PII)S1347-4367(23)00041-1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Tomida, Takeshi |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A model-based pharmacokinetic assessment of drug-drug interaction between tacrolimus and nirmatrelvir/ritonavir in a kidney transplant patient with COVID-19 |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 16.12.2023 | ||
| 500 | |a Date Revised 16.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics. | ||
| 520 | |a We experienced a patient with a remarkable and prolonged increase in tacrolimus blood concentrations when nirmatrelvir/ritonavir was concomitantly used. The inhibitory intensity and duration of nirmatrelvir/ritonavir on tacrolimus pharmacokinetics were examined using a model-based analysis. A renal transplant patient taking oral tacrolimus continuously was treated with nirmatrelvir/ritonavir for 5 days. The baseline tacrolimus trough blood concentration was 4.2 ng/mL. Tacrolimus was discontinued on Day 6 after the concomitant administration of nirmatrelvir/ritonavir, and the trough concentration increased to 96.4 ng/mL on Day 7. The model-based analysis showed that tacrolimus clearance decreased to 35% and bioavailability increased by 18.7-fold after the coadministration of nirmatrelvir/ritonavir, compared with before the coadministration. Therefore, nirmatrelvir/ritonavir drastically decreased both the apparent clearance and apparent volume of distribution. Simulated tacrolimus concentrations could be best fitted to the observed concentrations when the inhibitory effects of nirmatrelvir/ritonavir were modeled to disappear over about 10 days by first-order elimination. In conclusion, nirmatrelvir/ritonavir greatly increases tacrolimus concentrations by not only reducing clearance, but also increasing bioavailability. Interactions between nirmatrelvir/ritonavir and low-bioavailability drugs which are substrates for CYP3A and P-glycoprotein, such as tacrolimus, are harmful, and concomitant use of these medicines should be avoided | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Bioavailability | |
| 650 | 4 | |a CYP3A4 | |
| 650 | 4 | |a Dug-drug interaction | |
| 650 | 4 | |a Kidney transplantation | |
| 650 | 4 | |a Nirmatrelvir/ritonavir | |
| 650 | 4 | |a P-glycoprotein | |
| 650 | 4 | |a Tacrolimus | |
| 650 | 7 | |a Tacrolimus |2 NLM | |
| 650 | 7 | |a WM0HAQ4WNM |2 NLM | |
| 650 | 7 | |a nirmatrelvir |2 NLM | |
| 650 | 7 | |a 7R9A5P7H32 |2 NLM | |
| 650 | 7 | |a Immunosuppressive Agents |2 NLM | |
| 650 | 7 | |a Ritonavir |2 NLM | |
| 650 | 7 | |a O3J8G9O825 |2 NLM | |
| 700 | 1 | |a Itohara, Kotaro |e verfasserin |4 aut | |
| 700 | 1 | |a Yamamoto, Kazuhiro |e verfasserin |4 aut | |
| 700 | 1 | |a Kimura, Takeshi |e verfasserin |4 aut | |
| 700 | 1 | |a Fujita, Kohei |e verfasserin |4 aut | |
| 700 | 1 | |a Uda, Atsushi |e verfasserin |4 aut | |
| 700 | 1 | |a Kitahiro, Yumi |e verfasserin |4 aut | |
| 700 | 1 | |a Yokoyama, Naoki |e verfasserin |4 aut | |
| 700 | 1 | |a Hyodo, Yoji |e verfasserin |4 aut | |
| 700 | 1 | |a Omura, Tomohiro |e verfasserin |4 aut | |
| 700 | 1 | |a Yano, Ikuko |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Drug metabolism and pharmacokinetics |d 2002 |g 53(2023) vom: 18. Dez., Seite 100529 |w (DE-627)NLM151697248 |x 1880-0920 |7 nnns |
| 773 | 1 | 8 | |g volume:53 |g year:2023 |g day:18 |g month:12 |g pages:100529 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.dmpk.2023.100529 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 53 |j 2023 |b 18 |c 12 |h 100529 | ||