Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants
© 2023 British Pharmacological Society..
AIMS: To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P-glycoprotein substrate).
METHODS: PK was studied in 2 phase 1, open-label, fixed-sequence studies in healthy adults. Single oral doses of midazolam 2 mg (n = 12) or dabigatran 75 mg (n = 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment.
RESULTS: After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration-time curve extrapolated to infinity (AUCinf ) and maximum plasma concentration (Cmax ) increased 14.3-fold and 3.7-fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5-fold and 3.9-fold increases in midazolam geometric mean AUCinf and Cmax , respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUCinf and Cmax increased 1.9-fold and 2.3-fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7-fold increase in dabigatran geometric mean AUCinf and Cmax . Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran Cmax with nirmatrelvir/ritonavir vs. ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported.
CONCLUSION: Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran Cmax was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:89 |
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| Enthalten in: |
British journal of clinical pharmacology - 89(2023), 11 vom: 24. Nov., Seite 3352-3363 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cox, Donna S [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.10.2023 Date Revised 25.10.2023 published: Print-Electronic ClinicalTrials.gov: NCT05032950, NCT05064800 Citation Status MEDLINE |
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| doi: |
10.1111/bcp.15835 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM358554187 |
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| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Cox, Donna S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants |
| 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 23.10.2023 | ||
| 500 | |a Date Revised 25.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT05032950, NCT05064800 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 British Pharmacological Society. | ||
| 520 | |a AIMS: To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P-glycoprotein substrate) | ||
| 520 | |a METHODS: PK was studied in 2 phase 1, open-label, fixed-sequence studies in healthy adults. Single oral doses of midazolam 2 mg (n = 12) or dabigatran 75 mg (n = 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment | ||
| 520 | |a RESULTS: After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration-time curve extrapolated to infinity (AUCinf ) and maximum plasma concentration (Cmax ) increased 14.3-fold and 3.7-fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5-fold and 3.9-fold increases in midazolam geometric mean AUCinf and Cmax , respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUCinf and Cmax increased 1.9-fold and 2.3-fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7-fold increase in dabigatran geometric mean AUCinf and Cmax . Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran Cmax with nirmatrelvir/ritonavir vs. ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported | ||
| 520 | |a CONCLUSION: Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran Cmax was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a clinical pharmacology > medication safety | |
| 650 | 4 | |a pharmacokinetics > cytochrome P450 | |
| 650 | 4 | |a pharmacokinetics > drug interactions | |
| 650 | 4 | |a pharmacokinetics > p-glycoprotein | |
| 650 | 7 | |a Midazolam |2 NLM | |
| 650 | 7 | |a R60L0SM5BC |2 NLM | |
| 650 | 7 | |a Ritonavir |2 NLM | |
| 650 | 7 | |a O3J8G9O825 |2 NLM | |
| 650 | 7 | |a Dabigatran |2 NLM | |
| 650 | 7 | |a I0VM4M70GC |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP3A |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 700 | 1 | |a Rehman, Muhammad |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Tahira |e verfasserin |4 aut | |
| 700 | 1 | |a Ginman, Katherine |e verfasserin |4 aut | |
| 700 | 1 | |a Salageanu, Joanne |e verfasserin |4 aut | |
| 700 | 1 | |a LaBadie, Robert R |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Katty |e verfasserin |4 aut | |
| 700 | 1 | |a Damle, Bharat |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:89 |g year:2023 |g number:11 |g day:24 |g month:11 |g pages:3352-3363 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1111/bcp.15835 |3 Volltext |
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