Interactions of the protease inhibitor, ritonavir, with common anesthesia drugs

Svedmyr, Anders; Hack, Henrik; Anderson, Brian J.

doi:10.1111/pan.14529

Cited by 8 publications

(4 citation statements)

References 50 publications

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“…Increased exposure of midazolam and dabigatran upon coadministration with nirmatrelvir/ritonavir or ritonavir only could be expected to increase their pharmacological effects. Midazolam functions as a sedative, 30 and ritonavir coadministration is suspected to increase these effects based on simulations 46 . For the current study, somnolence was reported by more participants who received nirmatrelvir/ritonavir or ritonavir ( n = 3 [27.3%]) compared with midazolam alone ( n = 1 [10.0%]).…”

Section: Discussionmentioning

confidence: 73%

“…Midazolam functions as a sedative, 30 and ritonavir coadministration is suspected to increase these effects based on simulations. 46 For the current study, somnolence was reported by more participants who received nirmatrelvir/ritonavir or ritonavir (n = 3 [27.3%]) compared with midazolam alone (n = 1 [10.0%]). Although the study size is small, it is notable that no further increase in the number of participants reporting somnolence when midazolam was coadministered with nirmatrelvir/ ritonavir compared with ritonavir only.…”

Section: Midazolam Studymentioning

confidence: 76%

See 1 more Smart Citation

Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants

Cox

Rehman

Khan

et al. 2023

Brit J Clinical Pharma

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AimsTo 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).MethodsPK 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.ResultsAfter 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.ConclusionCoadministration 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.

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Section: Discussionmentioning

confidence: 73%

Section: Midazolam Studymentioning

confidence: 76%

Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants

Cox

Rehman

Khan

et al. 2023

Brit J Clinical Pharma

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“…HIV PIs interact with these substances by impacting their uptake, transport, and intrinsic hepatic clearances. Cytotoxic high levels of reactive metabolite formation, impaired methadone demethylation, and irreversible covalent binding to microsomal proteins were observed in hepatocytes and macrophages from HIV patients with SUD [100][101][102][103][104].…”

Section: Molecular Interactions Of Pis With Other Drugs/substancesmentioning

confidence: 99%

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Cheng

2023

IJMS

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Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.

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“…In these cases, dose adjustment or discontinuation with close therapeutic drug monitoring (TDM) is imperative 13. Concomitant administration of nirmatrelvir/ritonavir with especially immunosuppressive drugs (ISDs) (tacrolimus, cyclosporine, etc) requires specific consideration to avoid increased plasma concentrations of ISDs in the toxic level.…”

mentioning

confidence: 99%

Management of drug-related problems including drug–drug interactions caused by nirmatrelvir/ritonavir in paediatric patients with SARS-CoV-2

Yalçın

Demirkan

2022

Arch Dis Child

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Interactions of the protease inhibitor, ritonavir, with common anesthesia drugs

Cited by 8 publications

References 50 publications

Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants

Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Management of drug-related problems including drug–drug interactions caused by nirmatrelvir/ritonavir in paediatric patients with SARS-CoV-2

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