A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir

Clinical Pharmacokinetics, Journal Year: 2024, Volume and Issue: 63(1), P. 27 - 42

Published: Jan. 1, 2024

Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that used as an oral antiviral disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above in vitro 90% effective concentration value (EC90), nirmatrelvir coadministered with 100 mg ritonavir, pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir's cytochrome P450 (CYP) 3A4-mediated metabolism which results renal elimination becoming primary route when dosed concomitantly. exhibits absorption-limited nonlinear pharmacokinetics. When ritonavir patients mild-to-moderate COVID-19, reaches maximum 3.43 µg/mL (11.7× EC90) approximately 3 h on day 5 dosing, geometric mean 1.57 (5.4× EC90). Drug interactions nirmatrelvir/ritonavir (PAXLOVIDTM) are primarily attributed to ritonavir-mediated CYP3A4 inhibition, lesser extent CYP2D6 P-glycoprotein inhibition. Population pharmacokinetics quantitative systems pharmacology modeling support twice daily dosing 300 mg/100 for days, reduced 150 dose moderate impairment. Rapid clinical development response emerging COVID-19 pandemic was enabled by innovations research, including adaptive phase 1 trial design allowing direct pivotal development, fluorine nuclear magnetic resonance spectroscopy delineate absorption, distribution, metabolism, excretion profiles, innovative applications model-informed drug accelerate development.

Language: Английский

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Insights into monkeypox pathophysiology, global prevalence, clinical manifestation and treatments

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: March 21, 2023

On 23rd July 2022, the World Health Organization (WHO) recognized ongoing monkeypox outbreak as a public medical crisis. Monkeypox virus (MPV), etiological agent of monkeypox, is zoonotic, linear, double-stranded DNA virus. In 1970, Democratic Republic Congo reported first case MPV infection. Human-to-human transmission can happen through sexual contact, inhaled droplets, or skin-to-skin contact. Once inoculated, viruses multiply rapidly and spread into bloodstream to cause viremia, which then affect multiple organs, including skin, gastrointestinal tract, genitals, lungs, liver. By September 9, more than 57,000 cases had been in 103 locations, especially Europe United States. Infected patients are characterized by physical symptoms such red rash, fatigue, backache, muscle aches, headache, fever. A variety strategies available for orthopoxviruses, monkeypox. prevention following smallpox vaccine has shown up 85% efficacy, several antiviral drugs, Cidofovir Brincidofovir, may slow viral spread. this article, we review origin, pathophysiology, global epidemiology, clinical manifestation, possible treatments prevent propagation provide cues generate specific drugs.

Language: Английский

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Proof-of-concept studies with a computationally designed M ^pro inhibitor as a synergistic combination regimen alternative to Paxlovid

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(17)

Published: April 15, 2024

As the SARS-CoV-2 virus continues to spread and mutate, it remains important focus not only on preventing through vaccination but also treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a main protease (M pro ) DAA, has been significant for treatment patients. A limitation this however, is that antiviral component, nirmatrelvir, rapidly metabolized requires inclusion CYP450 3A4 metabolic inhibitor, ritonavir, boost levels active drug. Serious drug–drug interactions can occur Paxlovid patients who are taking other medications by CYP4503A4, particularly transplant or otherwise immunocompromised most at risk development severe symptoms. Developing an alternative improved pharmacological properties critical these By using computational structure-guided approach, we were able optimize 100 250 μM screening hit potent nanomolar inhibitor lead compound, Mpro61. In study, further evaluate Mpro61 as starting examination its mode binding M . vitro profiling established lack off-target effects, inhibition, well potential synergy currently approved alternate antiviral, molnupiravir. Development subsequent testing capsule formulation oral dosing in B6-K18-hACE2 mice demonstrated favorable properties, efficacy, molnupiravir, complete recovery from challenge SARS-CoV-2, establishing promising preclinical candidate.

Language: Английский

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

British Journal of Clinical Pharmacology, Journal Year: 2023, Volume and Issue: 89(11), P. 3352 - 3363

Published: June 25, 2023

To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) dabigatran P-glycoprotein substrate).PK was studied in 2 phase 1, open-label, fixed-sequence studies healthy adults. Single oral doses mg (n = 12) 75 24) were administered steady state (i.e. ≥2 days) 300 mg/100 100 mg. Midazolam plasma concentrations adverse events analysed for each treatment.After administration (test) (reference), geometric mean area under the concentration-time curve extrapolated to infinity (AUCinf ) maximum concentration (Cmax increased 14.3-fold 3.7-fold, respectively. coadministered (reference) resulted 16.5-fold 3.9-fold increases AUCinf Cmax , After 1.9-fold 2.3-fold, Dabigatran a 1.7-fold increase . exposures generally comparable when alone, slightly higher vs. alone. Nirmatrelvir/ritonavir safe without dabigatran. No serious severe reported.Coadministration systemic exposure suggesting no incremental effect nirmatrelvir. compared minor

Language: Английский

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Synthetic Approaches to the New Drugs Approved During 2021

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(15), P. 10150 - 10201

Published: Aug. 1, 2023

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These chemical entities (NCEs), particularly small molecules antibody–drug conjugates, provide insight into molecular recognition serve as potential leads design of future medicines. This annual review is part a continuing series highlighting most likely process-scale synthetic approaches 35 NCEs were first approved anywhere world during 2021.

Language: Английский

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Curcumin for the treatment of COVID‐19 patients: A meta‐analysis of randomized controlled trials

Phytotherapy Research, Journal Year: 2023, Volume and Issue: 37(3), P. 1167 - 1175

Published: Jan. 14, 2023

Curcumin is a low-cost and easily accessible therapeutic option for COVID-19 patients. We aimed to conduct meta-analysis assess the effect of curcumin on clinical outcomes in Various databases, including PubMed, Cochrane Library Embase were searched from inception until October 2022 randomized controlled trials (RCTs) evaluating use Results 13 RCTs pooled using R software version 4.1.0. reduced risk all-cause mortality (RR 0.38; 95% CI: 0.20-0.72; moderate certainty evidence), patients with no recovery status 0.54; 0.42-0.70; evidence) but had incidence mechanical ventilation hospitalization, rate positive viral PCR test. The results subgroup analysis suggested higher benefit early administration (within 5 days onset symptoms) combination regimens. likely be mild-to-moderate patients, large-scale are needed confirm these findings. limitations our include small sample sizes included variable formulations used across studies.

Language: Английский

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Structure-based design of SARS-CoV-2 papain-like protease inhibitors

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 264, P. 116011 - 116011

Published: Dec. 5, 2023

Language: Английский

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Clinical Outcomes Following Treatment for COVID-19 With Nirmatrelvir/Ritonavir and Molnupiravir Among Patients Living in Nursing Homes

JAMA Network Open, Journal Year: 2023, Volume and Issue: 6(4), P. e2310887 - e2310887

Published: April 27, 2023

Importance Older patients living in nursing homes are at very high risk of mortality after getting COVID-19. Objective To evaluate outcomes following oral antiviral treatment for COVID-19 among nonhospitalized older homes. Design, Setting, and Participants This is a territory-wide, retrospective cohort study conducted between February 16 March 31, 2022, with the last follow-up date on April 25, 2022. were Hong Kong. Data analysis was performed from May to June Exposures Molnupiravir, nirmatrelvir/ritonavir, or no treatment. Main Outcomes Measures The primary outcome hospitalization COVID-19, secondary inpatient disease progression (ie, admission intensive care unit, use invasive mechanical ventilation, and/or death). Results Of 14 617 (mean [SD] age, 84.8 [10.2] years; 8222 women [56.2%]), 8939 (61.2%) did not antivirals, 5195 (35.5%) used molnupiravir, 483 (3.3%) nirmatrelvir/ritonavir. Compared who those molnupiravir nirmatrelvir/ritonavir more likely be female less have comorbid illnesses past year. At median (IQR) 30 (30-30) days, 6223 (42.6%) hospitalized 2307 (15.8%) experienced progression. After propensity score weighting, both associated reduced (molnupiravir, weighted hazard ratio [wHR], 0.46; 95% CI, 0.37-0.57; P < .001; wHR, 0.32-0.65; .001) 0.35; 0.23-0.51; 0.17; 0.06-0.44; .001). Nirmatrelvir/ritonavir comparable achieving better clinical (hospitalization, 1.00; 0.75-1.33; = .99; progression, 0.49; 0.20-1.20; .12). Conclusions Relevance In this study, antivirals treat findings home residents could reasonably extrapolated other frail community.

Language: Английский

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Real-World Evidence of the Top 100 Prescribed Drugs in the USA and Their Potential for Drug Interactions with Nirmatrelvir; Ritonavir

The AAPS Journal, Journal Year: 2023, Volume and Issue: 25(5)

Published: July 20, 2023

Nirmatrelvir (coadministered with ritonavir as PAXLOVIDTM) reduces the risk of COVID-19-related hospitalizations and all-cause death in individuals mild-to-moderate COVID-19 at high progression to severe disease. Ritonavir is coadministered a pharmacokinetic enhancer. However, may cause drug-drug interactions (DDIs) due its various drug-metabolizing enzymes transporters, including cytochrome P450 (CYP) 3A, CYP2D6, P-glycoprotein transporters. To better understand extent DDIs (or lack thereof) nirmatrelvir; clinical setting, this study used real-world evidence (RWE) from Optum Clinformatics Data Mart database identify top 100 drugs most commonly prescribed US patients The were identified based on total counts associated high-risk (i.e., ≥ 1 medical condition an increased COVID-19) who continuously enrolled throughout 2019 had prescription claim. Each was then assessed for DDI their metabolism, excretion, transport pathways available prescribing literature sources. Seventy not expected have ritonavir, many cardiovascular agents, anti-infectives, antidiabetic antidepressants. Conversely, 30 drugs, corticosteroids, narcotic analgesics, anticoagulants, statins, sedatives/hypnotics, ritonavir. This RWE analysis complementary information other management tools guiding healthcare providers managing DDIs.

Language: Английский

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Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir

Fundamental and Clinical Pharmacology, Journal Year: 2023, Volume and Issue: 37(4), P. 726 - 738

Published: March 18, 2023

Abstract The COVID‐19 pandemic remains a major health concern worldwide, and SARS‐CoV‐2 is continuously evolving. There an urgent need to identify new antiviral drugs develop novel therapeutic strategies. Combined use of newly authorized medicines including molnupiravir, nirmatrelvir, remdesivir has been actively pursued. Mechanistically, nirmatrelvir inhibits replication by targeting the viral main protease (M pro ), critical enzyme in processing immediately translated coronavirus polyproteins for replication. Molnupiravir remdesivir, on other hand, inhibit RNA‐dependent RNA‐polymerase (RdRp), which directly responsible genome production subgenomic RNAs. targets RdRp induces severe RNA mutations (genome), commonly referred as error catastrophe. Remdesivir, contrast, causes chain termination arrests synthesis genome. In addition, all three undergo extensive metabolism with strong significance. hydrolytically activated carboxylesterase‐2 (CES2), inactivated cy tochrome P 450‐based oxidation (e.g., CYP3A4), CES1 but covalently CES2. Additionally, are oxidized same CYP enzymes. distinct mechanisms action provide rationale their combined use. On these that determines potential. This review discusses how pathways enzymes involved should be carefully considered during synergy.

Language: Английский

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