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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Molecular Evolution of SARS-CoV-2 during the COVID-19 Pandemic

Genes, Journal Year: 2023, Volume and Issue: 14(2), P. 407 - 407

Published: Feb. 4, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced diverse molecular variants during its recent expansion in humans that caused different transmissibility and severity of the associated disease as well resistance to monoclonal antibodies polyclonal sera, among other treatments. In order understand causes consequences observed SARS-CoV-2 diversity, a variety studies investigated evolution this virus humans. general, evolves with moderate rate evolution, 10

Language: Английский

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Precise motif and cross-presentation of coronavirus peptides by feline MHC class I: implications for the mild infection of SARS-CoV-2

The Journal of Immunology, Journal Year: 2025, Volume and Issue: 214(1), P. 115 - 129

Published: Jan. 1, 2025

Abstract As one of the earliest identified susceptible animals for SARS-CoV-2, cats are also vulnerable hosts feline coronaviruses, ie enteric coronavirus (FECV). Here, to understand cross-presentation coronavirus-derived peptides by cat major histocompatibility complex molecule leucocyte antigen (FLA) class I, unpredictable natural peptide motifs presented FLA-K*00701 and FLA-E*00301 were through elution further confirmed structural determination 2 FLA I molecules. Based on these precise peptides, atlas cross-presenting from different coronaviruses in sketched with 3 hotspots C-terminal half ORF1ab protein. The possibility is supported similar conformation corresponding KP-CoV-9 (RSFIEDLLF) KM-FECV-9 (RSAVEDLLF) FLA-K*00701. Our findings provide insights into understanding SARS-CoV-2 FECV development universal vaccine coronaviruses.

Language: Английский

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Enhanced Deep Convolutional Neural Network for SARS-CoV-2 Variants Classification

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 10, 2023

Abstract High-throughput sequencing techniques and sequence analysis have enabled the taxonomic classification of pathogens present in clinical samples. Sequencing provides an unbiased identification systematic this is generally achieved by comparing novel sequences to pre-existing annotated reference databases. However, approach limited large-scale databases which require considerable computational resources skills compare against. Alternative robust methods such as machine learning are currently employed genome classification, it can be applied classifying SARS-CoV-2 variants, whose continued evolution has resulted emergence multiple variants. We developed a deep Convolutional Neural Networks-Long Short Term Memory (CNN-LSTM) model classify dominant variants (omicron, delta, beta, gamma alpha) based on gene from surface glycoprotein (spike gene). trained validated using > 26,000 GISAID database. The was evaluated unseen 3,057 sequences. compared existing molecular epidemiology tool, nextclade. Our accuracy 98.55% training, 99.19% validation 98.41% test dataset. Comparing proposed nextclade, significant data. Nextclade identified presence recombinant strains evaluation data, mechanism that did not detect. This study alternative Timely will enable effective monitoring tracking inform public health policies control management COVID-19 pandemic.

Language: Английский

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Molecular Epidemiology of SARS-CoV-2 during Five COVID-19 Waves and the Significance of Low-Frequency Lineages

Viruses, Journal Year: 2023, Volume and Issue: 15(5), P. 1194 - 1194

Published: May 18, 2023

SARS-CoV-2 lineages and variants of concern (VOC) have gained more efficient transmission immune evasion properties with time. We describe the circulation VOCs in South Africa potential role low-frequency on emergence future lineages. Whole genome sequencing was performed samples from Africa. Sequences were analysed Nextstrain pangolin tools Stanford University Coronavirus Antiviral & Resistance Database. In 2020, 24 detected, B.1 (3%; 8/278), B.1.1 (16%; 45/278), B.1.1.348 B.1.1.52 (5%; 13/278), C.1 (13%; 37/278) C.2 (2%; 6/278) circulating during first wave. Beta emerged late dominating second wave infection. continued to circulate at low frequencies 2021 re-emerged 2022. outcompeted by Delta 2021, which thereafter Omicron sub-lineages 4th 5th waves Several significant mutations identified also detected lineages, including S68F (E protein); I82T (M P13L, R203K G204R/K (N R126S (ORF3a); P323L (RdRp); N501Y, E484K, D614G, H655Y N679K (S protein). Low-frequency variants, together circulating, may lead convergence that increase transmissibility, infectivity escape vaccine-induced or natural host immunity.

Language: Английский

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Poly(3,4-ethylenedioxythiophene) Nanorod Arrays-Based Organic Electrochemical Transistor for SARS-CoV-2 Spike Protein Detection in Artificial Saliva

ACS Sensors, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

The outbreak and continued spread of coronavirus disease 2019 (COVID-19) have significantly threatened public health. Antibody testing is essential for infection diagnosis, seroepidemiological analysis, vaccine evaluation. However, achieving convenient, fast, accurate detection remains challenging in this prolonged battle. This study reports a highly sensitive severe acute respiratory syndrome 2 (SARS-CoV-2) spike protein platform based on organic electrochemical transistors (OECTs) biosensing applications. We developed nanostructured poly(3,4-ethylenedioxythiophene) (PEDOT) conductive polymer with the carboxylic acid functional group (PEDOTAc) modifying specific antibodies an OECT channel COVID-19 protein. device features composed PEDOT:polystyrenesulfonate (PEDOT:PSS) bottom layer, upper layer decorated PEDOTAc nanorod arrays via oxidative polymerization trans-printing method. Our novel array-based exhibits promising potential future healthcare point-of-care sensing due to its rapid response, high sensitivity, accuracy. Through optimization, we achieved SARS-CoV-2 within minutes, detectable region from 10 fM 100 nM. These biosensors hold significant promise use diagnosis prognosis COVID-19.

Language: Английский

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An Immunological Review of SARS-CoV-2 Infection and Vaccine Serology: Innate and Adaptive Responses to mRNA, Adenovirus, Inactivated and Protein Subunit Vaccines

Vaccines, Journal Year: 2022, Volume and Issue: 11(1), P. 51 - 51

Published: Dec. 26, 2022

The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome 2 (SARS-CoV-2) virus, which defined its positive-sense single-stranded RNA (ssRNA) structure. It in order Nidovirales, suborder Coronaviridae, genus Betacoronavirus, and sub-genus Sarbecovirus (lineage B), together with two bat-derived strains a 96% genomic homology other bat coronaviruses (BatCoVand RaTG13). Thus far, Alphacoronavirus strains, HCoV-229E HCoV-NL63, along five Betacoronaviruses, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2, have been recognized as human (HCoVs). SARS-CoV-2 has resulted more than six million deaths worldwide since late 2019. appearance of this novel virus high variable transmission rate (RT) coexisting asymptomatic symptomatic propagation within across animal populations, longer-lasting impact. Most current therapeutic methods aim to reduce severity COVID-19 hospitalization symptoms, preventing infection from progressing chronic vulnerable populations. Now, pharmacological interventions including vaccines others exist, research ongoing. only ethical approach developing herd immunity develop provide therapeutics that can potentially improve on innate adaptive system responses at same time. Therefore, several developed acquired induced COVID-19-disease. initial evaluations began around 2020, followed clinical trials carried out during ongoing population adverse effect monitoring respective regulatory agencies. durability provided requires further characterization extensive available data, presented paper. When utilized globally, these may create an unidentified pattern antibody or memory B T cell need be researched, some now compared laboratory studies here. Several vaccine immunogens assess their safety efficacy, inducing cellular production through interactions protect against infection. This response virus-specific antibodies (anti-N anti-S antibodies), undergoing research. In article, we review four types contemporary vaccines, comparing profiles aspects involved immunology studies.

Language: Английский

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Structural understanding of SARS-CoV-2 virus entry to host cells

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: Nov. 2, 2023

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major global health concern associated with millions of fatalities worldwide. Mutant variants virus have further exacerbated COVID-19 mortality and infection rates, emphasizing urgent need for effective preventive strategies. Understanding viral mechanism crucial developing therapeutics vaccines. The entry SARS-CoV-2 into host cells key step in pathway has been targeted drug development. Despite numerous reviews virus, there lack comprehensive focusing on structural aspects entry. In this review, we analyze changes Spike proteins during process, dividing process prebinding, receptor binding, proteolytic cleavage, membrane fusion steps. By understanding atomic-scale details entry, can better target intervention We also examine impacts mutations proteins, including Omicron variant, Structural information provides insights effects guide development Finally, discuss available structure-based approaches Overall, review detailed analysis highlighting its significance vaccines against COVID-19. Therefore, our emphasizes importance combating infection.

Language: Английский

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SCB-2019 protein vaccine as heterologous booster of neutralizing activity against SARS-CoV-2 Omicron variants after immunization with other COVID-19 vaccines

Human Vaccines & Immunotherapeutics, Journal Year: 2024, Volume and Issue: 20(1)

Published: Jan. 11, 2024

We assessed the non-inferiority of homologous boosting compared with heterologous recombinant protein vaccine, SCB-2019, in adults previously immunized different COVID-19 vaccines. Three equal cohorts (N ~ 420) Philippino (18-80 years) Comirnaty, CoronaVac or Vaxzevria vaccines were randomized 1:1 to receive (SCB-2019) boosters. Neutralizing antibodies against prototype SARS-CoV-2 (Wuhan-Hu-1) measured all participants and Delta variant Omicron sub-lineages subsets (30‒50 per arm) 15 days after boosting. Participants recorded solicited adverse events for 7 unsolicited serious until Day 60. Prototype neutralizing responses on SCB-2019 statistically non-inferior boosters, superior CoronaVac, but lower than Comirnaty. BA.1, BA.2, BA.4 BA.5 variants higher Vaxzevria, Responses BF.7, BQ.1.1.3, XBB1.5 following Comirnaty booster significantly booster. reactogenicity was similar Comirnaty; most frequent mild/moderate injection site pain, headache fatigue. No vaccine-related reported. Heterologous well tolerated elicited tested SARS-COV-2 viruses including BA.4, BA.5, that not

Language: Английский

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Homologous and Heterologous Boosting of the Chadox1-S1-S COVID-19 Vaccine With the SCB-2019 Vaccine Candidate: A Randomized, Controlled, Phase 2 Study

Open Forum Infectious Diseases, Journal Year: 2022, Volume and Issue: 9(8)

Published: Aug. 1, 2022

Ongoing outbreaks of coronavirus disease 2019 (COVID-19) are driven by waning immunity following primary immunizations and emergence new severe acute respiratory syndrome 2 (SARS-CoV-2) variants that escape vaccine-induced neutralizing antibodies. It has been suggested heterologous boosters could enhance potentially maintain population immunity. We assessed the immunogenicity reactogenicity booster doses different formulations aluminium hydroxide-adjuvanted SCB-2019 vaccine (9 μg SCB-2019, with or without CpG-1018 adjuvant, 30 CpG-1018) in Brazilian adults primed ChAdOx1-S vector vaccine. S-protein antibodies ACE2-binding inhibition were measured enzyme-linked immunosorbent assay (ELISA) on days 1, 15, 29. Participants self-reported solicited adverse events reactions. All increased ELISA ACE2 binding to a greater extent than ChAdOx1-S. After + CpG hydroxide, titers against wild-type significantly higher after 15 29, as strain Beta, Gamma, Delta, Omicron variants. Boosting was well tolerated, no vaccine-related serious events. ChAdOx1-S-primed induced levels SARS-CoV-2 homologous booster, highest responses being 30-μg hydroxide formulation. NCT05087368.

Language: Английский

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