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Purpose The purpose of this study was to evaluate pharmacist prescribing of nirmatrelvir/ritonavir to ensure this method of increasing access to treatment is safe and effective. Methods This multicenter, retrospective observational study included patients receiving a prescription for nirmatrelvir/ritonavir by a physician, nurse practitioner (NP), physician assistant (PA), or pharmacist at an Indiana University (IU) Health West Central Region site over a 3-month period. Patients were divided into two groups: those who received nirmatrelvir/ritonavir prescribed by a pharmacist (the pharmacist prescribed group) and those who received nirmatrelvir/ritonavir prescribed by other providers (the physician/NP/PA prescribed group). Electronic health record (EHR) reviews were performed to assess the appropriateness of prescriptions based on the presence of risk factors and symptoms, day of symptom onset, and dosing. The primary endpoint was the overall appropriateness of nirmatrelvir/ritonavir prescriptions in the two study groups based on emergency use authorization inclusion and exclusion requirements. Secondary endpoints included appropriateness of nirmatrelvir/ritonavir dosing and medically attended visits or mortality within 30 days. Statistical analysis of the endpoints occurred post hoc utilizing the Fisher's exact test. Results A total of 259 patients were included in the pharmacist prescribed group and 265 patients in the physician/NP/PA prescribed group. Overall appropriate nirmatrelvir/ritonavir prescribing occurred in 258 patients (99.6%) and 232 patients (87.5%) in the pharmacist and physician/NP/PA prescribed groups, respectively (P < 0.0001). Nirmatrelvir/ritonavir dosing was appropriate in 256 patients (98.8%) and 240 patients (90.6%) in the pharmacist and physician/NP/PA prescribed groups, respectively (P < 0.0001). The 30-day rates of medically attended visits were similar between groups. No patients died within 30 days of treatment in either group. Conclusion Pharmacist prescribing of nirmatrelvir/ritonavir may result in a higher likelihood of prescriptions meeting overall appropriateness criteria. Pharmacists represent an important healthcare professional resource to improve nirmatrelvir/ritonavir prescribing and utilization. [ABSTRACT FROM AUTHOR]

We investigated the mutation profiles of severe acute respiratory syndrome coronavirus 2 in samples collected from a molnupiravir and nirmatrelvir/ritonavir combination therapy in macaques. We found that molnupiravir induced several nirmatrelvir resistance mutations at low abundance that were not further selected in combination therapy. Coadministration of nirmatrelvir/ritonavir lowered the magnitude of the mutagenetic effect of molnupiravir. [ABSTRACT FROM AUTHOR]

Paxlovid, a novel antiviral medication developed by Pfizer, has attracted considerable attention as a coronavirus disease 2019 therapeutic since it may be effective in treating the severe acute respiratory syndrome coronavirus type 2‐caused disease. Paxlovid is known as a combination therapy since it includes two agents, Nirmatrelvir and Ritonavir, which both are involved in the viral replication process inhibition. A further discussion of the molecular structure, pharmacokinetics, and pharmacodynamics of both components will help comprehend Paxlovid's mechanism of impact and effectiveness. High‐performance and spectroscopic methods, including high‐performance liquid chromatography (HPLC), infrared, and ultraviolet‐visible spectroscopy have been among the methods employed for compound identification, quantification, and structural elucidation. Bioanalytical methods have also made a significant contribution to the evaluation of Paxlovid's pharmacokinetic parameters, bioavailability, and metabolism in biological matrices. LC‐tandem mass spectrometry (LC‐MS/MS) is widely employed for the quantification of Paxlovid and its metabolites in plasma, serum, and other biological samples. This study brings forth an overview of the characteristics and properties of Paxlovid along with analytical and bioanalytical methods employed for its assessment and quantification. [ABSTRACT FROM AUTHOR]

Introduction: Nirmatrelvir/ritonavir (NMV/r) is approved in the United States (US) and more than 70 other countries for the treatment of mild to moderate COVID-19 in nonhospitalized adults at high risk for severe disease. Because ritonavir inhibits several drug metabolizing enzymes, potential drug–drug interactions (DDIs) between ritonavir and concomitant medications are an important consideration for prescribers. Here, we conducted a real-world analysis of data from Pfizer's global safety database regarding adverse events (AEs) reported during use of NMV/r concomitantly with potentially interacting drugs. Methods: Data were extracted regarding DDI cases occurring from the start of NMV/r authorization through October 31, 2023. Results regarding concomitant treatment, specific AEs, and clinical outcomes are summarized. Overall NMV/r exposure was estimated based on packs of medication dispensed and was used to calculate reporting rates. Results: Among 19,617,670 patients exposed globally to NMV/r, 966 cases of potential DDIs were reported. Of these, 594 occurred in the US against an estimated US exposure of 14,646,990 patients, representing a reporting rate of 0.004%. Globally and in the United States, 66.8% and 77.3% of cases, respectively, were nonserious. Simvastatin and tacrolimus were the most frequently reported drugs associated with potential DDIs, and the most frequently reported AE regarding a specific event or symptom was dysgeusia (altered sense of taste), an AE known to be associated with NMV/r. Conclusions: Low reporting rates of DDIs support the potential for NMV/r treatment to be safely managed with careful use of available drug interaction resources to aid in risk mitigation. [ABSTRACT FROM AUTHOR]

Despite the observed clinical benefits of nirmatrelvir/ritonavir (NMV/r), it is uncertain whether Taiwan will continue covering NMV/r for high-risk individuals with mild-to-moderate coronavirus disease 2019 (COVID-19). This analysis assessed the impact of sustained utilization of NMV/r on COVID-19-associated healthcare resource utilization (HCRU) and mortality from the Taiwanese health authority perspective (THAP). A decision tree model estimated the incremental number of clinical events associated with NMV/r utilization over a 30-day period. Model results compared (1) a base case using current rates of NMV/r from the THAP, and (2) a hypothetical scenario assuming the current supply of NMV/r is not extended in Taiwan. NMV/r utilization rates included 80% and 0% in the base case and hypothetical scenario, respectively. Outcomes included the number of hospitalizations involving a general ward (GW) stay, intensive care unit (ICU) stay, and mechanical ventilation (MV) use, as well as the number of bed days, symptom days, and hospitalization deaths. Based on epidemiologic data, 150,255 patients with COVID-19 were eligible for treatment from the THAP. In the hypothetical scenario, HCRU increased by 175% compared to the base case, including increases in hospitalizations involving GW, ICU, and MV use (differences: 2067; 623; 591, respectively), bed days (difference: 51,521), symptom days (difference: 51,714), and deaths (difference: 480). Findings indicate that sustained utilization of NMV/r from the THAP reduces the clinical burden of mild-to-moderate COVID-19 through the reduced incidence of COVID-19-related HCRU and deaths. [ABSTRACT FROM AUTHOR]

Background: This research article delves into the battle against the COVID-19 pandemic, focusing on the efficacy and, particularly, the safety of the combination of nirmatrelvir with ritonavir, which is found in the pharmaceutical product Paxlovid®. This study aims to analyze the potential interactions of commonly prescribed medicinal products with Paxlovid®, shedding light on its utilization in specific medical fields. Methods: Prescription data from the Czech Republic's Institute of Health Information and Statistics (IHIS CR) was analyzed, covering 4 million COVID-19 patients and 87.5 million medication records from September 2019 to February 2022. This study focused on potential drug interactions with Paxlovid among the 50 most frequently prescribed medications, with particular attention to four specialties: general medicine, internal medicine, infectious diseases, and diabetology. Results: In this study of the 50 most commonly prescribed drugs, 56% showed no interaction with Paxlovid, 30% had a potential for interaction, and 14% were not specifically mentioned in relation to Paxlovid, with no drugs found to be contraindicated overall. However, in specific medical fields, including diabetology, infectious diseases, internal medicine, and general medicine, certain drugs had potential interactions when co-administered with Paxlovid. Conclusions: Paxlovid remains a valuable option for early COVID-19 treatment but requires a careful consideration of potential drug interactions, especially in high-risk specialties. A thorough assessment of concurrent medications is essential to optimize safety and efficacy in patients receiving Paxlovid. [ABSTRACT FROM AUTHOR]

Introduction: Nirmatrelvir/ritonavir (Paxlovid) is an effective antiviral drug for treating coronavirus disease 2019 (COVID-19) in adults. However, Paxlovid treatment of children, especially those who are under 12 years and with severe underlying diseases, is rare. Case report: A three-year-old COVID-19 patient (weighing 14.5 kg) was infected by the Omicron variant (BA.5.2) after undergoing allogeneic hematopoietic stem cell transplantation. The patient had severe bilateral pneumonia along with recurrent fever. The patient was administered 150 mg of nirmatrelvir plus 50 mg of ritonavir twice daily for 5 days, starting 27 days after the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test. Clinical manifestations and chest computed tomography improved considerably after the treatment. The real time reverse transcriptase polymerase chain reaction (RT-PCR) cycle threshold values increased from 23.92 to 38.40 in the case of ORF 1-ab gene, and from 22.22 to 36.28 in the case of N gene. Only a mild increase in serum urea nitrogen (10.10 mmol/L), alanine transaminase (ALT, 65 IU/L), and aspartate transaminase (AST, 68.5 IU/L) was observed. Conclusions: Paxlovid can effectively inhibit the replication of SARS-CoV-2 and help in improving the clinical manifestations in pediatric COVID-19 patients. Our study provided novel information on Paxlovid treatment in very young children. [ABSTRACT FROM AUTHOR]

Background: Currently, the applicant has chosen a target plasma trough concentration for nirmatrelvir, which is adjusted to 292 ng/mL based on the drug's molecular weight (499.54 Daltons), its binding to human plasma proteins (69%), and the in vitro antiviral EC90 value (181 nM). However, the current exposure‐effect relationships (ER) analysis of viral load in patients enrolled in the EPIC‐HR study has not revealed clinically significant trends in the ER. Given that the lungs are the primary site of COVID‐19 infection, we aim to further understand this exposure relationship by exploring and analyzing the penetration characteristics of nirmatrelvir in the lungs. Objectives: To explore and understand the target plasma concentration of 292 ng/mL in antiviral activity. Methods: We identified all critically ill patients with coronavirus disease 2019 who received nirmatrelvir/ritonavir treatment in the respiratory intensive care unit of Changhai hospital between January 2023 and October 2023. Samples of plasma and bronchoalveolar lavage fluid were obtained at pre‐dose trough concentrations after administration of nirmatrelvir (NMV). The relationship between NMV levels in plasma and the epithelial lining fluid (ELF) was assessed by determining concentrations of NMV. Results: There was a significant relationship between NMV levels in plasma and ELF (ELF = 0.4976*PLASMA‐ 204; R = 0.96), with a correlation whose slope (0.4976) suggested that the blood‐to‐ELF ratio of drug penetration was 2:1. A negative value from the equation indicates that NMV requires to reach baseline concentration to penetrate the ELF. Conclusions: The relationship between NMV levels in plasma and ELF with low permeability and a negative baseline value suggests that the target plasma concentration of 292 ng/mL is insufficient for antiviral activity. This study provides a unique perspective to explore and understand no clinically meaningful trend of exposure‐response relationships in patients enrolled in EPIC‐HR. [ABSTRACT FROM AUTHOR]

Studies have demonstrated that methylene blue exhibits significant antiviral activity against SARS-CoV-2 or related coronaviruses at the cellular level, suggesting its potential as an anti-SARS-CoV-2 drug. Herein, we report that methylene blue does not exhibit noticeable antiviral activity in a lethal model involving SARS-CoV-2-related pangolin coronavirus GX_P2V (short_3UTR) infection in CAG-hACE2 transgenic mice. We employed plaque reduction assays and cell infection experiments to compare the extracellular virucidal activity of the compound and its ability to inhibit viral replication in cells to those of nirmatrelvir. Methylene blue demonstrated strong virucidal activity but did not inhibit viral replication in cells. The control compound nirmatrelvir lacked virucidal activity but exhibited strong abilities to inhibit viral replication. The virucidal activity of methylene blue was further tested in mouse plasma. Incubation in mouse plasma increased the virucidal EC50 value of methylene blue, indicating that mouse plasma can affect the stability of the compound, although mouse plasma has some extent of natural virucidal activity. These findings elucidate why methylene blue lacks antiviral efficacy in vivo and provide insights for the development of antiviral drugs. [ABSTRACT FROM AUTHOR]

Background: This study aimed to establish population pharmacokinetics (PPK) models of nirmatrelvir/ritonavir in critically ill Chinese patients with the coronavirus disease 2019 (COVID-19) infection, explore factors affecting the pharmacokinetics (PK) of nirmatrelvir/ritonavir. Methods: A total of 285 serum samples and clinical data were collected from 152 patients. The PPK models of nirmatrelvir/ritonavir were analyzed using nonlinear mixed-effect modeling (NONMEM) approach. The optimal dosing regimen for patients with different renal function was determined using Monte Carlo simulations. Results: The population typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) of nirmatrelvir were 2.26 L/h and 15.3 L, respectively. Notably, creatinine clearance (CrCL) significantly influenced the PK variation of nirmatrelvir. Monte Carlo simulations suggested that patients with mild-to-moderate renal impairment experienced a 22.0–59.9% increase in the area under the curve (AUC) when they were administered a standard dose of nirmatrelvir compared to those with normal renal function. The AUC in patients with severe renal impairment after administration of 150 mg q12h nirmatrelvir was similar to that in patients with normal renal function after administration of 300 mg q12h nirmatrelvir. Conclusions: PPK modeling and simulation provided a reference for the rational clinical application of nirmatrelvir/ritonavir in critically ill Chinese patients. [ABSTRACT FROM AUTHOR]

The novel human coronavirus known as SARS-CoV-2 poses a serious risk to human health. Regretfully, the US Food and Drug Administration (FDA) has approved very few oral antiviral medications for the treatment of COVID-19 patients. In the current study, we have explored the topological characterization of the orally bio-available SARS Mpro inhibitor nirmatrelvir which in combination with ritonavir (under the brand name Paxlovid) is recently approved for emergency use authorization by FDA. Topological indices are a useful tool in chemical graph theory to determine the diverse pharmaceutical, biological and physico-chemical properties of a molecule. In this study, we ascertain several well-known degree-dependent topological indices for the medication nirmatrelvir directly using their common definitions in mathematics and alternatively by utilising M-polynomial after deriving M-polynomial of nirmatrelvir. In addition, we plot the obtained topological indices and the M-polynomial to comprehend the geometric behaviour of them. The outcomes can aid in the investigation of the physical characteristics of the recently created medications utilised to treat COVID-19.

Runcong Zhang,1,2,&ast; Jing Fan,1,2,&ast; Lu Han,3,4,&ast; Juehui Mao,4,5 Liang Sun,1,2 Yuetian Yu,2,6,7 Weibin Fan,1,2 Jiao Xie,2,8 Bin Lin,1,2,7 Nengming Lin1,2,9 1Department of Pharmacy, Changxing People’s Hospital, Changxing, People’s Republic of China; 2Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Changxing, People’s Republic of China; 3School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 6Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 7Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education, Hangzhou, People’s Republic of China; 8Department of Pharmacy, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 9Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Lin, Department of Pharmacy, Changxing People’s Hospital, Changxing, 313100, People’s Republic of China, Tel/Fax +86-572-6267652, Email lb_wzmc@126.com Nengming Lin, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, 310006, People’s Republic of China, Tel/Fax +86-572- 56007905, Email lnm1013@zju.edu.cnPurpose: Nirmatrelvir/ritonavir (N/R) is the first drug to receive emergency authorization for the treatment of COVID-19 infection. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of potential covariates and explore dosing regimen.Patients and Methods: Sparse data of serum concentrations of N/R were obtained from 129 patients with COVID-19 infection receiving oral 300/100 mg N/R twice daily for 5 days. Plasma samples were assayed using ultra-high-performance liquid chromatography–tandem mass spectrometry. The PopPK model was developed using a nonlinear mixed effects approach utilizing the NONMEM 7.4 software. Monte Carlo simulation was conducted to optimize the dosage regimen.Results: A one-compartment model with first-order absorption and first-order elimination provided the best fit for the data. Allometric scaling of parameters on creatinine clearance (CrCl) and body weight were identified as covariates that significantly influenced exposure-efficacy after oral administration of nirmatrelvir. Monte Carlo simulation using the final model generated concentration-time profiles for virtual patients (1,000 per group) with varying renal functions and body weight. Furthermore, we developed a web-based dashboard to visualize the dynamic changes in nirmatrelvir concentration and provide individualized dosage regimens.Conclusion: This study showed that dosing regimen optimization of nirmatrelvir should be based on CrCl and body weight. Moreover, a web-based dashboard has been developed to facilitate individualized pharmacotherapy.Keywords: population pharmacokinetics, nirmatrelvir, COVID-19, simulations, dosing regimen

Despite the observed clinical benefits of nirmatrelvir/ritonavir (NMV/r), it is uncertain whether Taiwan will continue covering NMV/r for high-risk individuals with mild-to-moderate coronavirus disease 2019 (COVID-19). This analysis assessed the impact of sustained utilization of NMV/r on COVID-19-associated healthcare resource utilization (HCRU) and mortality from the Taiwanese health authority perspective (THAP). A decision tree model estimated the incremental number of clinical events associated with NMV/r utilization over a 30-day period. Model results compared (1) a base case using current rates of NMV/r from the THAP, and (2) a hypothetical scenario assuming the current supply of NMV/r is not extended in Taiwan. NMV/r utilization rates included 80% and 0% in the base case and hypothetical scenario, respectively. Outcomes included the number of hospitalizations involving a general ward (GW) stay, intensive care unit (ICU) stay, and mechanical ventilation (MV) use, as well as the number of bed days, symptom days, and hospitalization deaths. Based on epidemiologic data, 150,255 patients with COVID-19 were eligible for treatment from the THAP. In the hypothetical scenario, HCRU increased by 175% compared to the base case, including increases in hospitalizations involving GW, ICU, and MV use (differences: 2067; 623; 591, respectively), bed days (difference: 51,521), symptom days (difference: 51,714), and deaths (difference: 480). Findings indicate that sustained utilization of NMV/r from the THAP reduces the clinical burden of mild-to-moderate COVID-19 through the reduced incidence of COVID-19-related HCRU and deaths.

Oral nirmatrelvir/ritonavir is approved as treatment for acute COVID-19, but the effect of treatment during acute infection on risk of Long COVID is unknown. We hypothesized that nirmatrelvir treatment during acute SARS-CoV-2 infection reduces risk of developing Long COVID and rebound after treatment is associated with Long COVID. We conducted an observational cohort study within the Covid Citizen Science (CCS) study, an online cohort study with over 100 000 participants. We included vaccinated, nonhospitalized, nonpregnant individuals who reported their first SARS-CoV-2 positive test March-August 2022. Oral nirmatrelvir/ritonavir treatment was ascertained during acute SARS-CoV-2 infection. Patient-reported Long COVID symptoms, symptom rebound and test-positivity rebound were asked on subsequent surveys at least 3 months after SARS-CoV-2 infection. A total of 4684 individuals met the eligibility criteria, of whom 988 (21.1%) were treated and 3696 (78.9%) were untreated; 353/988 (35.7%) treated and 1258/3696 (34.0%) untreated responded to the Long COVID survey (n = 1611). Among 1611 participants, median age was 55 years and 66% were female. At 5.4 ± 1.3 months after infection, nirmatrelvir treatment was not associated with subsequent Long COVID symptoms (odds ratio [OR]: 1.15; 95% confidence interval [CI]: 0.80-1.64; p = 0.45). Among 666 treated who answered rebound questions, rebound symptoms or test positivity were not associated with Long COVID symptoms (OR: 1.34; 95% CI: 0.74-2.41; p = 0.33). Within this cohort of vaccinated, nonhospitalized individuals, oral nirmatrelvir treatment during acute SARS-CoV-2 infection and rebound after nirmatrelvir treatment were not associated with Long COVID symptoms more than 90 days after infection.

Abstract Introduction Nirmatrelvir/ritonavir (NMV/r) is approved in the United States (US) and more than 70 other countries for the treatment of mild to moderate COVID-19 in nonhospitalized adults at high risk for severe disease. Because ritonavir inhibits several drug metabolizing enzymes, potential drug–drug interactions (DDIs) between ritonavir and concomitant medications are an important consideration for prescribers. Here, we conducted a real-world analysis of data from Pfizer’s global safety database regarding adverse events (AEs) reported during use of NMV/r concomitantly with potentially interacting drugs. Methods Data were extracted regarding DDI cases occurring from the start of NMV/r authorization through October 31, 2023. Results regarding concomitant treatment, specific AEs, and clinical outcomes are summarized. Overall NMV/r exposure was estimated based on packs of medication dispensed and was used to calculate reporting rates. Results Among 19,617,670 patients exposed globally to NMV/r, 966 cases of potential DDIs were reported. Of these, 594 occurred in the US against an estimated US exposure of 14,646,990 patients, representing a reporting rate of 0.004%. Globally and in the United States, 66.8% and 77.3% of cases, respectively, were nonserious. Simvastatin and tacrolimus were the most frequently reported drugs associated with potential DDIs, and the most frequently reported AE regarding a specific event or symptom was dysgeusia (altered sense of taste), an AE known to be associated with NMV/r. Conclusions Low reporting rates of DDIs support the potential for NMV/r treatment to be safely managed with careful use of available drug interaction resources to aid in risk mitigation.