Paxlovid-Induced Symptomatic Bradycardia and Syncope.

Paxlovid (nirmatrelvir/ritonavir) is a game changer in the fight against COVID-19 due to its ease of administration and significant benefits of reducing progression to severe COVID-19, hospitalization, and death. Cardiac adverse events such as bradycardia and syncope are not known with this medication. We report a case of a 71-year-old patient who developed symptomatic bradycardia, syncopal episodes, and sinus pause after taking Paxlovid. Discontinuing medication and intravenous atropine helped to reverse the bradycardia and symptoms promptly. She did not require a pacemaker. We would like to report this possible association between Paxlovid and bradycardia. Until further information or studies are available, it is advised to promptly discontinue Paxlovid after any evidence of bradycardia and closely monitor for at least 40 hours in a hospital setting. The reported half-life (t 1/2) of the medication is 6.05 ± 1.79 hours and using 8 hours as a reference for the upper limit of t 1/2, around 97 % of the medication should be cleared off in about 40 hours (five half-lives).

Case Report: tacrolimus toxicity in the setting of concurrent Paxlovid use in a heart-transplant recipient.

Background: Tacrolimus toxicity in patient's status post-orthotropic heart transplantation is not commonly reported. Given its narrow therapeutic window and drug-drug interactions, it must be closely monitored by providers who are experienced in transplant management. There are no case series of patients with tacrolimus toxicity in the setting of treatment for Sars-2-CoV-19 (COVID 19) for heart-transplant recipients. We present a case of tacrolimus toxicity in the setting of concurrent ritonavir-nirmatrelvir (Paxlovid) use. Case summary: The patient was a 74-year-old male with a prior significant history of heart transplantation and on maintenance immunosuppression with tacrolimus. He contracted COVID-19 and was prescribed antiviral therapy with Paxlovid by an outside provider prior to admission. The patient complained of severe headaches, dehydration, and tremors. After eliminating acute intracranial processes with imaging, laboratory investigation revealed a severely elevated tacrolimus level with acute renal injury. The patient was taken off tacrolimus and treated conservatively with intravenous hydration. The symptoms improved, particularly the headaches. He was discharged with instructions to resume his home dosing of tacrolimus and return to clinic in 1 week with a repeat trough level. The subsequent trough level was no longer supra-therapeutic. Discussion: Tacrolimus has a potent drug-drug interaction with Paxlovid (ritonavir-nirmatrelvir) and can be supra-therapeutic. Toxicity is associated with multiple adverse effects, including but not limited to, acute renal injury, neurotoxicity, and infections due to over-immunosuppression. As Paxlovid is effective in treating Sars-2-CoV-19 in heart-transplant recipients, knowledge and understanding of drug-drug interactions is crucial in preventing and mitigating toxicity.

Mixed Warm and Cold Autoimmune Hemolytic Anemia With Concomitant Immune Thrombocytopenia Following Recent SARS-CoV-2 Infection and Ongoing Rhinovirus Infection.

Mixed-type autoimmune hemolytic anemia (AIHA) is a term used to describe hemolysis occurring in the context of both warm and cold reactive autoantibodies to red blood cells. Immune thrombocytopenia (ITP) is an acquired form of thrombocytopenia potentially complicated by hemorrhage due to autoantibodies reactive with platelets and megakaryocytes. Diagnosis of ITP requires exclusion of other known causes of thrombocytopenia. AIHA and ITP may be primary disorders or associated with lymphoproliferative, autoimmune, or viral infections. Here, we report a rare case of simultaneous mixed-type autoimmune hemolytic anemia with immune thrombocytopenia following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection treated with Paxlovid followed by Rhinovirus infection.

Molnupiravir, Nirmatrelvir/Ritonavir, or Sotrovimab for High-Risk COVID-19 Patients Infected by the Omicron Variant: Hospitalization, Mortality, and Time until Negative Swab Test in Real Life.

Background. Several drugs which are easy to administer in outpatient settings have been authorized and endorsed for high-risk COVID-19 patients with mild-moderate disease to prevent hospital admission and death, complementing COVID-19 vaccines. However, the evidence on the efficacy of COVID-19 antivirals during the Omicron wave is scanty or conflicting. Methods. This retrospective controlled study investigated the efficacy of Molnupiravir or Nirmatrelvir/Ritonavir (Paxlovid®) or Sotrovimab against standard of care (controls) on three different endpoints among 386 high-risk COVID-19 outpatients: hospital admission at 30 days; death at 30 days; and time between COVID-19 diagnosis and first negative swab test result. Multivariable logistic regression was employed to investigate the determinants of hospitalization due to COVID-19-associated pneumonia, whereas time to first negative swab test result was investigated by means of multinomial logistic analysis as well as Cox regression analysis. Results. Only 11 patients (overall rate of 2.8%) developed severe COVID-19-associated pneumonia requiring admission to hospital: 8 controls (7.2%); 2 patients on Nirmatrelvir/Ritonavir (2.0%); and 1 on Sotrovimab (1.8%). No patient on Molnupiravir was institutionalized. Compared to controls, hospitalization was less likely for patients on Nirmatrelvir/Ritonavir (aOR = 0.16; 95% CI: 0.03; 0.89) or Molnupiravir (omitted estimate); drug efficacy was 84% for Nirmatrelvir/Ritonavir against 100% for Molnupiravir. Only two patients died of COVID-19 (rate of 0.5%), both were controls, one (a woman aged 96 years) was unvaccinated and the other (a woman aged 72 years) had adequate vaccination status. At Cox regression analysis, the negativization rate was significantly higher in patients treated with both antivirals-Nirmatrelvir/Ritonavir (aHR = 1.68; 95% CI: 1.25; 2.26) or Molnupiravir (aHR = 1.45; 95% CI: 1.08; 1.94). However, COVID-19 vaccination with three (aHR = 2.03; 95% CI: 1.51; 2.73) or four (aHR = 2.48; 95% CI: 1.32; 4.68) doses had a slightly stronger effect size on viral clearance. In contrast, the negativization rate reduced significantly in patients who were immune-depressed (aHR = 0.70; 95% CI: 0.52; 0.93) or those with a Charlson index ≥5 (aHR = 0.63; 0.41; 0.95) or those who had started the respective treatment course 3+ days after COVID-19 diagnosis (aOR = 0.56; 95% CI: 0.38; 0.82). Likewise, at internal analysis (excluding patients on standard of care), patients on Molnupiravir (aHR = 1.74; 95% CI: 1.21; 2.50) or Nirmatrelvir/Ritonavir (aHR = 1.96; 95% CI: 1.32; 2.93) were more likely to turn negative earlier than those on Sotrovimab (reference category). Nonetheless, three (aHR = 1.91; 95% CI: 1.33; 2.74) or four (aHR = 2.20; 95% CI: 1.06; 4.59) doses of COVID-19 vaccine were again associated with a faster negativization rate. Again, the negativization rate was significantly lower if treatment started 3+ days after COVID-19 diagnosis (aHR = 0.54; 95% CI: 0.32; 0.92). Conclusions. Molnupiravir, Nirmatrelvir/Ritonavir, and Sotrovimab were all effective in preventing hospital admission and/or mortality attributable to COVID-19. However, hospitalizations also decreased with higher number of doses of COVID-19 vaccines. Although they are effective against severe disease and mortality, the prescription of COVID-19 antivirals should be carefully scrutinized by double opinion, not only to contain health care costs but also to reduce the risk of generating resistant SARS-CoV-2 strains. Only 64.7% of patients were in fact immunized with 3+ doses of COVID-19 vaccines in the present study. High-risk patients should prioritize COVID-19 vaccination, which is a more cost-effective approach than antivirals against severe SARS-CoV-2 pneumonia. Likewise, although both antivirals, especially Nirmatrelvir/Ritonavir, were more likely than standard of care and Sotrovimab to reduce viral shedding time (VST) in high-risk SARS-CoV-2 patients, vaccination had an independent and stronger effect on viral clearance. However, the effect of antivirals or COVID-19 vaccination on VST should be considered a secondary benefit. Indeed, recommending Nirmatrelvir/Ritonavir in order to control VST in high-risk COVID-19 patients is rather questionable since other cheap, large spectrum and harmless nasal disinfectants such as hypertonic saline solutions are available on the market with proven efficacy in containing VST.

Physiologically-Based Pharmacokinetic Modeling of PAXLOVID™ with First-Order Absorption Kinetics.

PURPOSE: PAXLOVID™ is nirmatrelvir tablets co-packaged with ritonavir tablets. Ritonavir is used as a pharmacokinetics (PK) enhancer to reduce metabolism and increase exposure of nirmatrelvir. This is the first disclosure of Paxlovid physiologically-based pharmacokinetic (PBPK) model. METHODS: Nirmatrelvir PBPK model with first-order absorption kinetics was developed using in vitro, preclinical, and clinical data of nirmatrelvir in the presence and absence of ritonavir. Clearance and volume of distribution were derived from nirmatrelvir PK obtained using a spray-dried dispersion (SDD) formulation where it is considered to be dosed as an oral solution, and absorption is near complete. The fraction of nirmatrelvir metabolized by CYP3A was estimated based on in vitro and clinical ritonavir drug-drug interaction (DDI) data. First-order absorption parameters were established for both SDD and tablet formulation using clinical data. Nirmatrelvir PBPK model was verified with both single and multiple dose human PK data, as well as DDI studies. Simcyp® first-order ritonavir compound file was also verified with additional clinical data. RESULTS: The nirmatrelvir PBPK model described the observed PK profiles of nirmatrelvir well with predicted AUC and Cmax values within ± 20% of the observed. The ritonavir model performed well resulting in predicted values within twofold of observed. CONCLUSIONS: Paxlovid PBPK model developed in this study can be applied to predict PK changes in special populations, as well as model the effect of victim and perpetrator DDI. PBPK modeling continues to play a critical role in accelerating drug discovery and development of potential treatments for devastating diseases such as COVID-19. NCT05263895, NCT05129475, NCT05032950 and NCT05064800.

Covid-19 for the Primary Care Clinician: Current Recommendations—Don't Blink!

The chapter will discuss the outpatient assessment of the patient with possible Covid-19. The outpatient provider's tasks are the following: Appropriately identify those who are sick enough to warrant inpatient treatment. Recognize those patients who are at high risk for progression to severe Covid-19 based on risk factors and to guide them toward interruptive therapy with antibody infusion or inhibitors of viral replication. Advise about testing, treatment, isolation/quarantine, and follow-up care including vaccination guidelines. Patients with post-acute sequelae of Covid-19 (Long Covid) are also usually under the aegis of the primary care provider. The post-acute course of Covid-19 is described, and the assessment and management of these patients are discussed. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Discovery of Novel Cysteine Protease Inhibitors for the Treatment of Coronavirus (COVID-19).

The application describes compounds, such as compounds of general Formula, with warheads and their use in treating medical diseases or disorders, such as viral infections. Pharmaceutical compositions and synthetic methods of various compounds with warheads are included. The compounds are inhibitors of proteases, such as the 3C, CL- or 3CL-like protease.

Recent Discovery of Peptidomimetics for the Treatment of Coronavirus (COVID-19), Human coronavirus, and Enteroviruses.

This patent describes the synthesis of compounds, methods, and compositions for preventing, treating, and/or curing Covid-19, human coronavirus, and enterovirus infections. Some peptidomimetic compounds are very potent and could be a game changer in new treatment therapy for COVID-19.

Ranolazine Toxicity Secondary to Paxlovid.

An Emergency Use Authorization (EUA) was issued by the FDA on December 22, 2021 for the investigational antiviral drug nirmatrelvir copackaged with the HIV-1 protease inhibitor ritonavir (Paxlovid - Pfizer) for outpatient treatment of mild to moderate COVID-19 in children 12 years and old that are high risk of severe disease. Due to the effects, Paxlovid has on liver metabolism it has a copious amount of drug-to-drug interactions. Here we present a rare case of a patient that was given Paxlovid and continued to take her Ranolazine at home. She presented to the emergency department obtunded and after an initial workup, it was determined to be secondary to ranolazine toxicity. She eventually recovered over 54 hours and returned to her baseline.

Clinical efficacy analysis of paxlovid in children with hematological diseases infected with the omicron SARS-CoV-2 new variant.

Objective: To summarize the clinical characteristics of children with hematological malignancies co-infected with novel coronavirus and explore the safety and effectiveness of Paxlovid treatment. Methods: From December 10, 2022, to January 20, 2023, the clinical data of children with hematological diseases diagnosed with novel coronavirus infection in the outpatient and emergency department of the Seventh Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. Results: According to whether to give paxlovid or not, it is divided into group A (paxlovid group) and group B (non-paxlovid group). The length of fever was 1-6 days in group A and 0-3 days in group B. The viral clearance time was shorter in group A than in group B. The inflammatory indexes CRP and PCT were significantly higher in group A than in group B (P < 0.05). Twenty patients were followed up for 1 month after leaving the hospital, and there were 5 cases of reappearance of fever, 1 case of increased sleep, 1 case of physical fatigue and 1 case of loss of appetite within 2 weeks. Conclusions: Paxlovid has no apparent adverse reactions in children 12 years old and younger with underlying hematological diseases infected with the new coronavirus. Focusing on the interaction between paxlovid and other drugs is necessary during the treatment.

Development and Validation of RP-HPLC Method for the simultaneous determination of Nirmatrelvir and Ritonavir in bulk and pharmaceutical formulation

In this study, a rapid and sensitive stability indicating reversed phase HPLC method was developed for quantitation of Nirmatrelvir and Ritonavir simultaneously in bulk and tablet formulation. Nirmatrelvir and ritonavir were separated on a Thermo C18 column with mobile phase containing 0.01M potassium dihydrogen phosphate buffer and acetonitrile (45:55, v/v). The flow rate was 1 mL/min and detection wavelength was 272 nm. Method linearity was established over a range of 75-225 μg/mL for nirmatrelvir and 50-150 μg/mL for ritonavir. Limit of quantification was 0.694μg/mL for nirmatrelvir and 0.820μg/mL for ritonavir. The recovery (%) was 99.96 to 100.45 (Nirmatrelvir) and 100.25 to 101.35 (Ritonavir). The method precisions were 0.11% (Nirmatrelvir) and 0.33% (Ritonavir). Method was suitable to assay nirmatrelvir and ritonavir in tablet formulation (Paxlovid). Stress degradation studies have shown that this method can be implemented to assay nirmatrelvir and ritonavir in the presence of its degradants. © 2023 World Research Association. All rights reserved.

Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir.

The main protease (Mpro or 3CLpro) is an enzyme that is evolutionarily conserved among different genera of coronaviruses. As it is essential for processing and maturing viral polyproteins, Mpro has been identified as a promising target for the development of broad-spectrum drugs against coronaviruses. Like SARS-CoV and MERS-CoV, the mature and active form of SARS-CoV-2 Mpro is a dimer composed of identical subunits, each with a single active site. Individual monomers, however, have very low or no catalytic activity. As such, inhibition of Mpro can be achieved by molecules that target the substrate binding pocket to block catalytic activity or target the dimerization process. In this study, we investigated GC376, a transition-state analog inhibitor of the main protease of feline infectious peritonitis coronavirus, and Nirmatrelvir (NMV), an oral, bioavailable SARS-CoV-2 Mpro inhibitor with pan-human coronavirus antiviral activity. Our results show that both GC376 and NMV are capable of strongly binding to SARS-CoV-2 Mpro and altering the monomer-dimer equilibrium by stabilizing the dimeric state. This behavior is proposed to be related to a structured hydrogen-bond network established at the Mpro active site, where hydrogen bonds between Ser1' and Glu166/Phe140 are formed in addition to those achieved by the latter residues with GC376 or NMV.

Proxalutamide for the treatment of COVID-19 rebound following Paxlovid treatment: Report of four cases and review of the literature.

BACKGROUND: The pandemic the coronavirus disease 2019 (COVID-19) has created a global health crisis. Although Paxlovid is recommended for the early-stage treatment of mild-to-moderate COVID-19 in patients at increased risk of progression to severe COVID-19, more and more cases are reported a COVID-19 rebound after Paxlovid treatment. Currently, information on the additional treatment for COVID-19 rebound following Paxlovid treatment is limited. CASE REPORT: Here, we present four cases with COVID-19 who were mild on admission. All cases experienced a COVID-19 rebound and progressed to severe COVID-19, following treatment with Paxlovid (300 mg of nirmatrelvir with 100 mg ritonavir, twice daily for 5 days). After being treated with proxalutamide (300 mg/day), all cases finally turned real-time reverse transcription polymerase chain reaction (RT-PCR) negative. CONCLUSION: Our cases suggested that proxalutamide might be an effective remedial treatment option for patients experiencing a COVID-19 rebound after Paxlovid treatment.

Nirmatrelvir-ritonavir compared with other antiviral drugs for the treatment of COVID-19 patients: A systematic review and meta-analysis.

At present, there are some differences in the research results of nirmatrelvir-ritonavir compared with other antiviral drugs for the treatment of COVID-19 patients. We aimed to evaluate the efficacy and safety of nirmatrelvir-ritonavir compared with other antiviral drugs and the impact of different antiviral drugs on the short- and long-term effects of COVID-19. PubMed, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, Google Scholar, and MedRxiv were searched to identify relevant studies from inception to March 30, 2023. We conducted a meta-analysis to estimate the effects of nirmatrelvir-ritonavir compared with other antiviral drugs for the treatment of COVID-19 patients and safety outcomes. The RoB1 and ROBINS-I were used to assess the bias risk of the included studies. Revman 5.4 software was used for meta-analysis (PROSPERO Code No: CRD42023397816). Twelve studies were included, including 30 588 COVID-19 patients, of whom 13 402 received nirmatrelvir-ritonavir. The meta-analysis results showed that the nirmatrelvir-ritonavir group had a lower proportion of patients than the control group in terms of long-term mortality (odds ratio [OR] = 0.29, 95% confidence interval [CI]: 0.13-0.66), hospitalization (OR = 0.44, 95% CI: 0.37-0.53, short term; OR = 0.52, 95% CI: 0.36-0.77, long term), and disease progression (OR = 0.56, 95% CI: 0.38-0.83, short term; OR = 0.60, 95% CI: 0.48-0.74, long term), and nirmatrelvir ritonavir showed little difference in safety compared to the control group. Nirmatrelvir-ritonavir can reduce the mortality and hospitalization of COVID-19 patients compared with other antiviral drugs. Further large-scale studies remain to validate these findings.

Optimizing the use of nirmatrelvir/ritonavir in solid organ transplant recipients with COVID-19: A review of immunosuppressant adjustment strategies.

The coronavirus disease 2019 (COVID-19) pandemic has caused a significant burden of morbidity and mortality worldwide, with solid organ transplant recipients (SOTRs) being particularly vulnerable. Nirmatrelvir and ritonavir have demonstrated the potential for reducing the risk of hospitalization and death in patients with mild-to-moderate COVID-19. However, ritonavir has a strong drug-drug interaction with CYP3A-dependent drugs such as calcineurin inhibitors, potentially leading to rapid increases in blood concentration. As SOTRs are commonly prescribed immunosuppressants, co-administration with nirmatrelvir/ritonavir requires careful consideration. To address this issue, we conducted a literature review to evaluate the use and adverse effects of nirmatrelvir/ritonavir in SOTRs and explore feasible immunosuppressant adjustment regimens. Our findings suggest that nirmatrelvir/ritonavir could be a feasible treatment option for COVID-19 in SOTRs, provided that appropriate immunosuppressive drug management is in place during co-administration. Although prescribing the novel anti-SARS-CoV-2 drug to transplant recipients poses challenges, potential strategies to overcome these issues are discussed. Further studies are needed to determine the optimal dosing strategies of nirmatrelvir/ritonavir, immunosuppressant adjustment, and monitoring in this patient population.

A Rare Case of Paxlovid-Induced Pancreatitis.

Acute pancreatitis can result secondary to an inflammatory cascade due to an insult to the pancreatic parenchyma, whether it be from infections, medications, etc. We present a case of a 37-year-old male with acute pancreatitis after being started on Paxlovid, a combination drug containing Nirmatrelvir and Ritonavir, for COVID-19 treatment. Multiple reports in the literature have documented such an association between acute pancreatitis and the protease inhibitor Ritonavir. We suspect that similar results may have taken place that link the initiation of this medication with pancreatic inflammation.

Antiviral Pills against SARS-CoV-2 Virus to Combat Future Epidemic Threats in Pakistan

Antiviral pills are oral medications that treat infections through the inhibition of the viral growth and replication cycle. Paxlovid by Pfizer and Molnupiravir by Merck are the two pills effective for high-risk SARS-CoV-2 patients. Paxlovid works by inhibiting the replication cycle of SARS-CoV-2 using cysteine residues in-vitro. These cysteine residues inhibit the main protease of the virus by functioning as reversible covalent inhibitors. Molnupiravir works by introducing a high rate of mutations in the viral RNA causing the virus to become biologically unstable and non-functional. Both antiviral drugs can bridge the gap in the preparedness for viral outbreaks in low-income countries like Pakistan by mitigating the chances of fatality and inpatient treatment in high-risk, unvaccinated individuals. Pakistan has been plagued by various epidemics over the years however SARS-CoV-2 outbreak caused many deaths along with an economic crisis. The country lacks the resources to endure high inpatient treatment rates in case of SARS-CoV-2 infections, which is why the need for antiviral pills like Paxlovid and Molnupiravir is empirical to overcome epidemics and viral outbreaks. This work outlines the antiviral pills and their efficacy against SARS-CoV-2 with a focus on how these drugs can overcome significant gaps in epidemic preparedness and response in Pakistan. We aim to highlight how antiviral pills against SARS-CoV-2 can ensure resilience to future epidemic threats in Pakistan. © Pakistan Academy of Sciences.

Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy?

Despite the need for novel, effective therapeutics for the COVID-19 pandemic, no curative regimen is yet available, therefore patients are forced to rely on supportive and nonspecific therapies. Some SARS-CoV-2 proteins, like the 3 C-like protease (3CLpro) or the major protease (Mpro), have been identified as promising targets for antiviral drugs. The Mpro has major a role in protein processing as well as pathogenesis of the virus, and could be a useful therapeutic target. The antiviral drug nirmatrelvir can keep SARS-CoV-2 from replicating through inhibiting Mpro. Nirmatrelvir was combined with another HIV protease inhibitor, ritonavir, to create Paxlovid (Nirmatrelvir/Ritonavir). The metabolizing enzyme cytochrome P450 3 A is inhibited by ritonavir to lengthen the half-life of nirmatrelvir, so rintonavir acts as a pharmacological enhancer. Nirmatrelvir exhibits potent antiviral activity against current coronavirus variants, despite significant alterations in the SARS-CoV-2 viral genome. Nevertheless, there are still several unanswered questions. This review summarizes the current literature on nirmatrelvir and ritonavir efficacy in treating SARS-CoV-2 infection, and also their safety and possible side effects.