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Paxlovid (Nirmatrelvir and Ritonavir) Use in Pregnant and Lactating Woman: Current Evidence and Practice Guidelines-A Scoping Review.

ABSTRACT: COVID-19 virus, since the detection of the first case in Wuhan in 2019, has caused a worldwide pandemic with significant human, economic and social costs. Fortunately, several vaccines and treatments, both IV and oral, are currently approved against the COVID-19 virus. Paxlovid is an oral treatment option for patients with mild-to-moderate disease, and it effectively reduces disease severity in high-risk patients. Paxlovid is an oral antiviral that consists of a combination of nirmatrelvir and ritonavi. As an oral medication suitable for outpatient treatment, it reduces the cost, hospitalization and mortality associated with COVID-19 infection. The pregnant population is a high-risk category for COVID-19 disease. Given their exclusion in clinical trials, there is limited data regarding Paxlovid use in pregnant and lactating women. Indirect evidence from ritonavir use as part of HAART therapy in the pregnant and lactating population with HIV has shown no significant teratogenicity. Moreover, animal studies on the use of nirmatrelvir do not suggest teratogenicity. This article summarizes the available data on ritonavir and nirmatrelvir use during pregnancy and in ongoing clinical trials. We also review the recommendations of major societies worldwide regarding Paxlovid use in pregnant and breastfeeding patients.

SUBMITTER: Chourasia P

PROVIDER: S-EPMC9866309 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Paxlovid (Nirmatrelvir and Ritonavir) Use in Pregnant and Lactating Woman: Current Evidence and Practice Guidelines-A Scoping Review.

Chourasia Prabal P Maringanti Babu Sriram BS Edwards-Fligner Morgan M Gangu Karthik K Bobba Aniesh A Sheikh Abu Baker AB Shekhar Rahul R

Vaccines 20230101 1

COVID-19 virus, since the detection of the first case in Wuhan in 2019, has caused a worldwide pandemic with significant human, economic and social costs. Fortunately, several vaccines and treatments, both IV and oral, are currently approved against the COVID-19 virus. Paxlovid is an oral treatment option for patients with mild-to-moderate disease, and it effectively reduces disease severity in high-risk patients. Paxlovid is an oral antiviral that consists of a combination of nirmatrelvir and r ...[more]

PMID: 36679952

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Project description:Patients with coronavirus disease 2019 (COVID-19) with cardiovascular diseases who are at higher risk of progressing to critical illness should be treated with nirmatrelvir/ritonavir (Paxlovid). Ritonavir, the booster in nirmatrelvir/ritonavir, modulates multiple drug metabolizing enzymes and transporters, complicating its use in real-world clinics. We aimed to apply physiologically-based pharmacokinetic (PBPK) modeling to simulate the complex drug-drug interactions (DDIs) of ritonavir with two anticoagulants, rivaroxaban and racemic warfarin, to address this important clinical conundrum. Simulations were implemented within Simcyp Simulator. Compound and population models were adopted from Simcyp and our previous studies. Upon verification and validation of the PBPK model of ritonavir, prospective DDI simulations with the anticoagulants were performed in both the general population (20-65 years) and geriatric subjects (65-85 years) with or without moderate renal impairment. Elevated rivaroxaban concentrations were simulated with nirmatrelvir/ritonavir treatment, where the impact was more profound among geriatric subjects with renal impairment. The overexposure of rivaroxaban was restored to normal range on day 4 post-discontinuation of nirmatrelvir/ritonavir, corroborating with the recovery of enzyme activity. A lower 10 mg daily dose of rivaroxaban could effectively maintain acceptable systemic exposure of rivaroxaban during nirmatrelvir/ritonavir treatment. Treatment of ritonavir marginally declined simulated S-warfarin concentrations, but substantially elevated that of R-warfarin, resulting in a decrease in the international normalized ratio (INR). As INR only recovered 2 weeks post-nirmatrelvir/ritonavir treatment, a longer surveillance INR for warfarin becomes important. Our PBPK-guided simulations evaluated clinically important yet untested DDIs and supports clinical studies to ensure proper anticoagulation management of patients with COVID-19 with chronic coagulative abnormalities when initiating nirmatrelvir/ritonavir therapy.

Project description:IntroductionOral administration of ritonavir-boosted nirmatrelvir (Paxlovid) was found to be promising in the treatment of coronavirus disease 2019. The active antiviral component nirmatrelvir in Paxlovid is co-formulated with ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor. Many oral targeted therapies indicated for lung cancer are known substrates of CYP 3A4, and concurrent use with Paxlovid may lead to potential drug-drug interaction (DDI). The purpose of this review is to evaluate the potential DDI between targeted therapies and supportive care for lung cancer and ritonavir-boosted nirmatrelvir.MethodsDrug database search in PubMed and the Food and Drug Administration was conducted to identify pharmacokinetic data on oral tyrosine kinase inhibitors (TKIs) used in NSCLC, both Food and Drug Administration approved and those in development. Metabolism pathways for various TKIs are extracted, and the impact of TKI area under the curves and maximum concentration by strong CYP 3A4 inducers and inhibitors is summarized. The most common toxicities and supportive care medications for the TKI were identified.ResultsAmong EGFR and exon 20 insertion inhibitors, afatinib is least likely to be affected by CYP 3A4, followed by dacomitinib and osimertinib. Among ALK inhibitors, alectinib is the least susceptible to CYP 3A4. ROS1 inhibitors are affected by CYP 3A4 inhibition with the exception of crizotinib. Among MET inhibitors, capmatinib is substantially affected by CYP 3A4 inhibition. Drug exposure of RET inhibitors is expected to increase with CYP 3A4 inhibition, with selpercatinib being the least affected. Certain supportive care medications for lung cancer TKI may have relevant DDIs.ConclusionsThe clinical impact of the DDI between lung cancer TKI and ritonavir-boosted nirmatrelvir varies largely on the basis of the susceptibility of CYP 3A4 inhibition caused by the antiviral. Close monitoring and medication adjustments (i.e., dose changes or alternative coronavirus disease 2019 therapy) can be used to overcome DDI to ensure patient safety.

Project description:BackgroundNirmatrelvir with ritonavir (Paxlovid) is indicated for patients with Coronavirus Disease 2019 (COVID-19) who are at risk for progression to severe disease due to the presence of one or more risk factors. Millions of treatment courses have been prescribed in the United States alone. Paxlovid was highly effective at preventing hospitalization and death in clinical trials. Several studies have found a protective association in real-world data, but they variously used less recent study periods, correlational methods, and small, local cohorts. Their estimates also varied widely. The real-world effectiveness of Paxlovid remains uncertain, and it is unknown whether its effect is homogeneous across demographic strata. This study leverages electronic health record data in the National COVID Cohort Collaborative's (N3C) repository to investigate disparities in Paxlovid treatment and to emulate a target trial assessing its effectiveness in reducing severe COVID-19 outcomes.Methods and findingsThis target trial emulation used a cohort of 703,647 patients with COVID-19 seen at 34 clinical sites across the United States between April 1, 2022 and August 28, 2023. Treatment was defined as receipt of a Paxlovid prescription within 5 days of the patient's COVID-19 index date (positive test or diagnosis). To emulate randomization, we used the clone-censor-weight technique with inverse probability of censoring weights to balance a set of covariates including sex, age, race and ethnicity, comorbidities, community well-being index (CWBI), prior healthcare utilization, month of COVID-19 index, and site of care provision. The primary outcome was hospitalization; death was a secondary outcome. We estimated that Paxlovid reduced the risk of hospitalization by 39% (95% confidence interval (CI) [36%, 41%]; p < 0.001), with an absolute risk reduction of 0.9 percentage points (95% CI [0.9, 1.0]; p < 0.001), and reduced the risk of death by 61% (95% CI [55%, 67%]; p < 0.001), with an absolute risk reduction of 0.2 percentage points (95% CI [0.1, 0.2]; p < 0.001). We also conducted stratified analyses by vaccination status and age group. Absolute risk reduction for hospitalization was similar among patients that were vaccinated and unvaccinate, but was much greater among patients aged 65+ years than among younger patients. We observed disparities in Paxlovid treatment, with lower rates among black and Hispanic or Latino patients, and within socially vulnerable communities. This study's main limitation is that it estimates causal effects using observational data and could be biased by unmeasured confounding.ConclusionsIn this study of Paxlovid's real-world effectiveness, we observed that Paxlovid is effective at preventing hospitalization and death, including among vaccinated patients, and particularly among older patients. This remains true in the era of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron subvariants. However, disparities in Paxlovid treatment rates imply that the benefit of Paxlovid's effectiveness is not equitably distributed.

Project description:IntroductionAntiviral treatment can reduce the burden of COVID-19. But utilisation can be suboptimal, even in a setting like Singapore where it is fully subsidized for those with selected medical conditions and older adults (≥ 50 years). We hence investigated the factors affecting awareness, acceptance, and initiative to request Paxlovid.MethodsWe assessed the Paxlovid awareness, factors impacting its uptake in a survey conducted from August 2022 to September 2022 through the SOCRATES cohort. Multivariable logistic regression was used to investigate associations between sociodemographics, perceptions, and attitudes with the key study outcomes.ResultsAmong respondents to the Paxlovid survey, 54% were aware of Paxlovid. On being provided essential details about Paxlovid, 75% reported they would likely be receptive to taking it if prescribed, and 38% indicated the initiative to request for it if it was not suggested by their doctors. Factors associated with awareness of Paxlovid include aged 40 years old and above, higher education, citing websites as an information source, greater trust in healthcare providers (aOR: 1.65, 95% CI 1.26 - 2.15) and government communications (aOR: 0.69, 95% CI 0.55 - 0.86), and higher perceived risk of COVID-19 infection (aOR: 1.25, 95% CI 1.10 - 1.42). Factors associated with acceptance to take Paxlovid include male gender, citing trust in healthcare providers (aOR: 1.49, 95% CI 1.11 - 1.99) and government communications (aOR: 1.38, 95% CI 1.09 - 1.76), and higher perceived severity of COVID-19 (aOR: 1.23, 95% CI 1.07 - 1.42). Factors associated with initiative to request Paxlovid include male gender, having pre-existing diabetes and higher perceived severity of COVID-19 (aOR: 1.24, 95% CI 1.09 - 1.40). The most common reasons for why respondents might not take Paxlovid were concerns about side effects (64%), concerns about costs (29%), and the perception that COVID-19 is a mild (25%).ConclusionThe majority of our respondents would take Paxlovid if it was prescribed to them, but a much smaller proportion would have the initiative to request for this. Key factors that may influence uptake are COVID-19 threat perceptions, trust in healthcare and government, and perceptions of the drug's side effects and cost.

Dataset Information

Paxlovid (Nirmatrelvir and Ritonavir) Use in Pregnant and Lactating Woman: Current Evidence and Practice Guidelines-A Scoping Review.

Publications

Paxlovid (Nirmatrelvir and Ritonavir) Use in Pregnant and Lactating Woman: Current Evidence and Practice Guidelines-A Scoping Review.

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