Simnotrelvir as a potential treatment for COVID-19.

INTRODUCTION: Simnotrelvir is a selective 3-chymotrypsin-like oral protease inhibitor with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). AREAS COVERED: On 18 January 2024, results of a double-blind, randomized, placebo-controlled trial of simnotrelvir as a treatment for mild-to moderate COVID-19-were published, indicating the drug, when given in combination with ritonavir, shortened the time to resolution of symptoms. EXPERT OPINION: Treatment options for most outpatients with mild-to-moderate COVID-19 are limited. The protease inhibitor nirmatrelvir in combination with ritonavir has proven effective in patients who are high risk for progression to severe COVID-19, but there are no approved therapies for standard-risk patients, who now comprise the majority of the population. Simnotrelvir appears to be effective in standard-risk patients, including those who have completed primary vaccination against COVID-19 and have received a booster dose. This manuscript examines the rationale for the development of simnotrelvir and explores how this drug may be used in the future to treat COVID-19.

Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19.

BACKGROUND: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial. METHODS: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed. RESULTS: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate. CONCLUSIONS: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).

Análisis de las interacciones de nirmatrelvir/ritonavir en pacientes ambulatorios en atención primaria / Nirmatrelvir/ritonavir drug-drug interactions in primary care outpatients

Fundamento. Nirmatrelvir/ritonavir es un antiviral oral con un alto potencial de producir interacciones farmacológicas. La población candidata a recibirlo es mayoritariamente vulnerable, con enfermedades crónicas y polimedicada. El objetivo es evaluar la validación farmacéutica previa a la ad-ministración del antiviral.Material y métodos. Las interacciones farmacológicas entre nirmatrelvir/ritonavir y el tratamiento habitual se consulta-ron en fichas técnicas y las herramientas de interacciones de UpToDate® y Universidad de Liverpool®. Se incluyeron las prescripciones validadas por un farmacéutico de atención primaria (abril/2022-abril/2023). Resultados. Se incluyeron 159 pacientes; en 83 se detecta-ron 168 interacciones que podían suponer un cambio en su tratamiento. Las estatinas (25,6%), anticoagulantes (10,7%) y antihipertensivos (10,7%) fueron los grupos terapéuticos más frecuentemente implicados. La suspensión (53,0%) y reducción de dosis (22,6%) fueron los cambios de trata-miento más frecuentes. Conclusiones. La revisión de potenciales interacciones far-macológicas, los ajustes posológicos y las modificaciones del tratamiento habitual del paciente han evitado potenciales to-xicidades, mejorando la seguridad de nirmatrelvir/ritonavir (AU)

Background. The oral antiviral nirmatrelvir/ritonavir inter-acts with a range of drugs. Candidate patients to receive this antiviral agent are usually vulnerable, multipathological and polymedicated. The objective is to evaluate the phar-maceutical validation prior to the administration of the an-tiviral.Material and methods. Drug-drug interactions between nirmatrelvir/ritonavir and patients’ usual treatment medi-cations were checked in product information and in the Up-ToDate® and the University of Liverpool® interaction tools. We included validated prescriptions between April/2022 and April/2023 by a Primary Care pharmacist.Results. Of the 159 study patients, 168 interactions were found in 83 individuals, which may have led to changes of their usual treatment. Statins (25.6%), anticoagulants (10.7%), and antihypertensives (10.7%) were the most fre-quently implicated therapeutic groups. Discontinuation (53.0%) and dose reduction (22.6%) were the most common treatment changes. Conclusions. Our search of potential drug interactions and subsequent dose adjustments and modifications of the pa-tient’s usual treatment has helped avoid potential toxicities ensuring a safe use of nirmatrelvir/ritonavir (AU)

Clinical-epidemiological characterization of women who received post-exposure HIV prophylaxis in a public hospital in Porto Alegre, Rio Grande do Sul / Caracterização clínico-epidemiológica de mulheres que receberam a profilaxia pós-exposição ao HIV em um hospital público de Porto Alegre, Rio Grande do Sul

Introduction: Prevention strategies are key to combating the epidemic of infections such as HIV and syphilis. The epidemiological scenario of Porto Alegre/RS for these infections shows the need for greater efforts in the area of prevention, seeking to characterize both the population that uses these strategies and the services involved in the care of exposed people. Objective: This study aimed to characterize the clinical and epidemiological profile of patients who received post-exposure prophylaxis (PEP) to HIV treated in a public hospital in Porto Alegre/RS. Methods: This is a retrospective, research, descriptive study based on the Clinical Protocol and Therapeutic Guidelines for PEP, updated in 2018 by the Ministry of Health. Prophylaxis request forms and medical records of patients treated were analyzed. Results: The population consisted of 87 women who received PEP from January to September 2019. There was a predominance of women aged between 20 and 29 years old (55.2%). The most frequent sexual exposure was consensual (69.0%) followed by sexual assault (31.0%). Porto Alegre was the place of residence of most patients (73.6%). The most frequently used therapeutic regimen was the combination of atazanavir, ritonavir, and tenofovir plus lamivudine. On the first visit, 8.0% of the patients showed reactive results for the treponemal syphilis test. Only 23.0% and 14.9% of patients returned for anti-HIV tests in the first and third months after exposure, respectively, and the results were non-reactive. Only 19 patients (21.8%) attended the consultations between 0 and 28 days after PEP. Conclusion: It was identified that a considerable percentage of women already had reactive serology for syphilis, most women did not return for follow-up within 28 and 90 days after the first consultation, more than half of the women were aged between 20 and 29 years old, and the most frequent sexual exposure was consensual. In this sense, efforts are needed, such as adequate counseling, adoption of interventions such as sending messages by cell phone, telephone calls, and preparation of educational materials, seeking to improve adherence to treatment and follow-up in the service, which is important given the scenario of epidemiology in Porto Alegre.Keywords: HIV. Sexually transmitted diseases. Post-exposure prophylaxis. Disease prevention

Introdução: Estratégias de prevenção são fundamentais para o combate à epidemia de infecções como o vírus da imunodeficiência humana (HIV) e sífilis. O cenário epidemiológico de Porto Alegre/RS para essas infecções mostra a necessidade de maiores esforços na área de prevenção, buscando caracterizar tanto a população que utiliza essas estratégias quanto os serviços envolvidos no atendimento das pessoas expostas. Objetivo: Caracterizar o perfil clínico-epidemiológico das pacientes que receberam a profilaxia pós-exposição (PEP) ao HIV atendidas em um hospital público de Porto Alegre/RS. Métodos: Trata-se de um estudo retrospectivo, documental, descritivo e baseado no Protocolo Clínico e Diretrizes Terapêuticas para PEP, atualizado em 2021 pelo Ministério da Saúde. Foram analisados os formulários de solicitação da profilaxia e prontuários das pacientes atendidas. Resultados: A população foi composta de 87 mulheres que receberam a PEP no período de janeiro a setembro de 2019. Predominaram mulheres com idades entre 20 e 29 anos (55,2%). A exposição sexual mais frequente foi a consentida (69,0%), seguida pela violência sexual (31,0%). Porto Alegre foi o local de residência da maioria das pacientes (73,6%). O esquema terapêutico utilizado com maior frequência foi a combinação com atazanavir, ritonavir e tenofovir associado à lamivudina. No primeiro atendimento, 8,0% das pacientes demonstraram resultados reagentes para o teste treponêmico de sífilis. Retornaram para a realização dos testes anti-HIV no primeiro e terceiro mês após a exposição apenas 23,0 e 14,9% das pacientes, respectivamente, e os resultados foram não reagentes. Apenas 19 delas (21,8%) compareceram às consultas entre zero e 28 dias posteriores à PEP. Conclusão: Foi identificado que um percentual considerável de mulheres já apresentava sorologia reagente para sífilis, a maioria das mulheres não retornou para o seguimento no período de 28 e 90 dias após o primeiro atendimento, mais da metade delas tinha idade entre 20 e 29 anos e a exposição sexual mais frequente foi a consentida. Nesse sentido, são necessários esforços como aconselhamento adequado, adoção de intervenções como o envio de mensagens pelo celular, ligações telefônicas e elaboração de materiais educativos, buscando a melhoria da adesão ao tratamento e do acompanhamento no serviço, o que é importante diante do cenário epidemiológico de Porto Alegre.Palavras-chave: HIV. Infecções sexualmente transmissíveis. Profilaxia pós-exposição. Prevenção

VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19.

BACKGROUND: Nirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir). RESULTS: A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%). CONCLUSIONS: Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.

BACKGROUND: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro. METHODS: We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. RESULTS: A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. CONCLUSIONS: Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).

Mechanisms of COVID-19-induced kidney injury and current pharmacotherapies.

The COVID-19 pandemic created a worldwide debilitating health crisis with the entire humanity suffering from the deleterious effects associated with the high infectivity and mortality rates. While significant evidence is currently available online and targets various aspects of the disease, both inflammatory and noninflammatory kidney manifestations secondary to COVID-19 infection are still largely underrepresented. In this review, we summarized current knowledge about COVID-19-related kidney manifestations, their pathologic mechanisms as well as various pharmacotherapies used to treat patients with COVID-19. We also shed light on the effect of these medications on kidney functions that can further enhance renal damage secondary to the illness.

Impact of Polymer Type on Thermal Degradation of Amorphous Solid Dispersions Containing Ritonavir.

High-temperature exposure during hot melt extrusion processing of amorphous solid dispersions may result in thermal degradation of the drug. Polymer type may influence the extent of degradation, although the underlying mechanisms are poorly understood. In this study, the model compound, ritonavir (Tm = 126 °C), undergoes thermal degradation upon high-temperature exposure. The extent of degradation of ritonavir in amorphous solid dispersions (ASDs) formulated with poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone) vinyl acetate copolymer (PVP/VA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and hydroxypropyl methylcellulose (HPMC) following isothermal heating and hot melt extrusion was evaluated, and mechanisms related to molecular mobility and intermolecular interactions were assessed. Liquid chromatography-mass spectrometry (LC-MS/MS) studies were used to determine the degradation products and pathways and ultimately the drug-polymer compatibility. The dominant degradation product of ritonavir was the result of a dehydration reaction, which then catalyzed a series of hydrolysis reactions to generate additional degradation products, some newly reported. This reaction series led to accelerated degradation rates with protic polymers, HPMCAS and HPMC, while ASDs with aprotic polymers, PVP and PVP/VA, had reduced degradation rates. This work has implications for understanding mechanisms of thermal degradation and drug-polymer compatibility with respect to the thermal stability of amorphous solid dispersions.

Rifampin and ritonavir increase oral availability and elacridar enhances overall exposure and brain accumulation of the NTRK inhibitor larotrectinib.

INTRODUCTION: Larotrectinib is an FDA-approved oral small-molecule inhibitor for neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive cancer treatment. Here larotrectinib pharmacokinetic behavior upon co-administration with prototypical inhibitors of the efflux transporters ABCB1/ABCG2 (elacridar), the SLCO1A/1B (OATP1A/1B) uptake transporters (rifampin), and the drug-metabolizing enzyme CYP3A (ritonavir), respectively, was investigated. METHODS: Inhibitors were orally administered prior to oral larotrectinib (10 mg/kg) to relevant genetically modified mouse models. Larotrectinib plasma and tissue homogenate concentrations were measured by a liquid chromatography-tandem mass spectrometric assay. RESULTS: Elacridar increased oral availability (2.7-fold) and markedly improved brain-to-plasma ratios (5.0-fold) of larotrectinib in wild-type mice. Mouse (m)Oatp1a/1b but not hepatic transgenic human (h)OATP1B1 or -1B3 restricted larotrectinib oral availability and affected its tissue distribution. Rifampin enhanced larotrectinib oral availability not only in wild-type mice (1.9-fold), but surprisingly also in Slco1a/1b-/- mice (1.7-fold). Similarly, ritonavir increased the larotrectinib plasma exposure in both wild-type (1.5-fold) and Cyp3a-/- mice (1.7-fold). Intriguingly, both rifampin and ritonavir decreased liver and/or intestinal larotrectinib levels in all related experimental groups, suggesting additional inhibition of enterohepatic Abcb1a/1b activity. CONCLUSIONS: Elacridar enhances both larotrectinib plasma and tissue exposure and especially relative brain penetration, which might be therapeutically relevant. Hepatic mOatp1a/1b but not hOATP1B1 or -1B3 transported larotrectinib. Additionally, rifampin enhances larotrectinib systemic exposure, most likely by inhibiting mOatp1a/1b, but probably also hepatic and/or intestinal mAbcb1. Similar to rifampin, dual-inhibition functions of ritonavir affecting both CYP3A enzymes and enterohepatic Abcb1 transporters enhanced larotrectinib oral availability. The obtained insights may be used to further optimize the clinical-therapeutic application of larotrectinib.

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19.

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.

Impact of Simulated Intestinal Fluids on Dissolution, Solution Chemistry, and Membrane Transport of Amorphous Multidrug Formulations.

The solution behavior and membrane transport of multidrug formulations were herein investigated in a biorelevant medium simulating fasted conditions. Amorphous multidrug formulations were prepared by the solvent evaporation method. Combinations of atazanavir (ATV) and ritonavir (RTV) and felodipine (FDN) and indapamide (IPM) were prepared and stabilized by a polymer for studying their dissolution (under non-sink conditions) and membrane transport in fasted state simulated intestinal fluid (FaSSIF). The micellar solubilization by FaSSIF enhanced the amorphous solubility of the drugs to different extents. Similar to buffer, the maximum achievable concentration of drugs in combination was reduced in FaSSIF, but the extent of reduction was affected by the degree of FaSSIF solubilization. Dissolution studies of ATV and IPM revealed that the amorphous solubility of these two drugs was not affected by FaSSIF solubilization. In contrast, RTV was significantly affected by FaSSIF solubilization with a 30% reduction in the maximum achievable concentration upon combination to ATV, compared to 50% reduction in buffer. This positive deviation by FaSSIF solubilization was not reflected in the mass transport-time profiles. Interestingly, FDN concentrations remain constant until the amount of IPM added was over 1000 µg/mL. No decrease in the membrane transport of FDN was observed for a 1:1 M ratio of FDN-IPM combination. This study demonstrates the importance of studying amorphous multidrug formulations under physiologically relevant conditions to obtain insights into the performance of these formulations after oral administration.

Risk factors for prolonged virus shedding of respiratory tract and fecal in adults with severe acute respiratory syndrome coronavirus-2 infection.

BACKGROUND: The dynamic alteration and comparative study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding pattern during treatment are limited. This study explores the potential risk factors influencing prolonged viral shedding in COVID-19. METHODS: A total of 126 COVID-19 patients were enrolled in this retrospective longitudinal study. A multivariate logistic regression analysis was carried out to estimate the potential risk factors. RESULTS: 38.1% (48/126) cases presented prolonged respiratory tract viral shedding, and 30 (23.8%) cases presented prolonged rectal swab viral shedding. Obesity (OR, 3.31; 95% CI, 1.08-10.09), positive rectal swab (OR, 3.43; 95% CI, 1.53-7.7), treatment by lopinavir/ritonavir with chloroquine phosphate (OR, 2.5; 95% CI, 1.04-6.03), the interval from onset to antiviral treatment more than 7 days (OR, 2.26; 95% CI, 1.04-4.93), lower CD4+ T cell (OR, 0.92; 95% CI, 0.86-0.99) and higher NK cells (OR, 1.11; 95% CI, 1.02-1.20) were significantly associated with prolonged respiratory tract viral shedding. CD3-CD56+ NK cells (OR, 0.87; 95% CI, 0.76-0.99) were related with prolonged fecal shedding. CONCLUSIONS: Obesity, delayed antiviral treatment, and positive SARS-CoV-2 for stool were independent risk factors for prolonged SARS-CoV-2 RNA shedding of the respiratory tract. A combination of LPV/r and abidol as the initial antiviral regimen was effective in shortening the duration of viral shedding compared with LPV/r combined with chloroquine phosphate. CD4+ T cell and NK cells were significantly associated with prolonged viral shedding, and further studies are to be warranted to determine the mechanism of immunomodulatory response in virus clearance.

Prescribing intranasal steroids in HIV-positive patients: systematic review of the literature.

BACKGROUND: There are significant drug-drug interactions between human immunodeficiency virus antiretroviral therapy and intranasal steroids, leading to high serum concentrations of iatrogenic steroids and subsequently Cushing's syndrome. METHOD: All articles in the literature on cases of intranasal steroid and antiretroviral therapy interactions were reviewed. Full-length manuscripts were analysed and the relevant data were extracted. RESULTS: A literature search and further cross-referencing yielded a total of seven reports on drug-drug interactions of intranasal corticosteroids and human immunodeficiency virus protease inhibitors, published between 1999 and 2019. CONCLUSION: The use of potent steroids metabolised via CYP3A4, such as fluticasone and budesonide, are not recommended for patients taking ritonavir or cobicistat. Mometasone should be used cautiously with ritonavir because of pharmacokinetic similarities to fluticasone. There was a delayed onset of symptoms in many cases, most likely due to the relatively lower systemic bioavailability of intranasal fluticasone.

Enhancement of Docetaxel Absorption Using Ritonavir in an Oral Milk-Based Formulation.

OBJECTIVE: The current study aimed to develop a novel milk-based formulation of docetaxel, a sparingly soluble antineoplastic agent, administered so far exclusively by the intravenous route and evaluate its oral bioavailability. METHODS: Pre-formulation studies included the determination of docetaxel solubility in water-alcohol mixtures as well as short-term content uniformity experiments of the final formulation. The pharmacokinetic (PK) performance of the developed milk-based formulations was further evaluated in vivo in mice using ritonavir, a potent P-glycoprotein inhibitor, as an absorption enhancer of docetaxel and the marketed intravenous docetaxel formulation, Taxotere®, as a control. RESULTS: In vivo PK results in mice showed that all the administered oral docetaxel formulations had limited absorption in the absence of ritonavir. On the contrary, ritonavir co-administration given as pre-treatment significantly enhanced oral bioavailability of both the marketed and milk-based docetaxel formulations; an even more marked increase in drug exposure was observed when ritonavir was incorporated within the docetaxel milk-based formulation. The fixed-dose combination also showed a more prolonged absorption of the drug compared to separate administrations. CONCLUSIONS: The current study provides insights for the discovery of a novel milk-based formulation that could potentially serve as an alternative, non-toxic and patient-friendly carrier for an acceptable docetaxel oral chemotherapy.

Pharmacokinetic interactions between the potential COVID-19 treatment drugs lopinavir/ritonavir and arbidol in rats.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has occasioned worldwide alarm. Globally, the number of reported confirmed cases has exceeded 84.3 million as of this writing (January 2, 2021). Since there are no targeted therapies for COVID-19, the current focus is the repurposing of drugs approved for other uses. In some clinical trials, antiviral drugs such as remdesivir (Grein et al., 2020), lopinavir/ritonavir (LPV/r) (Cao et al., 2020), chloroquine (Gao et al., 2020), hydroxychloroquine (Gautret et al., 2020), arbidol (Wang et al., 2020), and favipiravir (Cai et al., 2020b) have shown efficacy in COVID-19 patients. LPV/r combined with arbidol, which is the basic regimen in some regional hospitals in China including Zhejiiang Province, has shown antiviral effects in COVID-19 patients (Guo et al., 2020; Xu et al., 2020). A retrospective cohort study also reported that this combination therapy showed better efficacy than LPV/r alone for the treatment of COVID-19 patients (Deng et al., 2020).