Design and evaluation of oseltamivir phosphate dual-phase extended-release tablets for the treatment of influenza.

In this study, once-daily extended-release tablets with dual-phase release of oseltamivir phosphate were developed for the treatment of influenza. The goal was to improve patient adherence and offer more therapeutic choices. The tablets were manufactured using wet granulation, bilayer tablet compression, and enteric membrane-controlled coating processes. Various polymers, such as hydroxypropyl methylcellulose (HPMC K100MCR, K15MCR, K4MCR, K100LV), enteric polymers (HPMC AS-LF, Eudragit L100-55) and membrane-controlled polymers (OPADRY® CA), were used either individually or in combination with other common excipients. The formulations include enteric-coated extended-release tablet (F1), hydrophilic matrix extended-release tablet (F2), semipermeable membrane-controlled release tablet (F3) and a combination extended-release tablet containing both enteric and hydrophilic matrix (F4). The in vitro drug release profile of each formulation was fitted to the first-order model, and the Ritger-Peppas model suggested that Fickian diffusion was the primary mechanism for drug release. Comparative bioequivalence studies with Tamiflu® (oseltamivir phosphate) capsules revealed that formulations F1, F2, and F3 did not achieve bioequivalence. However, under fed conditions, formulation F4 achieved bioequivalence with a relative bioavailability of 95.30% (90% CI, 88.83%-102.15%). This suggests that the formulation F4 tablet could potentially be a new treatment option for patients with influenza.

A noninferiority randomized open-label pilot study of 3- versus 7-day influenza postexposure prophylaxis with oseltamivir in hospitalized children.

Short influenza postexposure prophylaxis (PEP) showed high efficacy in adults, but studies in children are lacking. This randomized open-label pilot trial aimed to verify noninferiority of a 3- versus 7-day prophylaxis with oral oseltamivir in hospitalized children. Influenza contacts were randomized to the 3- or 7-day group and efficacy, relative risk of adverse events (AEs), and the cumulative costs of drugs and AEs management were compared. The intention-to-treat (ITT) analysis included 59 children (n = 28 and n = 31 in the 3- and 7-day group, respectively). The efficacy was 100% (95% CI 87.7-100%) versus 93.6% (95% CI 78.6-99.2%) in the 3- and 7-day group; the differences were statistically insignificant. A per-protocol (PP) analysis including 56 patients (n = 27 and n = 29, respectively) showed 100% (95% CI 87.2-100%) and 93.1% (95% CI 77.2-99.2%) efficacy, respectively, without statistical significance. Differences were within the predefined noninferiority margin with an efficacy difference Δ = 6.45 percentage points (p.p.) with 1-sided 95% CI (- 2.8, - 1.31, p = 0.86; ITT) and Δ = 6.9 p.p. (1-sided 95% CI - 2.83, - 1.27, p = 0.85; PP). Adverse events did not differ significantly, while the cumulative costs of the prophylaxis and AEs management were higher in the 7-day group (median 10.5 euro vs. 4.5 euro, p < 0.01). This pilot study showed the noninferiority of the 3-day versus 7-day PEP, which was associated with lower costs.Trial registration number: NCT04297462, 5th March 2020, restrospectively registered.

Does oseltamivir prevent hospitalisation in people with influenza?

Overview of: Hanula R, Bortolussi-Courval É, Mendel A, et al. Evaluation of oseltamivir used to prevent hospitalization in outpatients with influenza: a systematic review and meta-analysis. JAMA Internal Medicine 2024;184:18-27.

Simultaneous analyses of hemodynamic and electrophysiological effects of oseltamivir along with its pharmacokinetic profile using the canine paroxysmal atrial fibrillation model.

Since information of antiviral drug oseltamivir on the anti-atrial fibrillation (AF) property is still limited, we assessed it using the canine paroxysmal AF model. Oseltamivir in doses of 3 and 30 mg/kg/10 min was intravenously infused to the isoflurane-anesthetized, chronic atrioventricular block dogs (n = 6) with monitoring hemodynamic and electrophysiological variables, in which AF was induced by 10 s of burst pacing on atrial septum. Oseltamivir decreased AF incidence and AF duration, and prolonged AF cycle length in a dose-dependent manner. The low and high doses attained the peak plasma drug concentrations of 9.7 and 96.5 µg/mL, which were approximately 100 and 1000 times greater than those observed in human clinical cases, respectively. The low dose of oseltamivir decreased mean blood pressure without altering sinoatrial or idioventricular rate, whereas its high dose reduced each of them. Oseltamivir delayed inter-atrial conduction in dose- and frequency-dependent manners, whereas it prolonged atrial effective refractory period in dose-dependent but frequency-independent manners. The high dose prolonged ventricular effective refractory period, which was not detected with the low dose. These findings can be used for repurposing oseltamivir as an anti-AF drug candidate.

Dexamethasone plus oseltamivir versus dexamethasone in treatment-naive primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Primary immune thrombocytopenia is an autoimmune bleeding disorder. Preclinical reports suggest that the sialidase inhibitor oseltamivir induces a platelet response in the treatment of immune thrombocytopenia. This study investigated the activity and safety of dexamethasone plus oseltamivir versus dexamethasone alone as initial treatment in adult patients with primary immune thrombocytopenia. METHODS: This multicentre, randomised, open-label, parallel group, phase 2 trial was done in five tertiary medical hospitals in China. Eligible patients were aged 18 years or older with newly diagnosed, treatment-naive primary immune thrombocytopenia. Participants were randomly assigned (1:1), using block randomisation, to receive either dexamethasone (orally at 40 mg per day for 4 days) plus oseltamivir (orally at 75 mg twice a day for 10 days) or dexamethasone monotherapy (orally at 40 mg a day for 4 days). Patients who did not respond to treatment (platelet counts remained <30 × 109 cells per L or showed bleeding symptoms by day 10) were given an additional cycle of dexamethasone for 4 days in each group. Patients in the dexamethasone plus oseltamivir group who relapsed (platelet counts reduced again to <30 × 109 cells per L) after an initial response were allowed a supplemental course of oseltamivir (75 mg twice a day for 10 days). The coprimary endpoints were 14-day initial overall response and 6-month overall response. Complete response was defined as a platelet count at or above 100 × 109 cells per L and an absence of bleeding. Partial response was defined as a platelet count at or above 30 × 109 cells per L but less than 100 × 109 cells per L and at least a doubling of the baseline platelet count and an absence of bleeding. A response lasting for at least 6 months without any additional primary immune thrombocytopenia-specific intervention was defined as sustained response. All patients who were randomly assigned and received the allocated intervention were included in the modified intention-to-treat population analysis. This study has been completed and is registered with ClinicalTrials.gov, number NCT01965626. FINDINGS: From Feb 1, 2016, to May 1, 2019, 120 patients were screened for eligibility, of whom 24 were ineligible and excluded, 96 were enrolled and randomly assigned to receive dexamethasone plus oseltamivir (n=47) or dexamethasone (n=49), and 90 were included in the modified intention-to-treat analysis. Six patients did not receive the allocated intervention. Patients in the dexamethasone plus oseltamivir group had a significantly higher initial response rate (37 [86%] of 43 patients) than did those in the dexamethasone group (31 [66%] of 47 patients; odds ratio [OR] 3·18; 95 CI% 1·13-9·23; p=0·030) at day 14. The 6-month sustained response rate in the dexamethasone plus oseltamivir group was also significantly higher than that in the dexamethasone group (23 [53%] vs 14 [30%]; OR 2·17; 95 CI% 1·16-6·13; p=0·032). During the median follow-up of 8 months (IQR 5-14), two of 90 patients discontinued treatment due to serious adverse events (grade 3); one (2%) patient with general oedema in the dexamethasone plus oseltamivir group and one (2%) patient with fever in the dexamethasone group. The most frequently observed adverse events of any grade were fatigue (five [12%] of 43 in the dexamethasone plus oseltamivir group vs eight [17%] of 47 in the dexamethasone group), gastrointestinal reactions (eight [19%] vs three [6%]), insomnia (seven [16%] vs four [9%]), and anxiety (five [12%] vs three [6%]). There were no grade 4 or 5 adverse events and no treatment-related deaths. INTERPRETATION: Dexamethasone plus oseltamivir offers a readily available combination therapy in the management of newly diagnosed primary immune thrombocytopenia. The preliminary activity of this combination warrants further investigation. Multiple cycles of oseltamivir, as a modification of current first-line treatment, might be more effective in maintaining the platelet response. FUNDING: National Natural Science Foundation of China.

Comparing intravenous peramivir with oral oseltamivir for patients with influenza: a meta-analysis of randomized controlled trials.

BACKGROUND: The study was to compare the efficacy between IV peramivir and oral oseltamivir treatments in patients with influenza. METHODS: The PubMed, EMBASE, Scopus, ClinicalTrials.gov, and Cochrane Library databases were searched for studies published before January 2020. RESULTS: The meta-analysis was conducted to calculate the pooled effect size by using a random-effects model. Seven randomized controlled trials (RCTs) including 1,138 patients were reviewed. The incidence of total complications revealed no significant difference between 600 mg IV peramivir (P600) and 75 mg oral oseltamivir (O75) treatments (2.8% vs. 4.1%; risk ratio [RR] = 0.70; 95% confidence interval [CI]: 0.36-1.38). The incidence of pneumonia was not significantly different between the P600 and O75 treatment groups (2.2% vs. 2.7%; RR = 0.74; 95% CI: 0.37-1.51). Regarding the time to the alleviation of symptoms, no difference was found in P600 and O75 treatment (MD = -3.00; 95% CI: -11.07 to 5.06). The rate of fever clearance in 24 h and the time to fever resolution were not statistically different between the IV peramivir and oral oseltamivir treatments (at different dosages) groups. CONCLUSIONS: The treatment of influenza with IV peramivir or oral oseltamivir had similar clinical efficacy.

Effect of triple antimicrobial therapy on electrocardiography parameters in patients with mild-to-moderate coronavirus disease 2019.

OBJECTIVE: The effects of treatment of coronavirus disease 2019 (COVID-19) with a triple combination composed of hydroxychloroquine, an an-tiviral, and an antibiotic on electrocardiography (ECG) parameters in patients with mild-to-moderate symptoms are not wholly understood. We aimed to explore the changes in ECG parameters after treatment with triple combination therapy in patients with mild-to-moderate symptomatic COVID-19. METHODS: This retrospective, single-center case series analyzed 91 patients with mild-to-moderate symptomatic COVID-19 at Ankara Gazi Mus-tafa Kemal State Hospital of Ankara City, Turkey, from April 1, 2020, to April 30, 2020. Forty-three patients were treated with hydroxychloroquine+oseltamivir+azithromycin (Group 1) and 48 patients were treated with hydroxychloroquine+oseltamivir+levofloxacin (Group 2). Heart rate, P wave duration, P wave dispersion, PR interval, QRS duration, corrected QT interval (QTc), QTc dispersion (QTD), delta QTc, Tp-e, Tp-e dispersion, and Tp-e/QTc ratio were all calculated from the baseline and posttreatment 12-lead ECG recordings. RESULTS: The QTc, QRS duration, Tp-e, PR interval, and P wave duration were significantly increased after treatment (p<0.001; p<0.001; p<0.001; p=0.001; p=0.001). The posttreatment C-reactive protein level was significantly lower than at baseline in Group 1 (p=0.014). At admission, 30% of patients had QT prolongation, and 4.3% of them had a QT duration >500 ms. Both Group 1 and Group 2 showed significant prolongation of the QTc interval (Group 1; p<0.001 vs. Group 2; p<0.001), QRS duration (Group 1; p=0.006 vs. Group 2; p=0.014), Tp-e (Group 1; p=0.036 vs. Group 2; p<0.001), and PR interval (Group 1; p=0.002 vs. Group2; p=0.05). The QTD was significantly decreased in Group 1 (p<0.001). None of the patients experienced any overt ventricular arrhythmia. CONCLUSION: To the best of our knowledge, this study is the first to investigate QT prolongation in a population of COVID-19 patients treated with triple combination therapy. We found that there was a significant decrease in the QTD after the treatment in patients who were taking triple therapy including azithromycin.

Features of patients that died for COVID-19 in a hospital in the south of Mexico: A observational cohort study.

BACKGROUND: Due to the wide spread of SARS-CoV2 around the world, the risk of death in individuals with metabolic comorbidities has dangerously increased. Mexico has a high number of infected individuals and deaths by COVID-19 as well as an important burden of metabolic diseases; nevertheless, reports about features of Mexican individuals with COVID-19 are scarce. The aim of this study was to evaluate demographic features, clinical characteristics and the pharmacological treatment of individuals who died by COVID-19 in the south of Mexico. METHODS: We performed an observational study including the information of 185 deceased individuals with confirmed diagnoses of COVID-19. Data were retrieved from medical records. Categorical data were expressed as proportions (%) and numerical data were expressed as mean ± standard deviation. Comorbidities and overlapping symptoms were plotted as Venn diagrams. Drug clusters were plotted as dendrograms. RESULTS: The mean age was 59.53 years. There was a male predominance (60.1%). The mean hospital stay was 4.75 ± 4.43 days. The most frequent symptoms were dyspnea (88.77%), fever (71.42%) and dry cough (64.28%). Present comorbidities included diabetes (60.63%), hypertension (59.57%) and obesity (43.61%). The main drugs used for treating COVID-19 were azithromycin (60.6%), hydroxychloroquine (53.0%) and oseltamivir (27.3%). CONCLUSIONS: Mexican individuals who died of COVID-19 had shorter hospital stays, higher frequency of shortness of breath, and higher prevalence of diabetes than individuals from other countries. Also, there was a high frequency of off-label use of drugs for their treatment.

Comparative efficacy assessment of antiviral alone and antiviral-antibiotic combination in prevention of influenza-B infection associated complications.

OBJECTIVE: The study aimed to compare the efficacy of antiviral drug alone and antiviral-antibiotic combination therapy in prevention of complications associated with influenza B hospitalized patients. METHOD: Laboratory confirmed influenza B hospitalized patients presented in emergency room after 48 hours of symptoms onset were identified and divided into two groups; Group-1 patients were initiated on Antiviral drug (oseltamivir) alone while Group-2 patients were initiated on Antiviral drug (oseltamivir) in combination with Antibiotic for at least 3 days. Patients were evaluated for different clinical outcomes among both treatment group. RESULTS: A total of 153 and 131 patients were identified for Group-1 and Group-2, respectively. Clinical outcomes such as secondary bacterial infections (20.9%-vs-9.1%; P = 0.031), need of respiratory support (28.7%-vs-12.9%; P = 0.002), length of hospitalization stay (6.57-vs-4.95 days; P = <0.001), incidences of ICU admission (15.7%-vs-7.6%; P = 0.036), early clinical failure (32.6%-vs-16.1%; P = 0.01), and time to clinical stability (4.83-vs-4.1 days; P = 0.001) were found to be statistically less significant (P-value <0.05) for Group-2 patients. CONCLUSION: Early initiation of antibiotic therapy in combination with oseltamivir was found to be more efficacious than oseltamivir alone in prevention of influenza B-associated complications especially in high-risk influenza patients.

Reconstitution of Oseltamivir Capsules for Pediatric Use on a Long-Term Cruise: A Treatment Option.

Influenza is a concerning disease in terms of risk management for cruise passengers during a voyage. Currently, cruise passengers include children in addition to elderly people. Oral oseltamivir can be used to treat pediatric influenza. In addition, early antiviral treatment may reduce the spread of influenza on board. However, the capsule form of oseltamivir is not of the recommended dosage for children. In this report, we describe 2 siblings who acquired influenza during travel on a world cruise ship and were treated with decapsulated oseltamivir. The siblings' mother was instructed to decapsulate a 75 mg oseltamivir capsule, suspend the powder in 15 mL of water (5 mg·mL-1), stir well, and administer the required amount of medicine orally to each patient using a syringe. Both patients recovered successfully with no complications. The presented case suggests that suspending decapsulated oseltamivir in water and measuring the required amount with a syringe for orally administration to children with influenza can be a safe treatment strategy in resource-limited settings.

Oseltamivir-Current Dosing Recommendations Reduce the Therapeutic Benefit in Patients With Mild to Moderate Renal Function and/or Large Body Mass: A Review of the Literature With Recommendations to Optimize Dosing, Including the Use of Therapeutic Drug Monitoring.

PURPOSE: Oseltamivir is indicated for the treatment and prophylaxis of influenza infections. Achieving therapeutic concentrations EARLY in the course of the infection impacts greatly on the magnitude of benefit. Oseltamivir is renally cleared and dose reductions are advised for patients with renal impairment. The purpose of this review was to determine whether these dose reductions facilitate the early attainment of therapeutic concentrations. The review also examined the effect of body mass on the same outcome. METHOD: Oseltamivir is administered as a prodrug and converted to the active carboxylate moiety in the liver. Published articles that included oseltamivir carboxylate (OC) pharmacokinetics in patients with renal impairment and those with large body mass were reviewed. Concentrations of OC achieved in the first 24 hours were compared with those from patients with normal renal function and body mass. RESULTS: Studies that informed dosage regimens for patients with mild to moderately impaired renal function focused on attaining steady-state concentrations similar to those observed in patients with normal renal function. They overlooked the importance of achieving therapeutic concentrations EARLY in the course of the infection. As a result, many patients will not attain therapeutic concentrations until too late in the infection. This is also true for patients with a large body mass. CONCLUSIONS: Current dosing advice for oseltamivir in patients with mild to moderate renal impairment and those with a larger body mass are likely to reduce (or even negate) its efficacy. The first dose should be 75 mg for patients with normal body mass and proportionately larger when body mass is larger. Subsequent doses should be reduced in proportion to the degree of renal impairment. Timely therapeutic drug monitoring can provide invaluable dosing (and other) information to the clinician treating patients with influenza and could improve patient outcomes.

Association between oseltamivir use and neuropsychiatric adverse events in influenza patients: a nationwide population-based cohort study.

Background: A potential risk of neuropsychiatric adverse events (NPAEs) of oseltamivir has remained controversial by retrospective cohort studies. This nationwide population-based cohort study aimed to assess the risk of NPAEs in influenza patients undergoing oseltamivir treatment (users) compared with a propensity score-matched cohort of patients not receiving oseltamivir (non-users). Research design and methods: Using the Korean National Health Service-Sample Cohort Database, patients diagnosed with incident influenza during 2003-2013 were divided into two cohorts: oseltamivir users and non-users. We calculated adjusted hazard ratios (aHRs) for the 5-day treatment course with oseltamivir using Cox regression analysis. Results: The incidence rate of NPAEs during 5-day oseltamivir treatment was 0.0029 and 0.0023 in oseltamivir users and non-users, respectively. The risk of NPAEs was different according to age, with an increased risk in patients aged 10-19 years (aHR 2.69, 95% CI 1.05-6.93) and a decreased risk in patients aged 0-9 years (aHR 0.46, 95% CI 0.24-0.88). The non-significant positive associations were observed in patients aged 20-64 years and those aged greater than 65 years. Conclusions: Although the reason for the inverse association in children aged 0-9 years is unknown, oseltamivir could increase the risk of NPAEs for children or adolescents aged greater than 10 years.

Encefalopatía necrotizante aguda asociada a influenza A / Influenza A-associated acute necrotizing encephalopathy

INTRODUCCIÓN: La encefalopatía necrotizante aguda (ENA) es una patología rara, caracterizada por compromiso de conciencia y presencia de múltiples lesiones encefálicas simétricas localizadas principalmente en tá lamo. Se asocia a alta letalidad e importantes secuelas. OBJETIVO: Describir el caso de un paciente escolar con ENA asociada a influenza-A con evolución favorable. CASO CLÍNICO: Paciente de 6 años de edad, con historia de 3 días de evolución de síntomas respiratorios altos asociados a fiebre (39 °C). Veinticuatro horas previo a la consulta destacaba compromiso de conciencia cualicuantitativo. Se realizó punción lumbar con proteinorraquia leve. En resonancia magnética (RM) se identificó focos de restricción a la difusión bilaterales de distribución simétrica, talámicos, en cuerpos mamila res, periacueductales, de tegmento pontino, hipocampales y en ambas cápsulas externas, asociado a componente hemorrágico y edema vasogénico, sugerente de ENA. Recibió tratamiento empírico con metilprednisolona y oseltamivir. Posteriormente, se recibió resultado positivo para virus influenza- AH1. Dado diagnóstico, se decidió administrar inmunoglobulina, evolucionando lento pero favora blemente. Al alta levemente bradipsíquico, con disminución de agudeza visual, lenguaje espontáneo y marcha con apoyo. A los 6 meses de seguimiento presentaba lenguaje y marcha normales, persis tiendo alteración visual a derecha. CONCLUSIÓN: Nuestro paciente presentó una ENA cuyo diagnóstico y manejo oportunos se asociaron a una favorable evolución neurológica en el largo plazo. Si bien la ENA es una patología infrecuente, la morbimortalidad asociada es altísima, por lo que resulta de gran importancia tener un alto grado de sospecha, a fin de solicitar estudio imagenológico dirigido, buscar causas infecciosas relacionadas e iniciar un manejo oportuno.

INTRODUCTION: Acute necrotizing encephalopathy of childhood (ANEC) is a rare disease characterized by alteration of consciousness and multiple symmetric brain lesions mainly involving the thalamus. It presents a high mortality rate and severe sequelae. OBJECTIVE: To describe a school-age patient with influenza A-related ANEC with favorable evolution. CLINICAL CASE: Six-year-old boy with 3 days history of upper respiratory symptoms and fever (39 °C). One day previous to admission, he presented altered state of consciousness. A lumbar puncture was performed, showing a mild increase of protein level in CSF. MRI showed bilateral foci of symmetric restricted signal in the thalamus, mammillary bodies, periaqueductal gray, ventral tegmentum, hippocampus, and in both external capsules, which was compatible with ANEC. The patient received empirical treatment with methylprednisolone and oseltamivir. Subsequently, a positive result was received for influenza. Considering diagnosis and severity of illness, it was decided to administer immunoglobulin. The patient got better slowly but favorably. At discharge, he still was mildly bradypsychic with decreased visual acuity, spontaneous speech and walking with assistance. At 6 months of follow-up, the patient presented normal speech and gait, with persistent visual impairment in the right eye. CONCLUSIONS: Our patient presented ANEC, whose timely diagnosis and management were associated with a favorable neurological evolution in the long term. Although ANEC is an infrequent pathology, it has very high morbidity and mortality rates, so it is very important to have a high degree of suspicion in order to request a targeted imaging study, search for related infectious causes, and start proper treatment.

COVID-19 pandemic and biological therapy in rheumatologic disorders: how to deal with?

The outbreak of coronavirus disease 2019 (COVID-19) has involved more than 159 countries and more than 5 million people worldwide. A 40-year-old man with a history of rheumatoid arthritis treated with prednisolone, Disease-Modifying Anti-Rheumatic Drugs (DMARDs), and biologic agents was admitted with chief complaints of fever, chills, malaise, myalgia, and dyspnea. Chest computed tomography showed bilateral subsegmental atelectasis and diffuse ground-glass opacities in both lungs inducing the suspicion of COVID-19 infection. The oro-nasopharynx swab sample for COVID-19 polymerase chain reaction was positive. In addition to supportive care, lopinavir/ritonavir 400/100 mg twice daily and oseltamivir (75 mg) twice daily were started in combination with a starting dose of hydroxychloroquine (400 mg). The methotrexate dose was decreased, and the dose of prednisolone was increased to 30 mg for 10 days. Azathioprine and adalimumab were continued at previous doses. The use of biologic agents and DMARDs in rheumatic patients is a serious challenge in the COVID-19 pandemic. In conclusion, during the COVID-19 pandemic, due to the key roles of cytokines in the promotion of the disease, the rheumatic patients may benefit from continuing their previous treatment, which may have protective effects.

Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza.

BACKGROUND: The pharmacokinetics and appropriate dose regimens of favipiravir are unknown in hospitalized influenza patients; such data are also needed to determine dosage selection for favipiravir trials in COVID-19. METHODS: In this dose-escalating study, favipiravir pharmacokinetics and tolerability were assessed in critically ill influenza patients. Participants received one of two dosing regimens; Japan licensed dose (1600 mg BID on day 1 and 600 mg BID on the following days) and the higher dose (1800 mg/800 mg BID) trialed in uncomplicated influenza. The primary pharmacokinetic endpoint was the proportion of patients with a minimum observed plasma trough concentration (Ctrough) ≥20 mg/L at all measured time points after the second dose. RESULTS: Sixteen patients were enrolled into the low dose group and 19 patients into the high dose group of the study. Favipiravir Ctrough decreased significantly over time in both groups (p <0.01). Relative to day 2 (48 hrs), concentrations were 91.7% and 90.3% lower in the 1600/600 mg group and 79.3% and 89.5% lower in the 1800/800 mg group at day 7 and 10, respectively. In contrast, oseltamivir concentrations did not change significantly over time. A 2-compartment disposition model with first-order absorption and elimination described the observed favipiravir concentration-time data well. Modeling demonstrated that less than 50% of patients achieved Ctrough ≥20 mg/L for >80% of the duration of treatment of the two dose regimens evaluated (18.8% and 42.1% of patients for low and high dose regimen, respectively). Increasing the favipravir dosage predicted a higher proportion of patients reaching this threshold of 20 mg/L, suggesting that dosing regimens of ≥3600/2600 mg might be required for adequate concentrations. The two dosing regimens were well-tolerated in critical ill patients with influenza. CONCLUSION: The two dosing regimens proposed for uncomplicated influenza did not achieve our pre-defined treatment threshold.

Efficacy comparison of oseltamivir alone and oseltamivir-antibiotic combination for early resolution of symptoms of severe influenza-A and influenza-B hospitalized patients.

OBJECTIVES: To assess the comparative efficacy of oseltamivir alone and oseltamivir-antibiotic therapy for early relief of symptoms associated with severe influenza-A (non-H1N1) and influenza-B infection hospitalized patients. METHODS: In this retrospective multicenter study conducted from 2016-2019, enrolled patients were divided into 2 treatment groups. Group 1 patients were started on Antiviral drug (oseltamivir) alone therapy. Group 2 patients were initiated on Antiviral drug (oseltamivir) in combination with Antibiotic therapy. Using acute respiratory illness scoring, symptom severity score was assessed daily for 8 symptoms namely, fever, fatigue, headache, cough, sore throat, wheezing, muscle ache and nasal congestion. For each symptom the severity was scored from scale 0-3. Results: Overall mean ARI severity score was statistically significantly lower (p less than 0.05) on day 2 (14.65-vs-13.68), day 3 (12.95-vs-11.67) and day 4 (10.31-vs-9.12 ) for influenza-A (non-H1N1) while day 3 (12.52-vs-11.87) and day 4 (11.21-vs-10.18) for influenza-B patients for patients who were initiated on oseltamivir-antibiotic combination therapy. Fever, cough and nasal congestion showed statistically significant improvement within 4 days of initiation of combination treatment. Fatigue, sore throat and muscle ache improvement pattern was same for both treatment protocols. CONCLUSION: Oseltamivir-antibiotic combination treatment showed early resolution of some symptoms with cumulatively reduced mean symptom severity score in severe influenza infection hospitalized patients.

Pharmacokinetics of the Monoclonal Antibody MHAA4549A Administered in Combination With Oseltamivir in Patients Hospitalized With Severe Influenza A Infection.

MHAA4549A is a human anti-influenza A monoclonal antibody developed to treat influenza A. We report MHAA4549A serum, nasopharyngeal, and tracheal aspirate pharmacokinetics from a phase 2b study in hospitalized patients with severe influenza A. Patients were randomized 1:1:1 into 3 groups receiving single intravenous doses of 3600 mg (n = 55) or 8400 mg (n = 47) MHAA4549A or placebo (n = 56). Patients also received oral oseltamivir twice daily for ≥5 days. Serum, nasopharyngeal, and tracheal aspirate pharmacokinetic samples were collected on days 1-60 from MHAA4549A-treated groups. Day 5 plasma samples from all groups were collected for assessing the pharmacokinetics of oseltamivir and its active metabolite, oseltamivir carboxylate. Noncompartmental pharmacokinetic analysis was performed using Phoenix WinNonlin. Data were collected during a preplanned interim analysis that became final when the trial terminated because of a lack of efficacy. Serum MHAA4549A concentrations were dose-proportional and biphasic. Mean MHAA4549A clearance was 288-350 mL/day, and mean half-life was 17.8-19.0 days. Nasopharyngeal MHAA4549A concentrations were non-dose-proportional. We detected MHAA4549A in tracheal aspirate samples, but intersubject variability was high. MHAA4549A serum and nasopharyngeal exposures were confirmed in all MHAA4549A-treated patients. Serum MHAA4549A had faster clearance and a shorter half-life in influenza A-infected patients compared with healthy subjects. MHAA4549A detection in tracheal aspirate samples indicated exposure in the lower respiratory tract. Oseltamivir and oseltamivir carboxylate exposures were similar between MHAA4549A-treated and placebo groups, suggesting a lack of MHAA4549A interference with oseltamivir pharmacokinetics.

Combinatory Treatment with Oseltamivir and Itraconazole Targeting Both Virus and Host Factors in Influenza A Virus Infection.

Influenza virus infections and their associated morbidity and mortality are a major threat to global health. Vaccination is an effective influenza prevention measure; however, the effectiveness is challenged by the rapid changes in the influenza virus genome leading to viral adaptation. Emerging viral resistance to the neuraminidase inhibitor oseltamivir limits the treatment of acute influenza infections. Targeting influenza virus­host interactions is a new and emerging field, and therapies based on the combination of virus­ and host­directed drugs might significantly improve treatment success. We therefore assessed the combined treatment with oseltamivir and the repurposed antifungal drug itraconazole on infection of polarized broncho­epithelial Calu-3 cells with pdm09 or Panama influenza A virus strains. We detected significantly stronger antiviral activities in the combined treatment compared to monotherapy with oseltamivir, permitting lower concentrations of the drug than required for the single treatments. Bliss independence drug interaction analysis indicated that both drugs acted independently of each other. The additional antiviral effect of itraconazole might safeguard patients infected with influenza virus strains with heightened oseltamivir resistance.