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Aims: To optimise the dosing regimen of oseltamivir for immunocompromised (IC) paediatric patients (<18 years) with influenza, we used an extrapolation approach alongside clinical data. Methods: Efficacy was extrapolated from adult IC patients to paediatric IC patients by leveraging existing efficacy, safety, pharmacokinetic (PK)/pharmacodynamic (PD), and disease‐progression models of oseltamivir and oseltamivir carboxylate (OC). Data of IC paediatric patients from two studies (NV25719 and NV20234) were included in the population PK (n = 30), PK/PD analysis (n = 22) and disease modelling approach (n = 36). Simulations were performed to identify the optimal dosing regimen. Results: Clearance of oseltamivir (CL) and OC (CLM) were similar in IC and otherwise‐healthy (OwH) patients <10 years, but decreased by 44.4% (95% CI: 26.8–62.0) and 49.1% (95% CI: 34.5–63.8), respectively, in IC patients aged 10–17 years versus OwH patients. There were no notable exposure–response relationships for any of the virologic PD analyses. Thus, no additional benefit was seen with oseltamivir carboxylate exposures higher than achieved with the conventional dose (75 mg twice daily, age‐ and weight‐adjusted for children <13 years). The disease model illustrated that doses above the conventional oseltamivir dose had limited impact on viral kinetics in IC paediatric patients and a prolonged treatment duration of 10 days was favoured to limit potential viral rebound. Conclusion: An oseltamivir dosage recommendation (conventional dose, twice daily for 10 days) was established in IC paediatric patients with influenza, based on extrapolation of efficacy from IC adults, leveraging population PK, PK/PD, and disease modelling, whilst taking resistance and safety data into account. [ABSTRACT FROM AUTHOR]

Prompt antiviral treatment has the potential to reduce influenza virus transmission to close contacts, but rigorous data on the magnitude of treatment effects on transmission are limited. Animal model data indicate that rapid reductions in viral replication after antiviral treatment reduce the risk of transmission. Observational and clinical trial data with oseltamivir and other neuraminidase inhibitors indicate that prompt treatment of household index patients seems to reduce the risk of illness in contacts, although the magnitude of the reported effects has varied widely across studies. In addition, the potential risk of transmitting drug-resistant variants exists with all approved classes of influenza antivirals. A controlled trial examining baloxavir treatment efficacy to reduce transmission, including the risk of transmitting virus with reduced baloxavir susceptibility, is currently in progress. If reduced transmission risk is confirmed, modeling studies indicate that early treatment could have major epidemiologic benefits in seasonal and pandemic influenza. [ABSTRACT FROM AUTHOR]

Aim: Pharmacologic effects were analysed to determine a dose recommendation for oseltamivir in immunocompromised (IC) adults with influenza. Methods: Quantitative clinical pharmacology methods were applied to data from 160 adult IC patients (aged 18‐78 years) from two studies (NV20234, 150 patients; NV25118, 10 patients) who received oseltamivir 75‐200 mg twice daily for up to 10 days. An established population‐pharmacokinetic (PK) model with additional effects on oseltamivir and oseltamivir carboxylate (OC) clearance described the PK characteristics of oseltamivir in IC patients versus otherwise healthy (OwH) patients from previous clinical trials. Estimated PK parameters were used to evaluate exposure‐response relationships for virologic endpoints (time to cessation of viral shedding, viral load measures and treatment‐emergent resistance). A drug‐disease model characterized the viral kinetics of influenza accounting for the effect of OC on viral production. Results: Oseltamivir clearance was 32.5% lower (95% confidence interval [CI], 26.1‐38.8) and OC clearance was 33.7% lower (95% CI, 23.2‐44.1) in IC versus OwH patients. No notable exposure‐response relationships were identified for exposures higher than those achieved after conventional dose oseltamivir 75 mg, which appeared to be close to the maximum effect of oseltamivir. Simulations of the drug‐disease model predicted that initiating treatment within 48 hours of symptom onset had maximum impact, and a treatment duration of 10 days was favourable over 3‐5 days to limit viral rebound. Conclusions: Our findings support the use of conventional‐dose oseltamivir 75 mg twice daily for 10 days in the treatment of IC adult patients with influenza. [ABSTRACT FROM AUTHOR]

Hepatitis B virus RNA (HBV RNA)–containing particles are encapsidated pre‐genomic RNA (pgRNA) detectable in chronically infected patients in addition to virions (HBV DNA) that have been suggested as a marker of the treatment efficacy. This makes promising the use of core protein allosteric modulators, such as RG7907, which disrupt the nucleocapsid assembly and profoundly reduce HBV RNA. Here, we developed a multiscale model of HBV extending the standard viral dynamic models to analyse the kinetics of HBV DNA and HBV RNA in 35 patients treated with RG7907 for 28 days. We compare the predictions with those obtained in patients treated with the nucleotide analog tenofovir. RG7907 blocked 99.3% of pgRNA encapsidation (range: 92.1%–99.9%) which led to a decline of both HBV DNA and HBV RNA. As a consequence of its mode of action, the first phase of decline of HBV RNA was rapid, uncovering the clearance of viral particles with half‐life of 45 min. In contrast, HBV DNA decline was predicted to be less rapid, due to the continuous secretion of already formed viral capsids (t1/2 = 17 ± 6 h). After few days, both markers declined at the same rate, which was attributed to the loss of infected cells (t1/2 ≅ 6 ± 0.8 days). By blocking efficiently RNA reverse transcription but not its encapsidation, nucleotide analog in contrast was predicted to lead to a transient accumulation of HBV RNA both intracellularly and extracellularly. The model brings a conceptual framework for understanding the differences between HBV DNA and HBV RNA dynamics. Integration of HBV RNA in viral dynamic models may be helpful to better quantify the treatment effect, especially in viral‐suppressed patients where HBV DNA is no longer detectable. [ABSTRACT FROM AUTHOR]

Clinical Development Phases I ‐ III Regulatory, Quality, Manufacturing Mericitabine is the prodrug of RO4995855, a selective inhibitor of the hepatitis C virus (HCV) NS5B polymerase. This study assessed the effect of renal impairment on RO4995855 pharmacokinetics. In this open ‐ label study, HCV ‐ negative volunteers (18 – 75 years) with normal renal function (NRF: creatinine clearance [CLCR] >80 mL/min, n = 10) or stable renal impairment (mild: CLCR 50 – 80 mL/min, n = 10; moderate: CLCR 30 – 49 mL/min, n = 10) received oral mericitabine 1000 mg twice daily (BID) (500 mg BID for moderate renal impairment) for 5 days. Primary outcome measures were renal clearance, maximum plasma concentration (Cmax), and area under the concentration ‐ time curve (0 – 12 h) (AUC0 – 12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC0 – 12 and Cmax in mild renal impairment subjects were 1.45 (90% confidence interval [CI], 1.26 – 1.66) and 1.14 (1.02 – 1.28), respectively. For moderate renal impairment subjects, the dose ‐ normalized GMR for AUC0 – 12 and Cmax relative to NRF subjects were 2.51 (90% CI, 2.19 – 2.88) and 1.76 (1.56 – 1.97), respectively. Renal clearance of RO4995855 declined in subjects with mild/moderate renal impairment following mericitabine. Dose adjustment of mericitabine may be required in patients with moderate renal impairment. [ABSTRACT FROM AUTHOR]