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Br J Clin Pharmacol . Pharmacologic effects of oseltamivir in immunocompromised adult patients as assessed by population PK/PD analysis and drug-disease modeling for dosing regimen optimization

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  • Br J Clin Pharmacol . Pharmacologic effects of oseltamivir in immunocompromised adult patients as assessed by population PK/PD analysis and drug-disease modeling for dosing regimen optimization


    Br J Clin Pharmacol


    . 2020 Aug 17.
    doi: 10.1111/bcp.14523. Online ahead of print.
    Pharmacologic effects of oseltamivir in immunocompromised adult patients as assessed by population PK/PD analysis and drug-disease modeling for dosing regimen optimization


    Stefan Sturm 1 , Annabelle Lemenuel-Diot 1 , Kashyap Patel 2 , Leonid Gibiansky 3 , Rajinder Bhardwaj 2 , Patrick F Smith 2 , Steve Dang 4 5 , Elke Zwanziger 1 , Clare Nasmyth-Miller 6 , Patanjali Ravva 4 7



    Affiliations

    Abstract

    Aim: Pharmacologic effects were analyzed 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 (VK) 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 h of symptom onset had maximum impact, and a treatment duration of 10 days was favorable 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.

    Keywords: Clinical Trials; Immunosuppression; Modeling and Simulation; Pharmacokinetic-Pharmacodynamic; Population Analysis.

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