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Articles by G. Hoffmann
Total Records ( 2 ) for G. Hoffmann
  S. S. Jhee , M. Yen , L. Ereshefsky , M. Leibowitz , M. Schulte , B. Kaeser , L. Boak , A. Patel , G. Hoffmann , E. P. Prinssen and C. R. Rayner
  Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [Cmax], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean Cmax, 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding Cmax CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.
  C. Freichel , E. Prinssen , G. Hoffmann , L. Gand , M. Beck , T. Weiser and A. Breidenbach
  In order to support the potential use of the antiviral oseltamivir in children aged <1 year, a non-clinical study was undertaken to identify any potential behavioral and other effects of supratherapeutic doses of oseltamivir in juvenile rats in relation to plasma and brain drug exposure levels. Separate toxicology and toxicokinetic cohorts of 7-day old rats were divided into paired treatment groups such that individual dose groups from both cohorts received either vehicle or single oral doses of oseltamivir at 300, 500, 600, 700, 850 and 1000 mg kg-1. All rats were observed twice daily for mortality and moribundity. Approximately 2 h after dosing, modified Functional Observational Battery (FOB) data were recorded for all dose groups in the toxicology cohort and clinical observations were performed in the toxicokinetic cohort for changes in posture, convulsions and tremors. Blood and brain samples were taken from the second cohort for toxicokinetic analysis. Post-necropsy assessments included microscopic examination of brain tissue. Young adult rats (aged approximately 6 weeks) were also included in the study (1000 mg kg-1 single oral dose only) for comparison of oseltamivir toxicokinetics. No effects on FOB parameters were recorded at 300 mg kg-1. At 500 and 600 mg kg-1, changes noted in the FOB were inconclusive because of inconsistent responses in the control group. Following doses of ≥600 mg kg-1, drug-related changes indicative of non-specific systemic toxicity were noted. Therefore, the in-life assessments did not identify any specific CNS behavior that would predict toxicity in these very young animals. Necropsy revealed no histological changes at any dose level evaluated. Compared to levels following therapeutic doses, very high oseltamivir and oseltamivir carboxylate plasma concentrations of up to approximately 42,000 and 9000 ng mL-1, respectively, were already observed at the lowest dose of 300 mg kg-1 in juvenile rats. For all dose levels, the ratios of the oseltamivir and oseltamivir carboxylate concentrations in brain to those in plasma were low (≤0.3). The no observed effect level for single-dose oseltamivir was 300 mg kg-1, which, because of the very high oseltamivir and oseltamivir carboxylate plasma levels, suggests a wide safety margin in children younger than 1 year old.
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