Low Penetration of Oseltamivir and Its Carboxylate into Cerebrospinal Fluid in Healthy Japanese and Caucasian Volunteers

Jhee, S. S.; Yen, Mark; Ereshefsky, Larry; Leibowitz, Mark; Schulte, M.; Kaeser, B; Boak, Lauren; Patel, Anand C.; Hoffmann, Gerhard; Prinssen, Eric; Rayner, Craig R.

doi:10.1128/aac.00327-08

Cited by 53 publications

(47 citation statements)

References 29 publications

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“…A report of a case [9] failed to demonstrate the presence of oseltamivir or its metabolite, oseltamivir carboxylate, in the cerebrospinal fluid after administration to a patient with encephalitis. In the same way, another study [10] in healthy adult volunteers found a low penetration of oseltamivir into cerebrospinal fluid. These findings call into question the role of oseltamivir: it is not clear whether the treatment resulted in any clinical improvement or whether the neurologic symptoms were self-limited [11].…”

Section: Discussionmentioning

confidence: 80%

Novel influenza A (H1N1) encephalitis in a 3-month-old infant

et al. 2010

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Seasonal influenza virus infection has been associated with a variety of neurologic complications. We report a case of novel influenza A (H1N1) encephalitis in an infant aged 3 months with an upper respiratory infection, who presented seizures. The infection was confirmed in nasopharyngeal aspirate and cerebrospinal fluid. Treatment with oseltamivir was started. He was discharged without any neurologic sequelae.

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Section: Discussionmentioning

confidence: 80%

Novel influenza A (H1N1) encephalitis in a 3-month-old infant

et al. 2010

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“…This degree of CSF penetration is similar to that observed among healthy patients, with a Cmax CSF/plasma concentration ratio of 3.5% (at ≈8 hours), and a ratio of ≈10% at 18 hours (concentration-time profi les for plasma/CSF differ). Assuming a similar ratio, the CSF OP concentration would have fallen below the assay's detection limit (0.25 ng/mL) by 18 hours (11,15). The low CSF drug-penetration, together with high cytokines in CSF and symptom progression despite drug withdrawal suggest that the manifestations of patient 3 may have been diseaserelated.…”

Section: Discussionmentioning

confidence: 99%

Acute Encephalopathy Associated with Influenza A Infection in Adults

Lee¹,

Wong²,

Chan³

et al. 2010

Emerg. Infect. Dis.

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“…CSF : plasma ratios (based on AUC) averaged 2.4% and 2.9% for the parent and metabolite, respectively. [60] In a 10-year-old with influenza B encephalitis, CSF samples obtained 3 hours after the last steady-state dose (75 mg twice daily) showed no measurable parent or metabolite despite concurrent plasma concentrations of 6.9 ng mL and 401 ng mL, respectively. [61] Finally, analysis of oseltamivir in autopsy specimens from a 13-year-old boy who fell to his death from a nine-storey building (after a single 75 mg dose) similarly revealed no measurable oseltamivir carboxylate in the CNS, although measurable concentrations were observed in the blood (1.4-1.7 mg mL, liver (18.3 mg g), kidney (3.4 mg g), and urine (14.3 mg mL).…”

Section: Distributionmentioning

confidence: 98%

“…Grey boxes with a solid border reflect the range, and grey boxes with a dashed border reflect 2 standard deviations. Closed circles represent the mean of discrete cohorts within independent adult studies [10][11][12]30,31,49,50,60,85,[96][97][98][99]. MW = molecular weight.…”

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confidence: 99%

Pharmacologic Considerations for Oseltamivir Disposition

2011

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Across much of the world, pandemic H1N1 infection has produced a significant healthcare crisis, reflected in significant morbidity and mortality. Statistics reveal that infection-associated deaths among individuals without pre-existing conditions (e.g. immunosuppression) are clustered in pregnant women and young infants. In developing countries where the availability of influenzae vaccine is limited, the only currently available pharmacologic counter-measure for H1N1 disease is oseltamivir, a neuraminidase inhibitor with excellent in vitro activity against the virus. This drug is available in oral solid and liquid formulations, has excellent peroral bioavailability in adults, and generally has a very favorable safety profile. Many observational studies indicate that oseltamivir treatment is associated with symptomatic improvement in pediatric patients with H1N1 infection and, therefore, is considered to represent a viable therapeutic option for use in children. However, the disposition of the ethyl ester prodrug and its active metabolite has not been well characterized in infants and children. Presently, data are available from only two published investigations and preliminary summary information from a recent presentation of an ongoing study. Given that recent in vitro data support the importance of a target exposure-response profile for the active metabolite of oseltamivir and that many processes known to modulate drug disposition have a developmental basis, understanding the potential impact of age on oseltamivir disposition becomes crucial in the development of age-appropriate dosing regimens for the drug. In this review, the impact of ontogeny on processes that are important in regulating the absorption, distribution, metabolism, and excretion of oseltamivir and its active metabolite are considered. Data from both animal and human investigations are presented in the context of defining how development might influence the dose-exposure relationship and, most importantly, the significant variability associated with it. In addition, the available pediatric pharmacokinetic data for oseltamivir and its active metabolite are summarized and current 'information gaps' deserving of future study are presented.

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Low Penetration of Oseltamivir and Its Carboxylate into Cerebrospinal Fluid in Healthy Japanese and Caucasian Volunteers

Cited by 53 publications

References 29 publications

Novel influenza A (H1N1) encephalitis in a 3-month-old infant

Novel influenza A (H1N1) encephalitis in a 3-month-old infant

Acute Encephalopathy Associated with Influenza A Infection in Adults

Pharmacologic Considerations for Oseltamivir Disposition

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