key: cord-0005892-eonedz8q
authors: Kromdijk, W.; Sikma, M. A.; van den Broek, M. P. H.; Beijnen, J. H.; Huitema, A. D. R.; de Lange, D. W.
title: Pharmacokinetics of oseltamivir carboxylate in critically ill patients: each patient is unique
date: 2013-02-27
journal: Intensive Care Med
DOI: 10.1007/s00134-013-2851-x
sha: 87935d98c14092ed0cd279892ef43f2dd8aafc52
doc_id: 5892
cord_uid: eonedz8q

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Dear Editor, Patients infected with the 2009 H1N1 pandemic influenza virus often develop severe viral pneumonia with acute respiratory distress syndrome (ARDS) and multiple organ failure. High-dose oseltamivir (C150 mg twice daily) has been advocated as optimal treatment [1] . However, the scientific evidence for this advice is lacking thus far [2] . Therefore, we explored the pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate in critically ill patients with H1N1 pandemic influenza following different dosing regimens.

All patients with H1N1 pandemic influenza admitted to the ICU of the University Medical Center Utrecht were eligible for inclusion. Patients received oseltamivir at a dose determined by their treating physician, and blood samples were drawn at t = 0, 1, 2, 3, 4 and 8 h on day three of treatment. Oseltamivir and oseltamivir carboxylate plasma concentrations were determined by HPLC-MS/MS [3] . The area under the concentration-time curve from 0 to 8 h (AUC 0-8 ) was estimated using noncompartmental analysis. Patient characteristics were obtained from the patient files.

Six patients were included in the analysis ( Table 1) . All patients had ARDS due to H1N1 pneumonitis. Additionally, patient 1 had a pulmonary embolism, patient 2 had kidney failure caused by multiple renal cysts and received continuous venovenous hemofiltration (CVVH; blood flow 200 mL/min, ultrafiltrate flow 2 L/h), patient 3 had received stem cell transplantation and suffered from pulmonary aspergillosis, patient 4 was 29 weeks pregnant (a cesarean section was performed a few hours before sampling), patient 5 was on extracorporeal membrane oxygenation, and patient 6 had newly diagnosed hairy cell leukemia and renal failure for which CVVH was started the day after sampling. The pharmacokinetic parameters, as well as the prescribed dose, were widely variable ( previous studies, tremendous carboxylate levels were found in a patient with decreased renal function, and doubling of the dose resulted in doubling of the exposure [2, 4] . However, if the standard dose of 75 mg twice daily had been administered to patient 4, exposure might have been below the previously established target AUC. This might be caused by an increased apparent distribution volume and an increased clearance during pregnancy, since the glomerular filtration rate may be increased by 50 % [5] . Additionally, a dose of 75 mg once daily resulted in adequate carboxylate exposure during CVVH (patient 2) in which up to fivefold increased AUCs have previously been observed [2] . This study showed conclusively that in critically ill patients dosing should be based upon the characteristics and knowledge of organ function in the individual patient: a oseltamivir dose of 150 mg twice daily is required during pregnancy, while 75 mg once daily results in adequate carboxylate exposure in patients with renal failure receiving CVVH. Monitoring oseltamivir carboxylate AUCs may optimize therapy in critically ill patients in whom pharmacokinetics are highly variable and unpredictable.

Guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza

Quantitative determination of oseltamivir and oseltamivir carboxylate in human fluoride EDTA plasma including the ex vivo stability using high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry

Oseltamivir in seasonal, avian H5N1 and pandemic 2009 A/H1N1 influenza: pharmacokinetic and pharmacodynamic characteristics

Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach

Louwesweg 6, 1066 EC Amsterdam, The Netherlands e-mail: wiete.kromdijk@slz