Oseltamivir pharmacokinetics in Vietnamese patients with severe human and H5N1 avian influenza.
Session VII – Taylor, Walter RJ
Title of Contribution: Oseltamivir pharmacokinetics in Vietnamese patients with severe human and H5N1 avian influenza.
Author(s):
Walter RJ Taylor1,2, Bui Nghia Thinh3, Giang Thuc Anh3, Peter Horby1,2, Heiman Wertheim1,2, Niklas Lingegardh2,4, Menno D. de Jong 2,5, Kasia Stepniewska2,4, Tran Thuy Hanh3, Nguyen Duc Hien6, Ngo Minh Bien3, Ngo Quy Chau3, Annette Fox1,2, Nguyen Dang Tuan3, Dao Xuan Co3, Nghiem My Ngoc5, Nguyen Thanh Liem7, Luong Thi San7, Phan Huu Phuc7, Ta Anh Tuan7, Martin Crusat5, Jeremy J Farrar2,5, Nicholas J White2,4, Nguyen Hong Ha6, Trinh Thi Lien6, Nguyen Vu Trung6, Nicholas Day2,4, Nguyen Gia Binh MD3.
Affiliation(s):
1 Oxford University Clinical Research Unit, Hanoi, Vietnam; 2 Centre for Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK; 3 Bach Mai hospital, Hanoi, Vietnam; 4 Mahidol Oxford Research Unit, Bangkok, Thailand; 5 Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam; 6 National Institute for Infectious and Tropical Diseases, Hanoi, Vietnam; 7 National Hospital of Paediatrics, Hanoi, Vietnam.
Abstract:
Background Severe (S) human (H) and avian (A) influenza (I) cause predominantly a severe pnemonitis with high mortality despite treatment with oseltamivir (OS). Recommended OS doses are extrapolated from mild influenza and may not be optimal in SI patients who may require haemofiltration (HF) or haemodialysis (HD). Respiratory secretion concentrations of oseltamivir carboxylate (OC), the antiviral metabolite, may be the prime pharmacokinetic (PK) parameter to determine pharmacodynamic (PD) responses but data are lacking in SI.
Methods We measured OS and OC concentrations by HPLC in AI (n=6) and human (n=4) influenza in: (i) blood, (ii) pleural fluid, (iii) endotracheal aspirate. Two (AI, SI) and one (SI) patients were sampled on haemofiltration (45 ml/kg/h) and haemodialysis (220 mls/min, 4 hours), respectively. Patients were treated with 60, 120, 75 or 150 mg 12 hourly. The HD patient received 75 mg intermittently.
Results Steady state, plasma, trough OC concentrations (range 350-2730 ng/ml) and area under the drug concentration time curves (n=3: 5932, 10,951 and 34,670 mg/ml*h) were higher than reported for healthy subjects given the same doses. Despite dose adjustment, the preHD OC concentrations were also high: 3000 to 6280 ng/ml. OC loss via the haemofilter was low (~23% of bioavailable dose) but high (~66%) following HD.
Tracheal aspirate (n=6 samples) concentrations ranged from 10-83 ng/ml for approximate ratios to plasma of 0.05-0.24. Pleural fluid concentrations (n=2) were comparable to plasma (803, 1320 ng/ml). H5N1 (n=1) and H2N3 (n=1) viruses cleared in two patients. Mortality was high 5/6 (AI) and 3/4 (SI).
Interpretation OS was well absorbed and converted to extensively to OC. Tracheal aspirate OC concentrations exceeded the mean, in vitro IC50s for sensitive avian (up to ~3.2 ng/ml) and human (generally ≤ 2 ng/ml) viruses but were lower for resistant H1N1 viruses (up to 278 ng/ml). These preliminary data point to the need for more detailed data and PK PD (viral clearance) analyses to determine optimal oseltamivir dosing.
