Kalayanee Chairat (1), Nguyen Van Kinh (2), Nguyen van Vinh Chau (3), Nguyen Thanh Liem (4), Truong Huu Khanh (5), Ha Manh Tuan (6), Peter Horby (7, 14), Charoen Chuchottaworn (8), Laura Merson (9), Ninh Thi Thanh Van (9), Vu Thi Lan Huong (9), Chariya Sangsajja (10), Tawee Chotpitayasunondh (11), Kulkanya Chokephaibulkit (12), Pilaipan Puthavathana (12), Wirongrong Chierakul (13), Bob Taylor (1, 14), Heiman Wertheim (7, 14), Tran Tinh Hien (9, 14), H. Rogier van Doorn (9, 14), Pham Van Toi (9), Nicholas P. Day (1, 14), Jeremy Farrar (9, 14), Nicholas J. White (1, 14), Joel Tarning (1, 14).
(1) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. (2) National Institute of Infectious and Tropical Diseases, Hanoi, Vietnam. (3) Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. (4) National Hospital of Pediatrics, Hanoi, Vietnam. (5) Pediatric Hospital No.1, Ho Chi Minh City, Vietnam. (6) Pediatric Hospital No.2, Ho Chi Minh City, Vietnam. (7) Oxford University Clinical Research Unit, National Hospital of Tropical Diseases, Hanoi, Viet Nam. (8) Chest Disease Institute, Nonthaburi, Thailand. (9) Oxford University Clinical Research Unit, Hospital of Tropical Diseases, Ho Chi Minh City, Vietnam. (10) Bamrasnaradura Infectious Disease Institute, Ministry of Public Health, Nonthaburi, Thailand. (11) Queen Sirikit National Institute of Child Health, Ministry of Public Health, Bangkok, Thailand. (12) Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (13) Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. (14) Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom.
Objectives: Our objective was to characterize the population pharmacokinetics and pharmacodynamics of oseltamivir and its active metabolite oseltamivir carboxylate in adults and children infected with influenza virus A(H1N1)pdm09.
Methods: Patients over 1 year of age with confirmed influenza virus A(H1N1)pdm09 infection who presented at 12 hospitals in Vietnam and Thailand were treated with oseltamivir at a standard oral dose regimen of 75 mg twice daily for 5 days or an adjusted dosage regimen for patients with renal impairment or children under 15 years of age. All patients with clinical and/or virological failures at day 5 were treated with oseltamivir for an additional 5 days. One hundred adults and 8 children had at least 4 plasma samples collected according to a randomized time schedule during the course of treatment. Forty-three adults and 17 children had only one plasma sample collected at 4 hours after the first dose on Day 3. Blood chemistry, hematology and virological analyses were performed on admission, during the treatment and/or after the treatment. Nonlinear mixed-effects modelling was performed using NONMEM v.7.
Results: The population pharmacokinetic properties of oseltamivir and oseltamivir carboxylate in adults and children with influenza virus A(H1N1)pdm09 infection were described successfully by a simultaneous 2-compartment oseltamivir and 1-compartment oseltamivir carboxylate model. Body weight was incorporated allometrically on all clearance and volume parameters. Patient age affected oseltamivir and oseltamivir carboxylate volume of distribution. Oral clearance of oseltamivir carboxylate decreased linearly with decreasing creatinine clearance. Time to virologically negative nasal and throat swab results were evaluated with a PK/PD time-to-event approach and revealed no statistically significant correlation between drug concentrations and time to viral clearance. Age was found to have an effect on baseline hazard where younger patients needed longer time to clear the virus.
Conclusions: This is the first population pharmacokinetic/pharmacodynamic analysis of oseltamivir and oseltamivir carboxylate in patients infected with the influenza virus A(H1N1)pdm09. The study provides insight into the impact of patient disease, age, and body weight on the pharmacokinetic properties of oseltamivir.
Acknowledgement: This study was collaboration between hospitals in Vietnam and Thailand and undertaken as part of the South East Asia Infectious Disease Clinical Research Network (SEAICRN) supported by Oxford University, the Wellcome Trust (UK) and the National Institutes of Health (USA).
Reference: PAGE 22 () Abstr 2845 [www.page-meeting.org/?abstract=2845]
Poster: Other Drug/Disease Modelling