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Title: Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children
Authors: Kulkanya Chokephaibulkit
Tim R. Cressey
Edmund Capparelli
Virat Sirisanthana
Petronella Muresan
Suchat Hongsiriwon
Chaiwat Ngampiyaskul
Chanin Limwongse
Orasri Wittawatmongkol
Linda Aurpibul
Bill Kabat
Mari Pat Toye
Mary Elizabeth Smith
Achara Eksaengsri
Kenneth McIntosh
Ram Yogev
Mahidol University
Chiang Mai University
Harvard School of Public Health
IRD Institut de Recherche pour le Developpement
University of California, San Diego
Chonburi Regional Hospital
Prapokklao Hospital
Ann & Robert H. Lurie Children's Hospital of Chicago
Baystate Medical Center
National Institute of Allergy and Infectious Diseases
Thailand Government Pharmaceutical Organization
Children's Hospital Boston
Keywords: Medicine;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 19-Dec-2011
Citation: Antiviral Therapy. Vol.16, No.8 (2011), 1287-1295
Abstract: Background: Alternatives to the available stavudine-containing paediatric fixed-dose combination (FDC) tablets are rapidly needed due to concerns regarding the cumulative toxicity of long-term stavudine exposure. We report the bioavailability and short-term safety of a novel paediatric FDC tablet of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP; 30/15/28 mg) in HIV-infected children. Methods: In this Phase I/II open-label pharmacokinetic study, 42 children weighing 6-30 kg treated with NVP-based HAART for ≥4 weeks were randomized to receive the FDC tablets (GPO-VIR Z30) or the liquid formulations. Dosing was weight-based. Intensive 12-h blood sampling was performed after 2 weeks; subjects then crossed-over to the alternate formulation at equal doses and sampling repeated 2 weeks later. Pharmacokinetic parameters were determined by non-compartmental analysis. Buccal-swab samples were collected for cytochrome P450 (CYP)2B6 polymorphism analysis. Results: With the FDC tablet, the geometric mean (90% CI) area under the curve (AUC) for ZDV, 3TC and NVP was 1.58 (1.49-1.68), 7.78 (7.38-8.19) and 68.88 (62.13-76.36) μg·h/ml, respectively. Rules for NVP therapeutic inadequacy were defined a priori, and despite lower NVP exposure with the tablet (P < 0.001), the levels remained therapeutically adequate. ZDV AUC was similar between formulations. 3TC exposure was significantly higher with the tablet but comparable to historical data in adults and children taking branded tablets. While receiving the tablet, NVP AUC in children with CYP2B 516 GG (45%), GT (45%) and TT (10%) genotypes were 67.0, 74.5 and 106.4 μg·h/ml, respectively (P=0.04). Conclusions: Disparities in drug exposure between formulations were observed; however, the FDC tablet delivered therapeutically adequate exposures of each drug and could well play an important role in simplifying antiretroviral treatment for children. ©2011 International Medical Press.
ISSN: 13596535
Appears in Collections:Scopus 2011-2015

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