Antiviral therapy · 2011
Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children.
Клиническое исследование I фазыКлиническое исследование II фазыСтатьяМногоцентровое исследованиеРандомизированное исследованиеПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Chokephaibulkit Kulkanya, Cressey Tim R, Capparelli Edmund, Sirisanthana Virat, Muresan Petronella, Hongsiriwon Suchat, Ngampiyaskul Chaiwat, Limwongse Chanin, Wittawatmongkol Orasri, Aurpibul Linda, Kabat Bill, Toye MariPat, Smith Mary Elizabeth, Eksaengsri Achara, McIntosh Kenneth, Yogev Ram, IMPAACT P1069 Team
Аннотация
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.
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.
Предметные рубрики MeSH
Anti-HIV AgentsArea Under CurveAryl Hydrocarbon HydroxylasesBiological AvailabilityBody WeightChildChild, PreschoolCytochrome P-450 CYP2B6Drug Administration ScheduleDrug CombinationsDrug Dosage CalculationsDrug Therapy, CombinationDrug-Related Side Effects and Adverse ReactionsFemaleHIVHIV InfectionsHumansInfantLamivudineMaleNevirapineOxidoreductases, N-DemethylatingReverse Transcriptase InhibitorsTabletsZidovudine