Browsing by Author "Ram Yogev"

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    A chewable pediatric fixed-dose combination tablet of stavudine, lamivudine, and nevirapine: Pharmacokinetics and safety compared with the individual liquid formulations in human immunodeficiency virus-infected children in Thailand
    (2010-01-01) Nirun Vanprapar; Tim R. Cressey; Kulkanya Chokephaibulkit; Petronella Muresan; Nottasorn Plipat; Virat Sirisanthana; Wasana Prasitsuebsai; Suchat Hongsiriwan; Tawee Chotpitayasunondh; Achara Eksaengsri; Maripat Toye; Mary Elizabeth Smith; Kenneth McIntosh; Edmund Capparelli; Ram Yogev; Mahidol University; Chiang Mai University; Harvard School of Public Health; University of Michigan School of Public Health; Chonburi Regional Hospital; Queen Sirikit National Institute of Child Health; Thailand Government Pharmaceutical Organization; Baystate Medical Center; National Institute of Allergy and Infectious Diseases; Children's Hospital Boston; University of California, San Diego; Ann & Robert H. Lurie Children's Hospital of Chicago
    Background: Pediatric fixed-dose combinations (FDCs) are needed to facilitate antiretroviral therapy in children. We evaluated the relative bioavailability, safety, and therapeutic adequacy of a novel chewable pediatric FDC tablet of stavudine (7 mg), lamivudine (30 mg), and nevirapine (50 mg), referred to as GPO-VIR S7, and compared it with the individual original brand-name liquid formulations in human immunodeficiency virus-infected Thai children. Methods: The International Maternal Pediatric Adolescent AIDS Clinical Trials group (IMPAACT) P1056 study was a phase I/II, 2-arm, randomized, open-label, multidose pharmacokinetic cross-over study. Children ≥6 to ≤30 kg receiving nevirapine-based HAART for at least 4 weeks were randomized to receive GPO-VIR S7 chewable tablets or the equivalent liquid formulations. Children were stratified by weight and dosing was weight-based. Intensive 12-hour blood sampling was performed on day 28, and subjects then crossed-over to the alternate formulation at equal doses with identical 12-hour sampling on day 56. Pharmacokinetic indices were determined by noncompartmental analysis. Results: Thirty-four children completed the study. While taking Government Pharmaceutical Organization (GPO)-VIR S7 the geometric mean (90% CI) area under the curve was 1.54 μg•hr/mL (1.42-1.67) for stavudine, 6.39 (5.82-7.00) for lamivudine, and 74.06 (65.62-83.60) for nevirapine. Nevirapine drug exposure for GPO-VIR S7 was therapeutically adequate. Geometric mean area under the curve ratios (90% CI) of GPO-VIR S7/liquid formulation for stavudine, lamivudine, and nevirapine were 0.97 (0.92-1.02), 1.41 (1.30-1.53), and 1.08 (1.04-1.13), respectively. No serious drug-related toxicity was reported. Conclusions: The chewable FDC was safe and provided therapeutically adequate plasma drug exposures in human immunodeficiency virus-infected children. Substituting the FDC for liquid formulations can simplify antiretroviral therapy. © 2010 by Lippincott Williams & Wilkins.
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    Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children
    (2011-12-19) 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
    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.
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    Rapid human immunodeficiency virus decay in Highly Active Antiretroviral Therapy (HAART)-experienced children after starting mega-HAART
    (2004-10-01) Nottasorn Plipat; Ping K. Ruan; Terence Fenton; Ram Yogev; Mahidol University; Harvard School of Public Health; Ann & Robert H. Lurie Children's Hospital of Chicago
    Increasing numbers of patients are treated with mega-highly active antiretroviral therapy (HAART), or multiple-combination antiretroviral therapy, in an attempt to overcome the viral resistance that has contributed to treatment failure. Studies of human immunodeficiency virus (HIV) viral dynamics are used to quantify the potency of a given regimen. While mega-HAART is expected to provide potent therapy, its potency among heavily experienced HIV-infected children who have failed previous treatment is untested. HIV dynamics studies performed in children have provided minimal information on viral dynamics during mega-HAART. The present study estimates first- and second-phase viral dynamics in six children on mega-HAART, following failure of combination therapy. The first phase of viral decay was rapid, relative to rates reported in previous pediatric studies (median δ = 0.778d-1 range = 0.583 to 1.088, half-life 1 [t11/2] = 0.894d), while the second phase revealed results similar to those of previous studies (median μ = 0.026d-1, range = -0.005 to 0.206, t21/2 = 9.316d). This indicates that mega-HAART can provide potent therapy among heavily experienced pediatric patients.