title: 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.
abstract: 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.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Nirun
authors.initials: N
authors.lastname: Vanprapar
authors.forename: Tim R
authors.initials: TR
authors.lastname: Cressey
authors.forename: Kulkanya
authors.initials: K
authors.lastname: Chokephaibulkit
authors.forename: Petronella
authors.initials: P
authors.lastname: Muresan
authors.forename: Nottasorn
authors.initials: N
authors.lastname: Plipat
authors.forename: Virat
authors.initials: V
authors.lastname: Sirisanthana
authors.forename: Wasana
authors.initials: W
authors.lastname: Prasitsuebsai
authors.forename: Suchat
authors.initials: S
authors.lastname: Hongsiriwan
authors.forename: Tawee
authors.initials: T
authors.lastname: Chotpitayasunondh
authors.forename: Achara
authors.initials: A
authors.lastname: Eksaengsri
authors.forename: MariPat
authors.initials: M
authors.lastname: Toye
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Smith
authors.forename: Kenneth
authors.initials: K
authors.lastname: McIntosh
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.forename: Ram
authors.initials: R
authors.lastname: Yogev
mesh_terms: D000284:Administration, Oral; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D019259:Lamivudine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D019829:Nevirapine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry; D018119:Stavudine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D013607:Tablets / Q000008:administration & dosage / Q000009:adverse effects; D013785:Thailand
chemical_list: D019380:Anti-HIV Agents; D013607:Tablets; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine
references.citation: Clin Infect Dis. 2005 Jul 1;41(1):100-7
references.pmid: 15937769
references.citation: Int J Infect Dis. 2008 Nov;12(6):e33-8
references.pmid: 18573672
references.citation: Antimicrob Agents Chemother. 2001 Mar;45(3):758-63
references.pmid: 11181356
references.citation: Pediatrics. 2004 Aug;114(2):e235-42
references.pmid: 15286262
references.citation: Clin Pharmacol Ther. 2007 Apr;81(4):517-20
references.pmid: 17329994
references.citation: Pediatr Infect Dis J. 2009 Mar;28(3):246-8
references.pmid: 19165130
references.citation: AIDS. 2001 Jun 15;15(9):1089-95
references.pmid: 11416710
references.citation: J Infect Dis. 1993 Jan;167(1):21-9
references.pmid: 8093363
references.citation: AIDS. 2003 Jul 25;17(11):1639-47
references.pmid: 12853746
references.citation: Clin Pharmacokinet. 2003;42(6):599-605
references.pmid: 12793844
references.citation: J Acquir Immune Defic Syndr. 2006 Feb 1;41(2):131-6
references.pmid: 16394842
references.citation: Ther Drug Monit. 2003 Jun;25(3):393-9
references.pmid: 12766571
references.citation: Pediatr Infect Dis J. 2007 Oct;26(10):953-6
references.pmid: 17901804
references.citation: Ther Drug Monit. 2006 Jun;28(3):367-74
references.pmid: 16778721
references.citation: AIDS. 2006 Oct 3;20(15):1955-60
references.pmid: 16988517
references.citation: J Infect Dis. 1996 Oct;174(4):713-21
references.pmid: 8843207
references.citation: AIDS. 2008 Mar 12;22(5):557-65
references.pmid: 18316996
references.citation: AIDS. 2007 Jan 2;21(1):59-64
references.pmid: 17148968
references.citation: AIDS. 2005 Sep 23;19(14):1495-9
references.pmid: 16135903
references.citation: Clin Pharmacokinet. 2001;40(9):695-700
references.pmid: 11605717
references.citation: AIDS Res Hum Retroviruses. 2002 Aug 10;18(12):825-34
references.pmid: 12201904
references.citation: Clin Pharmacokinet. 1999 Jan;36(1):41-66
references.pmid: 9989342
references.citation: Ann Pharmacother. 2005 Apr;39(4):603-9
references.pmid: 15713788