title: Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children.
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.
authors.affiliation: Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. sikch@mahidol.ac.th
authors.forename: Kulkanya
authors.initials: K
authors.lastname: Chokephaibulkit
authors.forename: Tim R
authors.initials: TR
authors.lastname: Cressey
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.forename: Virat
authors.initials: V
authors.lastname: Sirisanthana
authors.forename: Petronella
authors.initials: P
authors.lastname: Muresan
authors.forename: Suchat
authors.initials: S
authors.lastname: Hongsiriwon
authors.forename: Chaiwat
authors.initials: C
authors.lastname: Ngampiyaskul
authors.forename: Chanin
authors.initials: C
authors.lastname: Limwongse
authors.forename: Orasri
authors.initials: O
authors.lastname: Wittawatmongkol
authors.forename: Linda
authors.initials: L
authors.lastname: Aurpibul
authors.forename: Bill
authors.initials: B
authors.lastname: Kabat
authors.forename: MariPat
authors.initials: M
authors.lastname: Toye
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Smith
authors.forename: Achara
authors.initials: A
authors.lastname: Eksaengsri
authors.forename: Kenneth
authors.initials: K
authors.lastname: McIntosh
authors.forename: Ram
authors.initials: R
authors.lastname: Yogev
mesh_terms: D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis / Q000235:genetics; D001682:Biological Availability; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D065702:Cytochrome P-450 CYP2B6; D004334:Drug Administration Schedule; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D004359:Drug Therapy, Combination / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007223:Infant; D019259:Lamivudine / Q000097:blood* / Q000493:pharmacokinetics; D008297:Male; D019829:Nevirapine / Q000097:blood* / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000032:analysis / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D013607:Tablets; D015215:Zidovudine / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D018894:Reverse Transcriptase Inhibitors; D013607:Tablets; C109078:lamivudine, zidovudine drug combination; D019259:Lamivudine; D015215:Zidovudine; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating