title: Lopinavir/ritonavir plus lamivudine and abacavir or zidovudine dose ratios for paediatric fixed-dose combinations.
abstract: BACKGROUND
  Lopinavir/ritonavir (LPV/r) is available in a liquid formulation that is far from ideal for treatment of children in resource-poor settings. Flexible, low-cost, solid, oral fixed-dose combinations (FDC) of LPV/r with nucleoside reverse transcriptase inhibitors (LPV/r/abacavir [ABC]/lamivudine [3TC] and LPV/r/zidovudine [ZDV]/3TC) are needed to improve both management and adherence of children. This work aimed to develop appropriate drug ratios and dosing for each FDC.
  
  
  METHODS
  Data from 25 combined datasets included therapeutic drug monitoring and clinical studies from IMPAACT and PENTA. Population pharmacokinetic analyses were performed using Monolix. Monte-Carlo simulations of WHO and FDA dosing recommendations were performed to assess their ability to provide optimal exposure in children weighing 4 to 25 kg based on consensus plasma targets. The LPV/r:3TC:ZDV(ABC) dose ratios were 2.67:1:2(2), respectively.
  
  
  RESULTS
  Using WHO dosage, LPV efficacy target was reached in all weight bands. Given the recommended drug ratios, the dosage for the 4-5.9 kg weight band (LPV/ZDV: 120/90 mg twice daily [bid]) showed more than 20% of subjects had ZDV levels at high risk of neutropenia. Reducing the LPV/ZDV dose to 80/60 mg bid decreased frequency of high ZDV concentrations but retained the LPV efficacy criteria.
  
  
  CONCLUSIONS
  This defined a flexible and simple FDC containing 40 mg LPV, 10 mg ritonavir, 15 mg 3TC and 30 mg ABC or ZDV. According to the weight bands defined by WHO, 4-5.9 kg, 6-9.9 kg, 10-13.9 kg, 14-19.9 kg, 20-24.9 kg, therapeutic doses would be 2, 3, 4, 5 or 6 individual units administered by oral route bid.
authors.affiliation: EA 7323, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Naïm
authors.initials: N
authors.lastname: Bouazza
authors.forename: Frantz
authors.initials: F
authors.lastname: Foissac
authors.forename: Floris
authors.initials: F
authors.lastname: Fauchet
authors.forename: David
authors.initials: D
authors.lastname: Burger
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Kiechel
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Treluyer
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
authors.forename: Marc
authors.initials: M
authors.lastname: Lallemant
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000367:Age Factors; D023241:Antiretroviral Therapy, Highly Active; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007223:Infant; D019259:Lamivudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D061466:Lopinavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D015233:Models, Statistical; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019562:Viral Load / Q000187:drug effects; D015215:Zidovudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000099227:Abacavir
chemical_list: D015224:Dideoxynucleosides; D004338:Drug Combinations; D019259:Lamivudine; D061466:Lopinavir; D019438:Ritonavir; D000077385:Silybin; D012838:Silymarin; D015215:Zidovudine; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir