title: Optimization of the strength of the efavirenz/lamivudine/abacavir fixed-dose combination for paediatric patients.
abstract: Child-friendly, low-cost, solid, oral fixed-dose combinations (FDCs) of efavirenz with lamivudine and abacavir are urgently needed to improve clinical management and drug adherence for children.
  
  
  
  Data were pooled from several clinical trials and therapeutic drug monitoring datasets from different countries. The number of children/observations was 505/3667 for efavirenz. Population pharmacokinetic analyses were performed using a non-linear mixed-effects approach. For abacavir and lamivudine, data from 187 and 920 subjects were available (population pharmacokinetic models previously published). Efavirenz/lamivudine/abacavir FDC strength options assessed were (I) 150/75/150, (II) 120/60/120 and (III) 200/100/200 mg. Monte Carlo simulations of the different FDC strengths were performed to determine the optimal dose within each of the WHO weight bands based on drug efficacy/safety targets.
  
  
  
  The probability of being within the target efavirenz concentration range 12 h post-dose (1-4 mg/L) varied between 56% and 60%, regardless of FDC option. Option I provided a best possible balance between efavirenz treatment failure and toxicity risks. For abacavir and lamivudine, simulations showed that for option I >75% of subjects were above the efficacy target.
  
  
  
  According to simulations, a paediatric efavirenz/lamivudine/abacavir fixed-dose formulation of 150 mg efavirenz, 75 mg lamivudine and 150 mg abacavir provided the most effective and safe concentrations across WHO weight bands, with the flexibility of dosage required across the paediatric population.
authors: EA7323, Université Paris Descartes, Sorbonne Paris Cité, Paris, France naim.bouazza@aphp.fr.|Unité de Recherche Clinique Necker Cochin, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.|CIC-1419 Inserm, Paris, France.
authors: Naïm
authors: N
authors: Bouazza
authors: Program for HIV Prevention and Treatment (PHPT/IRD UMI 174), Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.|Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.|Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors: Tim R
authors: TR
authors: Cressey
authors: EA7323, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Necker Cochin, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.|CIC-1419 Inserm, Paris, France.
authors: Frantz
authors: F
authors: Foissac
authors: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors: Andrzej
authors: A
authors: Bienczak
authors: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors: Paolo
authors: P
authors: Denti
authors: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors: Helen
authors: H
authors: McIlleron
authors: Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: David
authors: D
authors: Burger
authors: HIV Department, World Health Organization, Geneva, Switzerland.
authors: Martina
authors: M
authors: Penazzato
authors: Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
authors: Marc
authors: M
authors: Lallemant
authors: University of California San Diego, La Jolla, CA, USA.
authors: Edmund V
authors: EV
authors: Capparelli
authors: EA7323, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Necker Cochin, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.|CIC-1419 Inserm, Paris, France.
authors: Jean-Marc
authors: JM
authors: Treluyer
authors: EA7323, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Unité de Recherche Clinique Necker Cochin, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.|CIC-1419 Inserm, Paris, France.
authors: Saïk
authors: S
authors: Urien
mesh_terms: D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D048588:Benzoxazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D019259:Lamivudine / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008962:Models, Theoretical; D055815:Young Adult; D000099227:Abacavir
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D004338:Drug Combinations; D019259:Lamivudine; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir; C098320:efavirenz