title: Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis.
abstract: BACKGROUND
  Coadministration of rifampicin dramatically reduces the concentrations of protease inhibitors. A pharmacokinetic study in healthy adults showed that doubling the dose of coformulated lopinavir/ritonavir was able to overcome the inducing effect of rifampicin. We evaluated this strategy in children treated with rifampicin-based antituberculosis therapy attending antiretroviral clinics in South Africa.
  
  
  METHODS
  Plasma concentrations of lopinavir were measured in children (aged 0.64-2.43 years) established on antituberculosis treatment who commenced antiretroviral therapy comprising double the usual recommended dose of lopinavir/ritonavir oral solution (460/115 mg/m(2) twice daily) plus two nucleoside reverse transcriptase inhibitors. Control children (0.57-4.23 years old) without tuberculosis received standard doses of lopinavir/ritonavir (230/57.5 mg/m(2) twice daily).
  
  
  RESULTS
  Pre-dose lopinavir concentrations were reduced by >80% in children with tuberculosis (median 0.7 mg/l, IQR 0.1-2.0) compared with controls (4.2 mg/l, IQR 3.4-8.1; P<0.001) and were below the minimum recommended concentration of 1 mg/l in 12 of 20 (60%) children with tuberculosis versus 2 of 24 (8%) controls (P<0.001).
  
  
  CONCLUSIONS
  Double doses of coformulated lopinavir/ritonavir results in inadequate lopinavir concentrations in young children treated concurrently with rifampicin. Suitable regimens are urgently needed for treating young children with HIV-associated tuberculosis.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. helen.mcilleron@uct.ac.za
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ren
authors.forename: James
authors.initials: J
authors.lastname: Nuttall
authors.forename: Lee
authors.initials: L
authors.lastname: Fairlie
authors.forename: Helena
authors.initials: H
authors.lastname: Rabie
authors.forename: Mark
authors.initials: M
authors.lastname: Cotton
authors.forename: Brian
authors.initials: B
authors.lastname: Eley
authors.forename: Tammy
authors.initials: T
authors.lastname: Meyers
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Concepta
authors.initials: C
authors.lastname: Merry
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002675:Child, Preschool; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006678:HIV; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007223:Infant; D061466:Lopinavir; D008297:Male; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012293:Rifampin / Q000008:administration & dosage* / Q000627:therapeutic use; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013019:South Africa; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D011744:Pyrimidinones; D061466:Lopinavir; D019438:Ritonavir; D012293:Rifampin