title: Pharmacokinetics and safety of rifabutin in young HIV-infected children receiving rifabutin and lopinavir/ritonavir.
abstract: OBJECTIVE
  Co-treatment of HIV and TB in young children is complicated by limited treatment options and complex drug-drug interactions. Rifabutin is an alternative to rifampicin for adults receiving a ritonavir-boosted PI. We aimed to evaluate the short-term safety and pharmacokinetics of rifabutin when given with lopinavir/ritonavir in children.
  
  
  METHODS
  We conducted an open-label study of rifabutin dosed at 5 mg/kg three times a week in HIV-infected children≤5 years of age receiving lopinavir/ritonavir. Intensive steady-state pharmacokinetic sampling was conducted after six doses. The Division of AIDS 2004, clarification 2009, table for grading severity of adverse events was used to classify drug toxicities. The study was registered with ClinicalTrials.gov, number NCT01259219.
  
  
  RESULTS
  Six children completed the study prior to closure by institutional review boards. The median (range) AUC0-48 of rifabutin was 6.91 (3.52-8.67) μg · h/mL, the median (range) Cmax of rifabutin was 0.39 (0.19-0.46) μg/mL, the median (range) AUC0-48 of 25-O-desacetyl rifabutin was 5.73 (2.85-9.13) μg · h/mL and the median (range) Cmax of 25-O-desacetyl rifabutin was 0.17 (0.08-0.32) μg/mL. The neutrophil count declined in all children; two children experienced grade 4 neutropenia, which resolved rapidly without complications. There was strong correlation between AUC0-48 measures and neutrophil counts.
  
  
  CONCLUSIONS
  Rifabutin dosed at 5 mg/kg three times per week resulted in lower AUC0-48, AUC0-24 and Cmax values for rifabutin and 25-O-desacetyl rifabutin compared with adults receiving 150 mg of rifabutin daily, the current recommended dose. We observed high rates of severe transient neutropenia, possibly due to immaturity of CYP3A4 in young children. It remains unclear whether a safe and effective rifabutin dose exists for treatment of TB in children receiving lopinavir/ritonavir.
authors.affiliation: Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa moultrieh@gmail.com.
authors.forename: Harry
authors.initials: H
authors.lastname: Moultrie
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Shobna
authors.initials: S
authors.lastname: Sawry
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Tracy
authors.initials: T
authors.lastname: Kellermann
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Gurpreet
authors.initials: G
authors.lastname: Kindra
authors.affiliation: Wits Reproductive Health and HIV Institute, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Hermien
authors.initials: H
authors.lastname: Gous
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Annelies
authors.initials: A
authors.lastname: Van Rie
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002675:Child, Preschool; D060085:Coinfection / Q000188:drug therapy*; D005260:Female; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1; D006801:Humans; D007223:Infant; D061466:Lopinavir / Q000627:therapeutic use; D008297:Male; D017828:Rifabutin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000627:therapeutic use; D016896:Treatment Outcome; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D017320:HIV Protease Inhibitors; D017828:Rifabutin; D061466:Lopinavir; D019438:Ritonavir
keywords: TB; treatment; tuberculosis