title: A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children.
abstract: OBJECTIVE
  Low rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to characterize the population pharmacokinetics (popPK) of rifampicin in Malawian children and adults with tuberculosis, simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin and examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations.
  
  
  METHODS
  Patients were recruited at least two weeks after initiation of the intensive phase of treatment and received RIF in FDC of anti-TB drugs. A total of 5-6 rich and 1-2 sparse samples were collected. nonmem (v7.2) was used to build a population-PK model.
  
  
  RESULTS
  A 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included in the one compartment model with first order absorption best described the data. The mean population estimate for CL/F was 23.9 (l h(-1)  70 kg(-1) ) with inter-individual variability of 46.6%. Exposure was unaffected by HIV status. Relative bioavailability in children was estimated at 49% lower compared to adults (100% relative bioavailability). Simulations showed significantly lower rifampicin exposure in children vs. adults. In children average AUC was 13.5 mg l(-1) h, which was nearly half that was observed in adults (26.3 mg l(-1)  h). Using age as a surrogate for weight in dosing bands gave similar results compared with the weight bands. Increasing dose to approximately 15 mg kg(-1) , increased AUC in children to an average of 22 mgl(-1)  h. bringing expected exposures in children closer to those predicted for adults.
  
  
  CONCLUSIONS
  The popPK model developed can be used to optimize rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed dose combination formulations of TB therapy.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Schipani
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Pertinez
authors.affiliation: Department of Medicine, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Rachel
authors.initials: R
authors.lastname: Mlota
authors.affiliation: Department of Medicine, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Molyneux
authors.affiliation: Department of Medicine, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Nuria
authors.initials: N
authors.lastname: Lopez
authors.affiliation: Department of Medicine, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Fraction K
authors.initials: FK
authors.lastname: Dzinjalamala
authors.affiliation: Department of Medicine, University of Malawi College of Medicine, Blantyre, Malawi.|Dignitas International, Zomba, Malawi.
authors.forename: Joep J
authors.initials: JJ
authors.lastname: van Oosterhout
authors.affiliation: Liverpool school of Tropical Medicine, Liverpool, UK.
authors.forename: Steve A
authors.initials: SA
authors.lastname: Ward
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
authors.forename: Gerry
authors.initials: G
authors.lastname: Davies
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007223:Infant; D008295:Malawi; D008875:Middle Aged; D008954:Models, Biological; D012293:Rifampin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014376:Tuberculosis / Q000097:blood / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D012293:Rifampin
keywords: children; dosing bands; nonmem; population PK; tuberculosis