title: Pharmacokinetic predictors for recurrent malaria after dihydroartemisinin-piperaquine treatment of uncomplicated malaria in Ugandan infants.
abstract: BACKGROUND
  Although dihydroartemisinin-piperaquine (DP) is used primarily in children, pharmacokinetic/pharmacodynamic (PK/PD) data on DP use in young children are lacking.
  
  
  METHODS
  We conducted a prospective PK/PD study of piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 episodes of malaria treatment, which occurred during follow-up periods of up to 5 months. Malaria follow-up was conducted actively to day 28 and passively to day 63.
  
  
  RESULTS
  The median capillary piperaquine concentration on day 7 after treatment was 41.9 ng/mL. Low piperaquine concentrations were associated with an increased risk of recurrent malaria for up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In children not receiving TMP-SMX, low piperaquine concentrations were only modestly associated with an increased risk of recurrent malaria. However, for children receiving TMP-SMX, associations were strong and evident for all sampling days, with PQ concentrations of ≤ 27.3 ng/mL on day 7 associated with a greatly increased risk of recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable piperaquine concentrations at the time of presentation with recurrent malaria.
  
  
  CONCLUSIONS
  These piperaquine PK/PD data represent the first in children <2 years of age. Piperaquine exposure on day 7 correlated with an increased risk of recurrent malaria after DP treatment in children receiving TMP-SMX prophylaxis. Interestingly, despite strong associations, infants remained at risk for malaria, even if they had residual levels of piperaquine.
authors: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Australia.
authors: Darren J
authors: DJ
authors: Creek
authors: Victor
authors: V
authors: Bigira
authors: Shelley
authors: S
authors: McCormack
authors: Emmanuel
authors: E
authors: Arinaitwe
authors: Humphrey
authors: H
authors: Wanzira
authors: Abel
authors: A
authors: Kakuru
authors: Jordan W
authors: JW
authors: Tappero
authors: Taylor G
authors: TG
authors: Sandison
authors: Niklas
authors: N
authors: Lindegardh
authors: Francois
authors: F
authors: Nosten
authors: Francesca T
authors: FT
authors: Aweeka
authors: Sunil
authors: S
authors: Parikh
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018890:Chemoprevention / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008288:Malaria / Q000188:drug therapy* / Q000517:prevention & control*; D008297:Male; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055502:Secondary Prevention; D013997:Time Factors; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000008:administration & dosage; D014454:Uganda; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011804:Quinolines; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; C039060:artenimol; C034759:piperaquine; D010879:Piperazines