TY - JOUR
T1 - Population pharmacokinetics and pharmacodynamics of lumefantrine in young Ugandan children treated with artemether-lumefantrine for uncomplicated malaria
AU - Tchaparian, Eskouhie
AU - Sambol, Nancy C.
AU - Arinaitwe, Emmanuel
AU - McCormack, Shelley A.
AU - Bigira, Victor
AU - Wanzira, Humphrey
AU - Muhindo, Mary
AU - Creek, Darren J.
AU - Sukumar, Nitin
AU - Blessborn, Daniel
AU - Tappero, Jordan W.
AU - Kakuru, Abel
AU - Bergqvist, Yngve
AU - Aweeka, Francesca T.
AU - Parikh, Sunil
PY - 2016/10/15
Y1 - 2016/10/15
N2 - Background. The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. Methods. Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. Results. Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P =. 0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. Conclusions. We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted.
AB - Background. The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. Methods. Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. Results. Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P =. 0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. Conclusions. We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted.
KW - Antimalarial
KW - Artemisinin combination therapy
KW - Lumefantrine
KW - Malaria
KW - Nonlinear mixed effects modeling
KW - Pharmacodynamics
KW - Population pharmacokinetics
KW - Trimethoprim-sulfamethoxazole
UR - http://www.scopus.com/inward/record.url?scp=84990929765&partnerID=8YFLogxK
U2 - 10.1093/infdis/jiw338
DO - 10.1093/infdis/jiw338
M3 - Article
AN - SCOPUS:84990929765
SN - 0022-1899
VL - 214
SP - 1243
EP - 1251
JO - The Journal of Infectious Diseases
JF - The Journal of Infectious Diseases
IS - 8
ER -