In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

ABSTRACT We have analyzed the in vitro chemosensitivity profiles of 115 Kenyan isolates for chloroquine (CQ), piperaquine, lumefantrine (LM), and dihydroartemisinin in association with polymorphisms in pfcrt at codon 76 and pfmdr 1 at codon 86, as well as with variations of the copy number of pfmdr 1 . The median drug concentrations that inhibit 50% of parasite growth (IC 50 s) were 41 nM (interquartile range [IQR], 18 to 73 nM), 50 nM (IQR, 29 to 96 nM), 32 nM (IQR, 17 to 46 nM), and 2 nM (IQR, 1 to 3 nM) for CQ, LM, piperaquine, and dihydroartemisinin, respectively. The activity of CQ correlated inversely with that of LM ( r 2 = −0.26; P = 0.02). Interestingly, parasites for which LM IC 50 s were higher were wild type for pfcrt -76 and pfmdr 1 - 86 . All isolates had one pfmdr 1 copy. Thus, the decrease in LM activity is associated with the selection of wild-type pfcrt - 76 and pfmdr 1 - 86 parasites, a feature that accounts for the inverse relationship between CQ and LM. Therefore, the use of LM-artemether is likely to lead to the selection of more CQ-susceptible parasites.