TY - JOUR
T1 - Investigating the efficacy of triple artemisinin-based combination therapies for treating plasmodium falciparum malaria patients using mathematical modeling
AU - Dini, Saber
AU - Zaloumis, Sophie
AU - Cao, Pengxing
AU - Price, Ric N.
AU - Fowkes, Freya J.I.
AU - Van Der Pluijm, Rob W.
AU - McCaw, James M.
AU - Simpson, Julie A.
PY - 2018/11
Y1 - 2018/11
N2 - The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative coadministered with a longer-acting partner drug. However, the spread of Plasmodium falciparum resistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites. One such strategy is triple artemisinin-based combination therapy (TACT). We developed a mechanistic within-host mathematical model to investigate the efficacy of a TACT (dihydroartemisinin-piperaquine-mefloquine [DHA-PPQ-MQ]) for use in South-East Asia, where DHA and PPQ resistance are now increasingly prevalent. Comprehensive model simulations were used to explore the degree to which the underlying resistance influences the parasitological outcomes. The effect of MQ dosing on the efficacy of TACT was quantified at various degrees of DHA and PPQ resistance. To incorporate interactions between drugs, a novel model is presented for the combined effect of DHA-PPQ-MQ, which illustrates how the interactions can influence treatment efficacy. When combined with a standard regimen of DHA and PPQ, the administration of three 6.7-mg/kg doses of MQ was sufficient to achieve parasitological efficacy greater than that currently recommended by World Health Organization (WHO) guidelines. As a result, three 8.3-mg/kg doses of MQ, the current WHO-recommended dosing regimen for MQ, combined with DHA-PPQ, has the potential to produce high cure rates in regions where resistance to DHA-PPQ has emerged.
AB - The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative coadministered with a longer-acting partner drug. However, the spread of Plasmodium falciparum resistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites. One such strategy is triple artemisinin-based combination therapy (TACT). We developed a mechanistic within-host mathematical model to investigate the efficacy of a TACT (dihydroartemisinin-piperaquine-mefloquine [DHA-PPQ-MQ]) for use in South-East Asia, where DHA and PPQ resistance are now increasingly prevalent. Comprehensive model simulations were used to explore the degree to which the underlying resistance influences the parasitological outcomes. The effect of MQ dosing on the efficacy of TACT was quantified at various degrees of DHA and PPQ resistance. To incorporate interactions between drugs, a novel model is presented for the combined effect of DHA-PPQ-MQ, which illustrates how the interactions can influence treatment efficacy. When combined with a standard regimen of DHA and PPQ, the administration of three 6.7-mg/kg doses of MQ was sufficient to achieve parasitological efficacy greater than that currently recommended by World Health Organization (WHO) guidelines. As a result, three 8.3-mg/kg doses of MQ, the current WHO-recommended dosing regimen for MQ, combined with DHA-PPQ, has the potential to produce high cure rates in regions where resistance to DHA-PPQ has emerged.
KW - Antimalarial agents
KW - Artemisinin-based combination therapy
KW - Drug efficacy
KW - Drugs interactions
KW - Mathematical modeling
UR - http://www.scopus.com/inward/record.url?scp=85055608553&partnerID=8YFLogxK
U2 - 10.1128/AAC.01068-18
DO - 10.1128/AAC.01068-18
M3 - Article
C2 - 30150462
AN - SCOPUS:85055608553
SN - 0066-4804
VL - 62
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 11
M1 - e01068-18
ER -