Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine

Abstract

Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.

Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus–Infected Women Receiving Efavirenz

“…Therefore, in settings of high malaria burden and antifolate resistance, HIV-infected women who take daily TMP-SMX will likely require an additional agent for effective malaria chemoprevention. PQ models in nonpregnant adult males and Ugandan children have predicted that a weekly dose of 960 mg PQ should be considered to improve the protective efficacy of DHA-PQ [18,19]. We also found improved PQ coverage with weekly regimens, with up to 34% of women predicted to achieve protective PQ coverage.…”

School-aged children based seasonal malaria chemoprevention using artesunate-amodiaquine in Mali

“…ASAQ appears as an interesting alternative for SMC in areas with seasonal malaria transmission. Others artemisinin-based combination therapies (ACT) such as Dihydroartemisinin-Piperaquine (DHA-PQ) have been tested for SMC ( Permala et al, 2017 ). DHA-PQ is being considered for mass treatment and for intermittent treatment during pregnancy.…”

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

“…Due to its generally excellent clinical efficacy and tolerability as well as the period of posttreatment prophylaxis protection, 106 dihydroartemisinin‐piperaquine is being evaluated as a potential mass treatment (intermittent preventive treatment) to control and eliminate artemisinin‐resistant falciparum malaria. The PK/PD simulation suggests that weekly dosing would be preferable to a monthly dosing regimen to improve malaria chemoprevention, as well as to reduce selection pressure for drug resistance, safety concerns driven by high piperaquine peak plasma concentrations, and sensitivity to poor adherence 107 …”