Table 1.
Criteria used to assess antimalarials
| Individual antimalarial drugs | Examples |
|---|---|
| Anti-parasitic activity | |
| Stage-specificity, e.g. blood schizonticide (treatment), gametocytocide or sporontocide (transmission-blocking), hypnozoiticide (relapse prevention), hepatic schizonticide (causal prophylaxis) | The artemisinin derivatives have the broadest stage-specificity of action of all registered antimalarials (trophozoites, including young rings, gametocytes, with the exception of Stage V) Only the 8-aminoquinolines (primaquine, tafenoquine) are active against hypnozoites for relapse prevention in vivax or ovale malaria |
| Pharmacokinetics | |
| Speed of action (including dependence on co-factors, e.g. for absorption) | Lumefantrine AUC is the principal determinant of cure following artemether–lumefantrine treatment (absorption is enhanced by coadministration with fat) |
| Speed of elimination | Slowly eliminated drugs (e.g. piperaquine) have the added advantage of a longer post-treatment prophylactic effect and hence fewer episodes of malaria in high-transmission areas [115] |
| Pharmacodynamics | |
| Parasiticidal effect: relates to asexual stage-specific activity | The most potent antimalarials have the greatest inhibitory effect on parasite multiplication. The average parasite biomass in an adult with uncomplicated falciparum malaria is > 1012. Artesunate reduces the biomass by ~ 104 per asexual life-cycle (48 h) in sensitive infections. Thus, if used alone ≥ 6-day treatment (3 cycles) must be given to have the best chance of cure [5] |
| Safety/toxicity | |
| Pregnant women and children | ACTs were contraindicated in the first trimester of pregnancy due to concerns of embryotoxicity in animals and a lack of safety data in humans until recently |
| Repeated dosing | Patients in high transmission areas may have multiple episodes of malaria per year. Repeated dosing of artesunate-pyronaridine was not recommended initially due to safety concerns (signal of hepatotoxicity). This caution has since been lifted |
| Propensity for resistance to develop | Atovaquone–proguanil is extremely vulnerable to resistance development due to rapid selection of cytochrome b mutations |
| Cost | Artemether–lumefantrine costs US$0.38–1.3 per treatment [116] |
| Antimalarial combinations | |
|---|---|
| Formulation | |
| Co-formulations, tablet burden | All leading ACTs now exist as fixed-dose combinations with the exception of AS-SP |
| Paediatric formulations | Most leading ACTs have paediatric dosage forms |
| Posology | |
| Dose number and frequency | Most antimalarials are given as 3-day treatments. Artemether lumefantrine has the highest dose frequency (6 doses) |
| Matched pharmacokinetics | |
| Elimination half-lives | For the ACTs in use there is a mismatch of the elimination kinetics of artemisinin derivatives and partner drugs, which leaves the slowly eliminated drug unprotected |
| Drug–drug interactions | Triple ACTs under evaluation exploit inverse resistance selection properties of different partner drug pairings, e.g. amodiaquine and lumefantrine |
| Global recommendations to add a single low dose of primaquine to ACTs in areas targeting elimination necessitate study of potential drug-drug interactions with any new treatment |