title: Altering Antimalarial Drug Regimens May Dramatically Enhance and Restore Drug Effectiveness.
abstract: There is considerable concern that malaria parasites are starting to evolve resistance to the current generation of antimalarial drugs, the artemisinin-based combination therapies (ACTs). We use pharmacological modeling to investigate changes in ACT effectiveness likely to occur if current regimens are extended from 3 to 5 days or, alternatively, given twice daily over 3 days. We show that the pharmacology of artemisinins allows both regimen changes to substantially increase the artemisinin killing rate. Malaria patients rarely contain more than 10(12) parasites, while the standard dosing regimens allow approximately 1 in 10(10) parasites to survive artemisinin treatment. Parasite survival falls dramatically, to around 1 in 10(17) parasites if the dose is extended or split; theoretically, this increase in drug killing appears to be more than sufficient to restore failing ACT efficacy. One of the most widely used dosing regimens, artemether-lumefantrine, already successfully employs a twice-daily dosing regimen, and we argue that twice-daily dosing should be incorporated into all ACT regimen design considerations as a simple and effective way of ensuring the continued long-term effectiveness of ACTs.
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom Katherine.Kay@LSTMed.ac.uk.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kay
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Eva Maria
authors.identifier: http://orcid.org/0000-0001-5821-1685
authors.initials: EM
authors.lastname: Hodel
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Hastings
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000493:pharmacokinetics* / Q000494:pharmacology; D002648:Child; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D004983:Ethanolamines / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D015233:Models, Statistical; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; C031327:artemisinin