title: Defining the Effectiveness of Antimalarial Chemotherapy: Investigation of the Lag in Parasite Clearance Following Drug Administration.
abstract: The emergence of drug-resistant malaria highlights the need for new agents. A desired characteristic of candidate antimalarials is rapid killing of parasites. This is typically measured by the rate of exponential clearance of parasitemia following treatment. However, this clearance rate excludes the highly variable lag phase, when the parasitemia level may increase, remain constant, or decrease. Understanding factors determining this lag phase is important for drug development.
  
  
  
  We assessed the kinetics of parasitemia in 112 volunteers infected with blood-stage Plasmodium falciparum and treated with 8 different antimalarials. The parasitemia level was measured by quantitative polymerase chain reaction. We analyzed the relationship between the timing of treatment in the parasite growth cycle, and whether the parasitemia level rose or fell in the first 12 or 24 hours after treatment.
  
  
  
  The timing of treatment in the parasite life cycle predicted whether subjects experienced rises or falls in parasitemia level after treatment. Antimalarials were unable to prevent rises in the parasitemia level in the first 12 hours. However, in the first 24 hours after treatment, fast-acting but not slow-acting drugs reduced the parasitemia level independent of when treatment was administered.
  
  
  
  The highly variable lag phase depends on the speed of action of an antimalarial and when in the periodic growth cycle it is administered.
authors.affiliation: Infection Analytics, Kirby Institute, UNSW Australia, Sydney.
authors.forename: David S
authors.initials: DS
authors.lastname: Khoury
authors.affiliation: Infection Analytics, Kirby Institute, UNSW Australia, Sydney.
authors.forename: Deborah
authors.initials: D
authors.lastname: Cromer
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Möhrle
authors.affiliation: QIMR Berghofer Medical Research Institute School of Medicine, University of Queensland, Herston, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: McCarthy
authors.affiliation: Infection Analytics, Kirby Institute, UNSW Australia, Sydney.
authors.forename: Miles P
authors.initials: MP
authors.lastname: Davenport
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage*; D015331:Cohort Studies; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D018512:Parasitemia / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000302:isolation & purification*; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome; D014838:Volunteers
chemical_list: D000962:Antimalarials
keywords: Plasmodium falciparum; antimalarial; blood-stage; drug efficacy; human challenge; lag phase; malaria; mathematical modeling