title: Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development.
abstract: Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ(-/-) (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.).
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia University of Queensland, Brisbane, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: McCarthy
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: Marquart
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Silvana
authors.initials: S
authors.lastname: Sekuloski
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia University of Queensland, Brisbane, Australia.
authors.forename: Katharine
authors.initials: K
authors.lastname: Trenholme
authors.affiliation: QPharm Pty. Ltd., Brisbane, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Elliott
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia University of Queensland, Brisbane, Australia QPharm Pty. Ltd., Brisbane, Australia Mater Health Services, Brisbane, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Griffin
authors.affiliation: University of Queensland, Brisbane, Australia Queensland Paediatric Infectious Diseases (QPID), Herston, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rockett
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Rourke
authors.affiliation: University of Queensland, Brisbane, Australia Queensland Paediatric Infectious Diseases (QPID), Herston, Australia.
authors.forename: Theo
authors.initials: T
authors.lastname: Sloots
authors.affiliation: GlaxoSmithKline, Tres Cantos Drug Development Campus, Diseases of the Developing World, Tres Cantos, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: GlaxoSmithKline, Tres Cantos Drug Development Campus, Diseases of the Developing World, Tres Cantos, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.affiliation: GlaxoSmithKline, Tres Cantos Drug Development Campus, Diseases of the Developing World, Tres Cantos, Spain.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.affiliation: GlaxoSmithKline, Tres Cantos Drug Development Campus, Diseases of the Developing World, Tres Cantos, Spain.
authors.forename: María-Santos
authors.initials: MS
authors.lastname: Martínez
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Rob
authors.identifier: 0000-0002-2261-9424
authors.initials: R
authors.lastname: Hooft van Huijsduijnen
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Timothy N C
authors.initials: TN
authors.lastname: Wells
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Baker
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland moehrlej@mmv.org.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Möhrle
mesh_terms: D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D015331:Cohort Studies; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D015767:Mefloquine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000962:Antimalarials; D015767:Mefloquine