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.).

FIG 1

Mefloquine exposure and parasitemia in P. falciparum-infected NOD SCID IL-2Rγ^−/− (NSG) mice. (A) Mefloquine concentrations in blood observed over time for various oral dosings. The lines represent the PK/PD model fit using parameters listed in Tables 1 and 2. (B and C) Mefloquine efficacy in P. falciparum-infected NSG mice. (B) Oral administration once daily for 4 days at 1, 2.5, 5, 10, 20, 30, 40, 50, 60, and 70 mg/kg/day (n = 1). (C) Same as in panel B but with dosing at 0.2, 1, 3, 10, and 30 mg/kg (n = 3). Results for the 0.2-, 1-, and 3-mg/kg dosings overlap. The observed data points were overlaid with model predictions (see the text).

FIG 2

(A) Time course of individual mefloquine levels following the oral administration of 5, 10, and 15 mg/kg in volunteers, logarithmic scale, overlaid with graphs using modeled parameters for each dose. The limit of detection was 25 ng/ml. (B) Mefloquine exposure for the three cohorts in the 1- to 6-h interval.

FIG 3

Parasitemia in mefloquine-treated, Plasmodium-infected volunteers (this study) or malaria patients. Black lines, treatment in this study with mefloquine; blue lines, treatment in earlier studies with mefloquine; red lines, treatment with chloroquine (CQ; 600/300 mg) (27, 28).