Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria

Abstract

Background: The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results.

Methods: Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of seven dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42 ± 2. The general pharmacodynamic interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study.

Results: For a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR₂₈), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR₂₈ in the phase 2b trial of 67.0%, 65.5%, and 75.4%, respectively.

Conclusions: These results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development.

Trial registration: This study was registered on ClinicalTrials.gov on 11 May 2018 with registration number NCT03542149.

Keywords: Antimalarial; Artefenomel; Combination; Pharmacodynamics; Pharmacokinetics; Piperaquine; Volunteer infection study.

Fig. 1

Trial profile. Enrolled participants were randomized within each cohort to a dose group on the day of dosing with artefenomel + piperaquine combination treatment (8 days following challenge with blood-stage P. falciparum). Two participants discontinued voluntarily prior to the end of the study; available data from both participants were included in the analysis of study endpoints

Fig. 2

Individual participant parasitemia-time profiles. Participants were inoculated intravenously with P. falciparum-infected erythrocytes and were administered a single oral dose of artefenomel and piperaquine in combination after 8 days (indicated by the vertical dashed line). Parasitemia was monitored using qPCR targeting the gene encoding P. falciparum18S rRNA. Artemether-lumefantrine was administered in response to parasite regrowth (indicated by the vertical arrows) or 35 ± 3 days after artefenomel + piperaquine dosing if parasite regrowth was not observed (indicated by the vertical dotted line). For the purpose of graphing on a log₁₀ logarithmic scale, time points at which parasitemia could not be detected were substituted with a value of 1 parasite/mL. ^aOne participant received early artemether-lumefantrine treatment due to voluntary withdrawal from the study

Fig. 3

Artefenomel and piperaquine plasma concentration–time profiles. Plots represent the arithmetic mean of the artefenomel (A) and piperaquine (B) plasma concentration of each dose group over the study. Plasma concentrations were measured using liquid chromatography with tandem mass spectrometry. The horizontal dotted lines indicate the lower limit of quantification (1 ng/mL)