A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers

Abstract

Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum-induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 (n = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 (n = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 parasite reduction ratios over 48 h [PRR48] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.).

Keywords: DSM265; Plasmodium falciparum; artefenomel; chemotherapy; clinical studies; combination therapy; controlled human malaria infection; malaria; volunteer infection study.

Copyright © 2019 McCarthy et al.

Figures

FIG 1

Individual subject plasma concentration-time profiles for artefenomel and DSM265. Subjects received a single dose of artefenomel-DSM265 on day 7. Cohort 1 received a dose of 200 mg artefenomel plus 100 mg DSM265, and cohort 2 received a dose of 200 mg artefenomel plus 50 mg DSM265. Lines indicate the artefenomel (A and C) and DSM256 (B and D) concentrations in the plasma over time for each subject in cohort 1 (A and B) and cohort 2 (C and D). The horizontal dotted line indicates the MIC calculated in previous IBSM studies (2, 4).

FIG 2

Individual subject parasitemia-time profiles. Subjects were inoculated with ∼1,800 viable parasites on day 0, and a single dose of artefenomel-DSM265 was administered on day 7 (indicated by the vertical dashed line). Cohort 1 received a dose of 200 mg artefenomel plus 100 mg DSM265, and cohort 2 received a dose of 200 mg artefenomel plus 50 mg DSM265. Parasitemia was quantified using qPCR targeting the gene encoding P. falciparum 18S rRNA. Thin lines represent the parasitemia for each subject in cohort 1 (A) and cohort 2 (B), and the bold lines represent the geometric mean. For the purpose of graphing the parasitemia data on a logarithmic scale, the time points at which parasites could not be detected were substituted for with a value of 1 parasite/ml.

FIG 3

Individual subject gametocytemia-time profiles. Gametocyte density was quantified using qRT-PCR targeting the female gametocyte transcript pfs25 from 7 days after a single dose of artefenomel-DSM265 was administered. Cohort 1 received a dose of 200 mg artefenomel plus 100 mg DSM265, and cohort 2 received a dose of 200 mg artefenomel plus 50 mg DSM265. Lines represent the gametocytemia for each subject in cohort 1 (A) and cohort 2 (B). Arrows indicate time points at which artemether-lumefantrine treatment was initiated for a particular subject in response to recrudescence of asexual parasitemia. For the purpose of graphing the gametocytemia data on a logarithmic scale, time points at which gametocytes could not be detected were substituted for with a value of 1 gametocyte/ml.