Comparative study of dihydroartemisinin and artesunate safety in healthy Thai volunteers.
OBJECTIVE
As part of new drug development initiatives in Thailand, a new tablet formulation of dihydroartemisinin (DHA, an antimalarial drug) has been developed. Our previous bioequivalence study indicated that the new and reference DHA formulations were well tolerated; however, a significant decrease in hemoglobin was detected after a single 200-mg oral dose. To explore further, a clinical study with an emphasis on hematological parameters was conducted.


METHODS
A single-center, randomized, single-blind, cross-over clinical study was conducted in 18 healthy volunteers with a dosage of 300 mg daily for 2 days. Artesunate was used as a comparator. Adverse events were monitored and laboratory parameters on study Days 0, 2, 5, and 7 post drug administrations were analyzed.


RESULTS
Eighteen volunteers completed both rounds of the study. Both drugs were well tolerated. All adverse events were mild. Significant decrease in hemoglobin compared to baseline was detected for both drugs 7 days after administration (DHA: 0.48 g/dl, p = 0.007; artesunate 0.38 g/dl, p = 0.001). Transient bone marrow suppression was evidenced by reduction of reticulocytes with a lowest number on study Day 5 (artesunate 75% reduction in reticulocyte count; DHA 47%, p < 0.001 for both drugs compared to baseline).


CONCLUSIONS
The present study confirmed our previous finding on significant decrease in hemoglobin. Artesunate appeared to have more negative effects on the numbers of reticulocytes and white blood cells than DHA. Systemic laboratory and toxicity profiles presented in this study may be used as a framework for future clinical studies of artemisinin and its derivatives.
Kongpatanakul
S
S
Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand. siskt@mahidol.ac.th
Chatsiricharoenkul
S
S
Khuhapinant
A
A
Atipas
S
S
Kaewkungwal
J
J
D000328:Adult; D000962:Antimalarials / Q000009:adverse effects*; D037621:Artemisinins / Q000009:adverse effects*; D000077332:Artesunate; D001772:Blood Cell Count; D001853:Bone Marrow / Q000187:drug effects; D018592:Cross-Over Studies; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D012156:Reticulocytes / Q000187:drug effects; D016037:Single-Blind Method; D013785:Thailand; D055815:Young Adult
D000962:Antimalarials; D037621:Artemisinins; D006454:Hemoglobins; D000077332:Artesunate; C039060:artenimol