Oral bioavailability of dihydroartemisinin in Vietnamese volunteers and in patients with falciparum malaria.
OBJECTIVE
To obtain comprehensive bioavailability data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following their separate oral administration to Vietnamese volunteers and to patients with acute, uncomplicated falciparum malaria.


METHODS
Volunteers were randomized to receive either i.v. ARTS (120 mg) followed by oral ARTS (150 mg) 8 h later (Group 1, n = 10), or i.v. ARTS (120 mg) followed by oral DHA (120 mg) 8 h later. Patients, also received oral ARTS (150 mg; Group 3, n = 8) or DHA (120 mg; Group 2, n = 7), in a randomized cross-over study design. Multiple blood samples were collected after each administration and plasma ARTS and/or DHA concentrations were determined by h.p.l.c. Pharmacokinetic descriptors were obtained from noncompartmental analysis and bioavailability was calculated from AUC data. In the patients, the time to 50% parasite clearance (PCT50) and fever clearance time (FCT) also were measured.


RESULTS
In Group 1 (volunteers), the mean (95% CI) absolute bioavailability of oral ARTS was 80% (62,98%), while in Group 2 (volunteers), the bioavailability of oral DHA was 45% (34,56%). In the patients (Group 3), the bioavailability of oral DHA relative to oral ARTS was 88% (49,127%). The median PCT50 and FCT were 2.3 and 28 h, respectively.


CONCLUSIONS
The study shows that the absolute bioavailability of DHA was significantly lower than that for ARTS in healthy volunteers. The bioavailability of ARTS in volunteers was consistent with previous studies in patients with uncomplicated falciparum malaria. The dose-normalized Cmax and AUC(0,infinity) for DHA were significantly greater in patients with falciparum malaria than in healthy volunteers. The high relative bioavailability of DHA in the patients may have been due to lower first-pass clearance. We conclude that, for the treatment of malaria, DHA is likely to be a suitable oral substitute for ARTS. Based on our mean AUC measurements, it appears that equal doses of DHA and ARTS (mg basis) should give equivalent systemic exposure to bioactive DHA in uncomplicated falciparum malaria.
Binh
T Q
TQ
Tropical Diseases Research Center, Cho Ray Hospital, Ho Chi Minh City, Vietnam.
Ilett
K F
KF
Batty
K T
KT
Davis
T M
TM
Hung
N C
NC
Powell
S M
SM
Thu
L T
LT
Thien
H V
HV
Phuöng
H L
HL
Phuong
V D
VD
D000284:Administration, Oral; D000328:Adult; D000962:Antimalarials / Q000378:metabolism* / Q000627:therapeutic use; D037621:Artemisinins; D001682:Biological Availability; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism* / Q000469:parasitology; D008657:Metabolic Clearance Rate / Q000502:physiology; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D014744:Vietnam
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C039060:artenimol