IngentaConnect Oral bioavailability of dihydroartemisinin in Vietnamese voluntee...

Authors: Binh, Tran Quang¹; Ilett, Kenneth F.; Batty, Kevin T.; Davis, Timothy M. E.²; Hung, Nguyen Canh³; Powell, Shane M.; Thu, Le Thi Anh¹; Van Thien, Huynh³; Phuöng, Hoang Lan¹; Phuong, Vu Duong Bich¹

Source: British Journal of Clinical Pharmacology, Volume 51, Number 6, June 2001 , pp. 541-546(6)

Publisher: Blackwell Publishing

Abstract:

Aims

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 C_max and AUC(0,∞) 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.

Keywords: artesunate; bioavailability; dihydroartemisinin; falciparum malaria; pharmacodynamics; pharmacokinetics

Document Type: Research article

DOI: 10.1046/j.1365-2125.2001.01395.x

Affiliations: 1: Tropical Diseases Research Center, Cho Ray Hospital, Ho Chi Minh City, Vietnam, 2: Department of Medicine, University of Western Australia, Fremantle Hospital, Fremantle, Australia and 3: Bao Loc Hospital, Lam Dong Province, Vietnam

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Oral bioavailability of dihydroartemisinin in Vietnamese volunteers and in patients with falciparum malaria