Orally formulated artemisinin in healthy fasting Vietnamese male subjects: a randomized, four-sequence, open-label, pharmacokinetic crossover study

Abstract

Background: Artemisinin derivatives are used in antimalarial drug combination therapy. Artemisinin and piperaquine have recently been proven to be prospective candidates for combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria.

Objective: The goal of this study was to evaluate the relative bioavailability and to characterize the pharmacokinetic properties of a new micronized powder formulation of artemisinin against the previous standard Vietnamese formulation when administered as a single oral dose or in combination with piperaquine.

Methods: This was a single-center, randomized, 4-sequence, open-label, crossover study conducted in 15 healthy male Vietnamese volunteers under fasting conditions with a washout period of 3 weeks between study visits. A single oral dose of 160 or 500 mg of artemisinin was administered alone or in combination with piperaquine. Potential adverse events were monitored daily by the clinician and by using laboratory test results. Frequent blood samples were drawn for 12 hours after dose. Artemisinin was quantified in plasma using LC-MS/MS. Pharmacokinetic parameters were computed from the plasma concentration-time profiles using a noncompartmental analysis method.

Results: Pharmacokinetic parameters T(max), C(max), AUC(0-∞), V(d)/F, CL/F, and t(1/2) (mean [SD]) for the new formulation of artemisinin were 1.83 (0.88) hours, 178 (97) ng/mL, 504 (210) h × ng/mL, 1270 (780) L, 401 (260) L/h, and 2.21 (0.29) hours, respectively. The mean percentage of the test/reference formulation ratio for the logarithmically transformed values of C(max), AUC(0-last,) and AUC(0-∞) were 121% (90% CI, 92.5-158), 122% (90% CI, 101-148), and 120% (90% CI, 98.0-146), respectively.

Conclusions: This single-dose study found that the dose-normalized C(max), AUC(0-last), and AUC(0-∞) mean geometric differences between the test and reference formulations were relatively small (<40%) and will probably not have a clinical impact in the treatment of malaria infections.

Figure 1

Mean (SD) plasma concentration–time curve of artemisinin in 15 healthy Vietnamese male volunteers in a 4-sequence crossover study receiving a single oral dose of 160-mg micronized test artemisinin formulation (group T1 ■) and 160-mg reference artemisinin formulation (group T2 ▲). Artemisinin concentrations are plotted on a log-linear scale with the base 10.

Figure 2

Individual plasma concentration–time curves of artemisinin in 15 healthy Vietnamese male volunteers in a 4-sequence crossover study. (A) Group T1 received a single dose of 2 gelatin capsules, each containing 80 mg of micronized artemisinin powder (test formulation); (B) Group T2 received a single dose of 2 gelatin capsules, each containing 80 mg of artemisinin (reference Vietnamese low-dose formulation); (C) Group T3 received a single dose of 2 gelatin capsules, each containing 250 mg of artemisinin powder (reference Vietnamese dose-strength formulation); and (D) Group T4 received a single dose of 2 tablets of micronized artemisinin powder, each containing 80 mg artemisinin (test formulation) and 360 mg of piperaquine phosphate. Artemisinin concentrations are plotted on a log-linear scale with the base 10.