Safety and pharmacokinetic properties of a new formulation of parenteral artesunate in healthy Thai volunteers

Abstract

Background: Parenteral artesunate is the first-line therapy for severe malaria. Artesunate, in its current formulation, must be prepared immediately before administration by first dissolving in sodium bicarbonate solution and then diluting in saline. A novel solvent for rapid and stable single step reconstitution of artesunate was recently developed showing improved solubility and stability. This study aimed to compare the safety and pharmacokinetic properties of the currently available and newly developed parenteral formulation of artesunate in healthy Thai volunteers.

Methods: This was an open-label, randomized, 4 periods, 4-treatments, 24-sequence, single-dose, cross-over study in 72 male and female healthy Thai volunteers. Frequent pharmacokinetic samples were collected in all volunteers at each dose occasion. Observed concentration-time profiles were analysed with a non-compartmental approach followed by a bioequivalence evaluation.

Results: Both intramuscular and intravenous administrations of the new parenteral formulation of artesunate were safe and well-tolerated, with no additional safety signals compared to the currently used formulation. The pharmacokinetic properties of artesunate and its active metabolite, dihydroartemisinin, were well-characterized, and showed rapid conversion of artesunate into dihydroartemisinin. Intramuscular administration of the newly formulated artesunate resulted in almost complete bioavailability of dihydroartemisinin. The pharmacokinetic properties were similar between the old and new formulation.

Conclusions: The new and more easily prepared formulation of artesunate was safe and well-tolerated, with similar pharmacokinetic properties compared to the currently used formulation. Dihydroartemisinin, the active metabolite responsible for the majority of the anti-malarial effect, showed equivalent exposure after both intravenous and intramuscular administration of artesunate, suggesting that both routes of administration should generate comparable therapeutic effects.

Trial registration: The study was registered to clinicaltrials.gov (#TCTR20170907002).

Keywords: Artesunate; Bioequivalence; Formulation; Healthy volunteer; Intramuscular; Intravenous; Malaria; Pharmacokinetics.

Fig. 1

Study design and enrolment. ALT, alanine transaminase; AST, aspartate aminotransferase; F/U, follow up; HCV hepatitis C virus; HIV, human immunodeficiency virus; INR, international normalized ratio; IV, intravenous; n, number of volunteers; PT, prothrombin time; PTT, partial prothrombin time; RIM, reference formulation administered intramuscularly; RIV, reference formulation administered intravenously; TIM, test formulation administered intramuscularly; TIV, test formulation administered intravenously; and ULN, upper limit of normal

Fig. 2

Pharmacokinetic concentration–time profiles of artesunate (left panel) and dihydroartemisinin (right panel), after IV administration of reference (upper panel) and test (lower panel) formulations. The open circles show individual drug measurements, and the solid lines and shaded areas show the average and 95% prediction interval of measured drug concentrations at each sampling time

Fig. 3

Pharmacokinetic concentration–time profiles of artesunate (left panel) and dihydroartemisinin (right panel), after IM administration of reference (upper panel) and test (lower panel) formulations. The open circles show individual drug measurements, and the solid lines and shaded areas show the average and 95% prediction interval of measured drug concentrations at each sampling time

Fig. 4

Bioequivalence of test formulation, compared to reference formulation, after IV and IM administration. Bioequivalence parameters are presented as the geometric mean ratio between the test and reference formulation (90% confidence interval). C_MAX is the maximum concentration; AUC_LAST is the area under the concentration–time curve from time zero to the last measurable observation; AUC_∞ is the area under the concentration–time curve from time zero to infinity; ART-DHA is the combined molar drug measurement of artesunate and dihydroartemisinin. The shaded area in the plot shows the 80–125% criterion for bioequivalence. * Indicates that the criterion for bioequivalence was not fulfilled, i.e. the CI 90% of the ratio (test/reference) was not contained within 80–125%