Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: phase 1b study

Abstract

Background: Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Research (WRAIR) has been developing a novel good manufacturing practice (GMP) injection of AS, which was approved by the US FDA for investigational drug use and distribution by the CDC.

Methods: Tolerability and pharmacokinetics of current GMP intravenous AS, as an anti-malarial agent, were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusion in 24 healthy subjects (divided into three groups) in the Phase 1 clinical trial study.

Results: Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment. After intravenous injection, parent drug rapidly declined and was converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15-0.23 hr for AS and 1.23-1.63 hr for DHA, but the peak concentration (C(max)) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and C(max) values of AS and DHA were increased proportionally to the AS climbing multiple doses.

Discussion: The safety of injectable AS, even at the highest dose of 8 mg/kg increases the probability of therapeutic success of the drug even in patients with large variability of parasitaemia.

Figure 1

Mean plasma concentration-time profiles of artesunate (AS, left) and dihydroartemisinin (DHA, right), an active metabolite of AS, measured by LC-MS/MS (markers) and computer pharmacokinetic fitting curves (solid-line) following multiple intravenous dosage with 2 min short-term infusion of AS at 2 (top), 4 (middle), and 8 (bottom) mg/kg in healthy volunteers. (n = 6 for each dose cohort).

Figure 2

Correlations (r² = 0.910-0.986) are shown between multiple intravenous doses and peak concentration (C_max) or area under the curve (AUC) with artesunate (AS) or dihydroartemisinin (DHA), an active metabolite from AS. A: mean samples (markers) were taken from C_max of AS; B: mean values were taken from AUC of AS; C: mean samples were taken from C_max of DHA; and D: mean values were taken from AUC of DHA in all three dose groups (2, 4, and 8 mg/kg) after AS treatments daily for three days. The line represents linear regression whose statistical parameters are shown in the inset (A-D).