Abstract. The pharmacokinetics of good manufacturing process injection of artesunate (AS) were evaluated after single doses at 0.5, 1, 2, 4, and 8 mg/kg with a 2-minute infusion in 40 healthy subjects. Drug concentrations were analyzed by validated liquid chromatography and mass spectrometry system (LC-MS/MS) procedures. The drug was immediately converted to dihydroartemisinin (DHA), with elimination half-lives ranging 0.12-0.24 and 1.15-2.37 hours for AS and DHA, respectively. Pharmacokinetic model-dependent analysis is suitable for AS, whereas DHA fits both model-dependent and -independent methods. Although DHA concentration was superior to that of AS with a 1.12-1.87 ratio of area under the curve (AUC) DHA/AS , peak concentration of AS was much higher than that of DHA, with a 2.80-to 4.51-fold ratio of peak concentration (C max AS/DHA ). Therefore, AS effectiveness has been attributed not only to its rapid hydrolysis to DHA, but also to itself high initial C max .

BackgroundSevere 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.MethodsTolerability 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.ResultsResults 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 (Cmax) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and Cmax values of AS and DHA were increased proportionally to the AS climbing multiple doses.DiscussionThe 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.

A randomized, double-blind, placebo-controlled study was conducted to assess the effect of tafenoquine, 200 mg weekly for 6 months on ophthalmic and renal safety. This trial was carried out after observations in previous clinical trials that tafenoquine may be associated with the development of corneal deposits and elevations in serum creatinine. In 120 healthy volunteers who received tafenoquine or placebo in a 2:1 randomization, there was no effect on night vision or other ophthalmic indices measured. Persons taking tafenoquine also showed no difference in mean change in glomerular filtration rate (GFR, mL/s/1.73 m(2)) after 6 months of dosing, with a treatment difference of -0.061 (95% confidence interval, -0.168, 0.045), and non-inferiority margin of -0.247 mL/s/1.73 m(2). Tafenoquine was well tolerated over the course of the study. The results of this study showed no clinically significant effects of tafenoquine on ophthalmic or renal function, and support its continued development as an antimalarial drug.

This exploratory randomized, double-blind, placebo-controlled, 5-treatment, 5-period crossover study was conducted using a thermally induced hyperalgesia pain model in 51 healthy volunteers (33 evaluable) to characterize the relative potency of fentanyl buccal tablet (FBT) versus intravenous morphine. Relative potency was assessed using the sum of pain intensity differences over 60 minutes after the application of a 43°C, 46°C, and 49°C painful stimulus following thermally induced hyperalgesia. Relative potency was also assessed by pupil diameter and responses to subjective questionnaires. The relative potency of FBT was 46.2 times that of intravenous morphine (95% confidence interval [CI], 17.6-575.3) based on the 49°C stimulus. The relative potency of FBT based on opiate-induced miosis was 44.6 (95% CI, 29.7-77.0) at 60 minutes. These results are an initial relative potency assessment and should not be considered guidance for dose-equivalent switching between agents in clinical practice.

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