Abstract.Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40–60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose–response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (−2.65 to −2.95 g/dL [N = 3]) and primaquine (−1.25 to −3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61–80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

BackgroundFluticasone furoate (FF; GW685698) is a novel inhaled corticosteroid that is active at 24 h and under development for once-daily administration in combination with the long-acting β2-adrenoceptor agonist vilanterol (GW642444) for chronic obstructive pulmonary disease and asthma. In vitro studies examining the respiratory tissue-binding properties of corticosteroids showed FF to have the largest cellular accumulation and slowest rate of efflux compared with other clinically used inhaled corticosteroids, consistent with greater tissue retention. The enhanced affinity of the glucocorticoid receptor binding of FF, coupled with its extended tissue association, may be expected to lead to greater and more prolonged anti-inflammatory effects and should provide relevant once-daily efficacy.ObjectiveThe aim of this study was to assess the rate and extent of systemic absorption of FF from the lung following inhaled administration of FF from three exploratory dry powder formulations (via DISKHALER®) compared with inhaled fluticasone propionate (FP) [via DISKHALER®] using deconvolution analysis.MethodsThis open-label, part-randomized, six-way crossover study evaluated three early development dry powder inhaled formulations of FF administered as single doses via DISKHALER®. Healthy male subjects (n = 24) each received FF (2,000 μg; three formulations), inhaled FP (1,000 μg; via DISKHALER®) and 250 μg of each molecule by intravenous infusion. The bioavailability of both inhaled FF and FP represents absorption from the lung as the oral bioavailability from the swallowed portion of the inhaled dose is negligible (<1.5 %). To investigate the absorption kinetics from the lung, the inhaled concentration–time data were subjected to deconvolution analysis using derived pharmacokinetic parameters from fitting of the intravenous concentration–time data.ResultsThe terminal elimination half-life (t½β) for inhaled FF was considerably longer (range 17–24 h) than the t½β estimated for intravenous FF (14 h), whereas t½β for FP was similar whether inhaled or given intravenously (11 and 14 h, respectively). This would suggest that FF is exhibiting absorption rate-limited pharmacokinetics following inhaled FF dosing and that the apparent t½β is an estimate of absorption rate. The lung mean absorption time for FF was approximately 7 h irrespective of formulation, which was considerably longer than FP (2.1 h). The time for 90 % absorption from the lung was significantly longer for FF (20–30 h) than for FP (8 h), indicating a significantly longer lung retention time for FF.ConclusionIn comparison with inhaled FP, inhaled FF (independent of formulation) demonstrated prolonged absorption from the lung into the systemic circulation, indicating a longer lung retention time and suggesting the potential for maintained efficacy with once-daily administration.

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An 8-day treatment course of intranasal FF 200 mcg given once-daily statistically significantly reduced symptoms of AR including associated eye symptoms. Statistical significance was declared where the relevant two-sided 95% confidence interval did not contain zero. This positive effect was sustained over 24 hours suggesting that fluticasone furoate could be efficacious as a once daily steroid.

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