Academia and industry agreement on a feasibility tool for first-time-in-human clinical trial units.

First-time-in-human (FTIH) trials are designed to generate information on the safety, tolerability, as well as the pharmacokinetic and pharmacodynamics profile of new drugs. To ensure the safety of participants, these trials need to be conducted at specifically equipped phase I clinical trial units (CTUs). In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) and the European Union (EU) regulatory guidelines, one of the aims of the European Regime Accelerator for Tuberculosis (ERA4TB) project is to collaboratively create a feasibility tool, through a partnership between public and private entities, for the validation of CTUs selected to conduct FTIH trials. A feasibility form, encompassing nine sections, was created to gather information on the unit in relation to key attributes of FTIH trials. Collaboratively, industry and academic partners defined the minimal criteria to ensure the adherence of CTUs to the principles of ICH GCP and regulations outlined by the European Medicines Agency (EMA) for the execution of FTIH trials. Subsequently, all CTUs available for the project were assessed for FTIH trial eligibility. The introduction of the certification procedure through the feasibility tool within ERA4TB resulted in the accreditation of the five academic CTUs, which are now prepared to carry out FTIH trials as part of the Consortium. The developed feasibility tool aims to establish open and widely used minimum requirements for the validation of academic CTUs as FTIH units, marking it as the inaugural tool for CTU validation resulting from the collaboration between industry and academia within the ERA4TB project. The established partnership has enabled an innovative and novel way of working.

Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers.

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.

Fluticasone furoate, a novel inhaled corticosteroid, demonstrates prolonged lung absorption kinetics in man compared with inhaled fluticasone propionate.

BACKGROUND: Fluticasone 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 ß(2)-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. OBJECTIVE: The 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. METHODS: This 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. RESULTS: The terminal elimination half-life (t(½ß)) for inhaled FF was considerably longer (range 17-24 h) than the t(½ß) estimated for intravenous FF (14 h), whereas t(½ß) 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 t(½ß) 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. CONCLUSION: In 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.

Fluticasone furoate versus placebo in symptoms of grass-pollen allergic rhinitis induced by exposure in the Vienna Challenge Chamber.

OBJECTIVE: The Vienna Challenge Chamber (VCC) offers a controlled and controllable paradigm in which to reproducibly evaluate the efficacy of anti-allergic treatment. The aim of this study was to assess the efficacy of the novel intranasal corticosteroid fluticasone furoate (FF) in the VCC. METHODS: The single-centre, randomised, double-blind, placebo-controlled, two-period crossover study was conducted in 59 adult males with grass pollen allergic rhinitis (AR). Patients received either Fluticasone furoate 200 mcg once-daily, or placebo intranasally for 8 days. AR symptoms were induced during 4-hour allergen challenges with grass pollen in the VCC at the end of each 8-day treatment period. A first challenge was conducted at 1-5 hours post-dose, followed by a second challenge at 22-26 hours post-dose. The primary endpoint was total nasal symptom score (TNSS; sum of itch, sneeze, rhinorrhoea, obstruction symptoms assessed on a categorical scale of 0-3) weighted mean over 2-5 hours post-dose. Secondary endpoints included: TNSS weighted mean over 23-26 hours post-dose and global symptom score, eye symptom score, nasal secretions and nasal airflow weighted means over 2-5 and 23-26 hours post-dose. RESULTS: Fluticasone furoate showed consistent attenuation of AR symptoms in both the early and late challenges. Compared with placebo, weighted mean of TNSS was reduced on average by 4.14 point-scores at 2-5 hours post-dose and 3.63 point scores at 23-26 hours post-dose. These positive effects were also seen across all secondary endpoints. CONCLUSION: 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.

Absolute bioavailability of intranasal fluticasone furoate in healthy subjects.

BACKGROUND: Fluticasone furoate (drug code GW685698) is an enhanced-affinity glucocorticoid that has been developed for the treatment of allergic rhinitis. OBJECTIVES: The objectives of this study were to estimate the absolute bioavailability of fluticasone furoate nasal spray and to describe the intranasal (IN) and IV pharmacokinetics of fluticasone furoate in healthy subjects. METHODS: This was a single-center, randomized, open label, 2-period crossover study. Healthy male and female subjects were randomized to receive supra-therapeutic doses of fluticasone furoate 880 microg IN qSh for 10 doses in 1 treatment period, and a single IV dose of 250 pg fluticasone furoate given as an infusion over 20 minutes in the other treatment period. Each treatment period was separated by a 4- to 5-day washout period. Blood sampling was carried out over 8 hours following the final IN dose and 24 hours following the IV dose to determine plasma fluticasone furoate concentrations. Plasma samples were analyzed for fluticasone furoate using online solid-phase extraction with high-performance liquid chromatography with tandem mass-spectrometric detection. The lower limit of quantification was 10 pg/mL. The sample size was based primarily on logistical considerations. Sample-size sensitivity was assessed by estimating the 90% CI for the absolute bioavailability of IN fluticasone furoate, based on different estimated bioavailabilities and within-subject SDs. The following pharmacokinetic parameters were derived: IN administration: AUC from time 0 to the end of the dosing interval (AUC(0-tau)), AUC(0-t), C(max), and T(max); IV administration: AUC(0-infinity), AUC(0-t), t(1/2), C(max), T(max), total systemic clearance, and volume of distribution at steady state. RESULTS: A total of 16 subjects were included in the study. Their mean age was 27.8 years (range, 19-45 years), and their mean body weight was 72.84 kg (range, 55.3-97.2 kg). The geometric mean AUC(0-tau) for 880 microg IN was 74.9 pg x mL/h and geometric mean AUC(0-infinity) for 250 microg IV was 4259 pg x mL/h. The geometric mean of the absolute bioavailability of fluticasone furoate nasal spray in these healthy subjects was 0.50% (90% CI, 0.34%-0.74%). The administration of large doses by the IN route did not elicit clinical concern. Three (19%) of 16 subjects reported adverse events (AEs) during the IN administration period, with 2 subjects experiencing dizziness and 1, toothache. Five (31%) subjects reported AEs during the IV administration period, with 3 subjects experiencing infusion-site or IV catheter-related events; 1 subject, dizziness; and 1 subject, headache. CONCLUSIONS: The geometric mean of the absolute bioavailability of fluticasone furoate 880 microg IN qSh for 10 doses in these healthy subjects was low--0.50%.