Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a Phase III, randomized, placebo-controlled trial Patients with HES *Secondary endpoints included time to first flare, annualized flare rate, proportion of patients experiencing a flare during Weeks 20-32 and change from baseline at Week 32 in fatigue severity; safety outcomes were also assessed. HES, hypereosinophilic syndrome; SC, subcutaneous. Mepolizumab Placebo REDUCTION in proportion of patients who experienced a flare or withdrew during study SIMILAR proportions of patients experienced on-treatment adverse events

In this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).

AimsWe have previously shown that the systemic exposure to inhaled fluticasone propionate (FP) is reduced in asthmatics compared with healthy subjects. We have now compared its pharmacokinetics in patients suffering from chronic obstructive pulmonary disease (COPD, n = 10) and matched healthy subjects ( n = 13). Methods A double-blind, randomized, cross-over study design was used. Plasma FP and serum cortisol were measured for 12 h after subjects received hydrofluoroalkane FP 1000 m g day -1 inhaled (via an MDI and spacer) for 7 days and following a single 1000-m g intravenous dose.Results The pharmacokinetics differed in the two groups. After inhalation, geometric least square means were significantly lower in the COPD group for the plasma AUC (1961 vs 2996 pg ml -1 h -1 for COPD and controls, respectively; P = 0.03) and the C max (235 vs 421 pg ml -1 for COPD and controls, respectively; P = 0.03). Suppression of serum cortisol concentration over 12 h was greater in healthy controls. Weighted mean serum cortisol concentration (nmol l -1 ) in healthy subjects and COPD was 93 and 170, respectively ( P = 0.03). The intravenous pharmacokinetic parameters for FP were comparable in the two groups, resulting in similar suppression of serum cortisol. Conclusions We conclude that the altered pharmacokinetics of inhaled fluticasone propionate in COPD caused less hypothalamic-pituitary-adrenal suppression than in healthy controls. This is further evidence that the systemic effects of inhaled corticosteroids should be assessed in patients and not healthy subjects.

Busulfan systemic exposure correlates with regimen-related toxicity, engraftment and relapse in select patients receiving high-dose oral busulfan (HD-BU) (1 mg/kg dose or 40 mg/m dose every 6 h for 16 doses) as part of a preparative regimen for bone marrow transplantation. Therapeutic drug monitoring is frequently conducted after the first HD-BU dose in order to determine necessary dose adjustments. Limitations with this method include the need for rapid determination of busulfan plasma concentration and difficulties with estimating apparent oral clearance in patients who exhibit delayed absorption of HD-BU. This pharmacokinetic study was conducted to evaluate the ability of the apparent oral clearance obtained after administering a lower (0.25 mg/kg) test dose and the traditional (1 mg/kg) first dose to predict the dose required to achieve a desired area under the concentration-time curve (AUC) at steady-state (13th dose). In addition, the pharmacokinetic parameters of test, first and 13th dose were compared to assess intrasubject variability. Twenty-nine patients received a test dose of oral busulfan (0.25 mg/kg) the day immediately prior to initiation of HD-BU. Busulfan serum concentrations were measured following the test, first and 13th doses using gas chromatography with electron capture detection. The AUC and apparent oral clearance were calculated using non-compartmental analysis. Therapeutic drug monitoring following the first dose of HD-BU was conducted for clinical purposes in six patients, and dose adjustment between the first and 13th dose occurred in only two patients. The dose-corrected test dose and first dose AUC and apparent oral clearance were not bioequivalent (two one-sided t-tests, +/-20%). The first dose and 13th dose AUC and apparent oral clearance were also not bioequivalent. Six of the 29 patients receiving HD-BU dose based on weight (1 mg/kg) would have achieved a steady-state AUC of 3600-5400 ng x h/ml, a frequently used target AUC, as compared to eight and 13 patients if their dose was based on the apparent oral clearance following the test dose and first dose HD-BU, respectively. Monitoring busulfan concentrations after a test dose or a first dose provides a better estimate of the dose needed to achieve the target steady-state AUC as compared to traditional weight-based dosing. However, significant intraindividual variability exists in the apparent oral clearance of busulfan and follow-up therapeutic drug monitoring is recommended particularly if the desired target AUC range is narrow.