In this study, the safety, tolerability, and pharmacokinetics of intravenous (i.v.)-to oral-dose regimens of voriconazole were evaluated with a group of 42 healthy men, 41 of whom completed the study. Two cohorts of subjects participated in the study. Cohort 1 (n ‫؍‬ 28) took part in two study periods, each consisting of 14 days separated by a minimum 7-day washout. In one of the periods, 14 subjects received 6 mg/kg i. 1-fold increases in C max and AUC , respectively. Similarly, a 2-fold increase in oral dosing resulted in 2.8-and 3.9-fold increases in C max and AUC , respectively. The mean values for C max observed following oral dosing were lower than those obtained after i.v. administration, ranging from 62.7 to 89.6% of the i.v. value. After the switch from i.v. to oral dosing, most subjects achieved steady state by day 4, and mean minimum concentrations in plasma remained above clinically important MICs. The pharmacokinetic profiles for saliva followed a pattern similar to those observed for plasma; there was a highly significant correlation between plasma and saliva voriconazole concentrations (P < 0.0001). Voriconazole was well tolerated; the most commonly reported adverse events in voriconazole-treated subjects were mild to moderate headache, rash, and abnormal vision. Visual function tests detected no further abnormalities during voriconazole treatment.

Summary This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmö, Sweden on 23–24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient‐reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient‐reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient‐reported symptoms were discussed [including the Patient‐Oriented SCOring Atopic Dermatitis index, Patient‐Oriented Eczema Measure (POEM), Self‐Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient‐reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.

Summary This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12–14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long‐term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole‐group and small‐group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small‐group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole‐group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long‐term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long‐term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon.

Aims Voriconazole is a new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. These studies evaluated the pharmacokinetics and safety of intravenous voriconazole in healthy male volunteers. Methods Two single-blind, placebo-controlled studies were conducted. In Study A, 12 subjects were randomized to voriconazole (3 mg kg -1 ) or placebo, administered once daily on days 1 and 12, and every 12 h on days 3-11. In Study B, 18 subjects were randomized to voriconazole or placebo, with voriconazole being administered as a loading dose at 6 mg kg -1 twice on day 1, then at 3 mg kg -1 twice daily on days 2-9, and once at 3 mg kg -1 on day 10. Results In both studies, the plasma concentrations of voriconazole increased rapidly following the initiation of dosing. Minimum observed plasma concentration ( C min ) values at steady state were above the in vitro minimum inhibitory concentrations (MICs) for most fungal pathogens ( C min > 0.8 m g ml -1 ). The use of a loading dose in Study B resulted in a shorter time to steady-state C min values than was observed in Study A. Values of the final day plasma pharmacokinetic parameters in Studies A and B were similar: maximum observed plasma concentration ( C max ) 3621 and 3063 ng ml -1 ; areas under the plasma concentration-time curve from time zero to the end of the dosing interval (AUC t ) 16 535 and 13 245 ng·h ml -1 , and terminal elimination phase half-lives ( t 1/2 ) 6.5 and 6.7 h, respectively. On multiple dosing, voriconazole accumulated (AUC t accumulation ratio 2.53-3.17, Study A) at a level that was not predictable from single-dose data. The mean concentration-time profiles for voriconazole in saliva were similar to those in plasma. Multiple doses of voriconazole were well tolerated and no subject discontinued from either study. Seven cases of possibly drug-related visual disturbance were reported in three subjects (Study B). Conclusions Administration of a loading dose of 6 mg kg -1 i.v. voriconazole on the first day of treatment followed by 3 mg kg -1 i.v. twice daily achieves steady state by the third day of dosing. This dosage regimen results in plasma levels of the drug that rapidly exceed the minimum inhibitory concentrations (MICs) against important fungal pathogens, including Aspergillus spp.

Aims Voriconazole is a potent new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing. Methods Sixty-four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg -1 twice daily, 4 mg kg -1 once daily, 2 mg kg -1 three times daily, or 3 mg kg -1 twice daily. Eleven subjects received 1.5 mg kg -1 three times daily, and 21 subjects were administered placebo. Results Voriconazole exhibited nonlinear (dose-and time-dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing k el values on multiple dosing, with a consequent increase in the terminal phase t 1/2 . There was also notable intersubject variability in C max and AUC t . The absorption of voriconazole was rapid (mean t max = 0.9-1.7 h) after single and multiple dosing and the decline in plasma concentration-time curves after t max was generally biphasic. By day 12, the C max , AUC t , t max , and t 1/2 values for the 3 mg kg -1 twice-daily group were 2356 ng ml -1 , 11 170 ng·h ml -1 , 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single-dose data. Accumulation ratios for C max and AUC t , which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg -1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of C min values together with statistical analyses of C max and AUC t values suggest that steady-state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens ( C min > 0.8 m g ml -1 ). Voriconazole was well tolerated: most treatmentrelated adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing. Conclusions The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg -1 twice daily.