Measurement of patient-relevant benefits in the treatment of chronic hand eczema--a novel approach.

BACKGROUND: The assessment of patient-relevant treatment benefit gains importance in treatment evaluation. The 'Patient Benefit Index' (PBI) is a validated instrument for the assessment of such benefits in patients with skin diseases. Patients rate the importance of specific treatment needs before treatment and benefits achieved after treatment. To date, no specific instrument for chronic hand eczema (CHE) has been published. OBJECTIVES: Development and validation of a specific PBI for treatment evaluation in patients with CHE. METHODS: Items reflecting disease burden and treatment needs were collected in 20 patients with CHE. Relevant items were selected by an expert panel of dermatologists, psychologists, and patients. The resulting 'Patient Benefit Index for chronic hand eczema' (PBI-HE) was validated in an open label treatment study with alitretinoin in n = 249 patients. RESULTS: Cronbach's alpha was 0.93. High convergent validity was demonstrated for clinical improvement and treatment success (Spearman r = 0.60-0.78, P < 0.001); 84.3% of patients reached a PBI >or= 1, indicating more than minimum patient-relevant benefit of alitretinoin. Feasibility was high, with a rate of missing data < 1%. CONCLUSIONS: The PBI-HE is a feasible, reliable, and valid instrument for the assessment of patient-relevant treatment benefits in CHE.

Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers.

BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by once-daily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815. In each cohort, six subjects received active drug and two subjects received the placebo. Study duration was 21 days (oral) and 14 days (intravenous). All adverse events reported were mild or moderate, except one severe rhinitis event which was not related to trial medication. After both routes of administration, maximum drug concentration observed in plasma (C(max)) and area under the concentration-time curve (AUC) values of BAL4815 increased proportionally to the administered dose. AUC values reflected a fourfold to fivefold accumulation of active drug in plasma during once-daily dosing, which is in line with the long elimination half-life of BAL4815 determined after the last administration (mean, 84.5 to 117 h). At steady state, the volume of distribution was large and amounted to 308 to 542 liters. Systemic clearance reached only 2.4 to 4.1 liter/h. At the levels obtained in the present study, C(max) values of 2.56 and 2.55 microg/ml after oral and intravenous administrations, respectively, there was no indication of CYP3A4 induction or inhibition (as revealed by the urinary 6-beta-hydroxycortisol/cortisol test). Based on AUC values after oral and intravenous administration, an excellent oral bioavailability can be predicted for BAL4815. Once-daily oral dosing of 50- or 100-mg equivalents of BAL8557 were recently demonstrated to be efficacious in a phase 2 study conducted with patients with esophageal candidiasis. These doses (preceded by adequate loading dose[s]) will be further explored in the treatment of systemic mycoses.