Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy

BACKGROUND: Voriconazole was introduced for the treatment of life-threatening fungal infections. The intravenous form includes the solvent vehicle sulphobutylether beta cyclodextrin sodium which shows an impaired clearance under intermittent dialysis therapy. This investigation aimed to determine first clinical data on sulphobutylether beta cyclodextrin sodium blood levels to verify the risk for accumulation. METHODS: In four patients suffering from renal insufficiency and intermittent dialysis therapy who needed a treatment with intravenous voriconazole as a reserve antifungal at the intensive care unit of the Mainz University Hospital the trough levels of voriconazole and sulphobutylether beta cyclodextrin sodium were measured. RESULTS: A 75-year-old woman showed a maximal sulphobutylether beta cyclodextrin sodium plasma level of 145 μg/ml in the initial phase. After a few days renal function recovered and the plasma levels came down to less than 20 μg/ml. In contrast to this patient with a recovery of renal function the remaining three patients showed renal failure during the complete period of intravenous treatment with voriconazole. In these patients an accumulation of sulphobutylether beta cyclodextrin sodium plasma levels was determined with a maximum of 523 μg/ml in a 18-year-old man, 409 μg/ml in a 57-year-old man, and 581 μg/ml in a 47-year-old man. CONCLUSION: The present data indicate an accumulation of sulphobutylether beta cyclodextrin sodium in patients treated with intravenous voriconazole and dialysis therapy. Fortunately, no toxic effects were observed, although the accumulated dose values were lower but comparable with those used in previous toxicity studies with animals

Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative)

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

Pharmacokinetics and Safety of Voriconazole following Intravenous- to Oral-Dose Escalation Regimens

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.v. twice a day (b.i.d.) on day 1 followed by 3 mg/kg i.v. b.i.d. on days 2 to 7 and were then switched to 200 mg orally b.i.d. for days 8 to 14. In the other period, subjects received 6 mg/kg i.v. b.i.d. on day 1 followed by 5 mg/kg i.v. b.i.d. on days 2 to 7and were then switched to 400 mg orally b.i.d. for days 8 to 14. The remaining 14 subjects in cohort 1 received a matching placebo throughout the study. In cohort 2 (n = 14), 7 subjects received 6 mg/kg i.v. b.i.d. on day 1 followed by 4 mg/kg i.v. b.i.d. on days 2 to 7 and were then switched to 300 mg orally b.i.d. for days 8 to 14. The remaining seven subjects in cohort 2 received a matching placebo. Blood samples were taken prior to dosing on days 1 to 6 and on days 8 to 13. Blood samples were drawn prior to dosing and at frequent intervals up to 12 h following the morning dose on days 7 and 14 of each study period. The samples were assayed for voriconazole by a high-performance liquid chromatography method. The maximum concentration in plasma (C(max)) occurred at the end of the 1-h i.v. infusion and between 1.4 and 1.8 h after oral administration. Voriconazole exhibited nonlinear pharmacokinetics, possibly due to saturable metabolism. For cohort 1, both C(max) and the area under the concentration-time curve within a dosage interval (AUC(τ)) increased disproportionately with dose for both i.v. and oral dosing. For i.v. dosing, a 1.7-fold increase in dose resulted in 2.4- and 3.1-fold increases in C(max) and AUC(τ), respectively. Similarly, a 2-fold increase in oral dosing resulted in 2.8- and 3.9-fold increases in C(max) and AUC(τ), 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

A phase 2a proof of concept clinical trial to evaluate ZPL-3893787 (ZPL-389) a potent, oral histamine H4, receptor antagonist for the treatment of moderate to severe atopic dermatitis (AD) in adults

peer reviewedIt is well documented that histamine-induced inflammation is largely mediated through the H4 receptor (H4R). T lymphocytes and keratinocytes from patients with atopic dermatitis (AD) express high levels of H4R which mediate cytokine upregulation and histamine-induced proliferation. The identification of IL-17 positive cells in psoriatic lesions, and the fact that these cells expressed a functional H4R, lends weight to its therapeutic potential in inflammatory skin diseases such as AD and psoriasis. ZPL-389 is a low nanomolar and selective H4R antagonist