A Thorough QT/QTc Study of Clobazam in Healthy Volunteers.

PURPOSE: A thorough QT study was conducted to assess the proarrhythmic potential of clobazam and its active metabolite, N-desmethylclobazam (N-CLB). METHODS: In this Phase I, single-site, randomized, double-blind, double-dummy, parallel-group study, healthy participants were randomized to 1 of 4 treatment groups: clobazam 40 mg/d (maximum therapeutic dosage), clobazam 160 mg/d (supratherapeutic dosage), placebo, or moxifloxacin 400 mg (active control). FINDINGS: Of 280 enrolled participants (n = 70 per treatment arm), 250 (92%) completed the study; 194 were included in the pharmacokinetics population (clobazam 40 mg/d, n = 66; clobazam 160 mg/d, n = 62; and moxifloxacin, n = 66). Mean changes from baseline in QT interval placebo-corrected for heart rate using the Fridericia formula (primary end point), Bazett formula, and individual correction method (QTcF, QTcB, and QTcI, respectively) with clobazam 40 and 160 mg/d revealed no effect on QTc. No clinically relevant or treatment-related arrhythmias were observed, and there were no instances of second- or third-degree atrioventricular block. Given that clobazam is primarily demethylated to N-CLB by cytochrome P450 (CYP) enzyme, CYP3A4, the mean plasma time-concentration profile of clobazam was unchanged with the exclusion of CYP2C19 poor metabolizers. As N-CLB is metabolized by CYP2C19, the exclusion of CYP2C19 poor metabolizers resulted in slightly decreased mean plasma time-concentration profiles of N-CLB. Using a linear mixed-effects model, the effects of the clobazam and N-CLB Cmax values on the placebo-corrected changes from baseline in QTcF, QTcI, and QTcB were near zero or slightly negative, and are not considered clinically important. The incidence of treatment-emergent adverse events was greatest in the clobazam groups (number of moderate AEs experienced by patients: PBO, 3/70; MOXI, 5/70; CLB 40 mg/d, 18/70; CLB 160 mg/d, 21/70; severe AEs: PBO, MOXI, & CLB 160 mg/d, 0; CLB 40 mg/d, 2/70); there were no serious AEs in any treatment group. A total of 10% of participants experienced benzodiazepine-withdrawal symptoms (16%, 23%, and 3% in the clobazam 40 and 160 mg/d groups and the moxifloxacin group, respectively). IMPLICATIONS: The findings from this thorough QT study are consistent with existing clinical data and support the lack of proarrhythmic potential with clobazam.

Assessment and prediction of pruritus in sickle cell disease patients: a preliminary study.

PURPOSE/OBJECTIVES: The purpose of this study was to better predict and assess pruritus in inpatients and outpatients with sickle cell disease. The aims were to describe the incidence and severity of pruritus using the visual analog scale (VAS) and the National Cancer Institute Common Toxicity Criteria (CTC) scale and to predict pruritus from common complications. DESIGN: This study was a prospective, cross-sectional design. SETTING: The study was conducted at a Midwestern National Cancer Institute hospital. SAMPLE: This prospective, cross-sectional design included patients with a diagnosis of sickle cell disease who were older than 18 years. METHODS: A demographic data form was used to collect biographical characteristics, and the CTC scale and VAS were used to evaluate pruritus. RESULTS: The participants (n = 56) were mostly women (62%) and outpatients (58%) and the mean number of complications was 1.9. The mean VAS score was 3.75, and the CTC score was 1.55. For inpatients, the mean VAS score was 5.17, and the CTC score was 1.65. For outpatients, the mean VAS score was 2.76, and CTC score was 1.56. The sensitivity and specificity for the VAS were 75% and 93%, respectively. The CTC scale was 56.2% and 100%, respectively. The difference in the area under the curve between the VAS and the CTC scale was 11.4% in favor of the VAS. Among complications (pulmonary hypertension, liver insufficiency, acute chest syndrome, renal insufficiency, iron overload, and chronic pain medication), chronic pain medication was the only significant predictor. CONCLUSIONS: Pruritus is common particularly in inpatients as well as outpatients. The VAS is a more sensitive and specific tool to measure pruritus. Chronic pain medication use is a predictor of pruritus. IMPLICATIONS: Clinicians must make patients aware that pruritus exists especially when pain medication is administered or prescribed.