Pharmacokinetics and short-term safety of etravirine in combination with fluconazole or voriconazole in HIV-negative volunteers.

The nonnucleoside reverse transcriptase inhibitor etravirine, approved for use in treatment-experienced, HIV-1-infected patients, is a substrate and inducer of cytochrome P450 (CYP) 3A4 and a substrate and inhibitor of CYP2C9/CYP2C19. Pharmacokinetic interactions and safety of etravirine 200 mg twice daily coadministered with fluconazole 200 mg daily or voriconazole 200 mg twice daily, both inhibitors of CYP3A4, CYP2C9, and CYP2C19, were evaluated in an open-label, randomized, 3-period crossover trial in 18 HIV-negative volunteers. Based on least squares means (LSM) ratios, coadministration of etravirine with fluconazole or voriconazole resulted in higher etravirine exposures (area under plasma concentration-time curve from 0-12 hours [AUC(12) (h) ] 1.86- and 1.36-fold, respectively). Fluconazole pharmacokinetics were unchanged with etravirine coadministration (AUC(12) (h) LSM ratio: 0.94), and voriconazole plasma concentrations were slightly raised (AUC(12) (h) LSM ratio: 1.14). All treatments and combinations were well tolerated, with no grade 3 or 4 adverse events observed during treatment. There was 1 adverse event-related trial withdrawal during treatment with fluconazole alone (leukocyturia). The most frequent adverse events were headache and blurred vision (11 and 8 volunteers, respectively), with blurred vision occurring exclusively during voriconazole-alone treatment. Pharmacokinetic interactions between etravirine and fluconazole or voriconazole are not expected to be clinically relevant; no dose adjustments are required during coadministration.

Pharmacotherapy of disruptive behavior and item changes on a standardized rating scale: pooled analysis of risperidone effects in children with subaverage IQ.

BACKGROUND: Disruptive behavior disorders (DBDs), excluding attention deficit/hyperactivity disorder (ADHD), are characterized by a repetitive pattern of antisocial, aggressive, and defiant behavior involving major violations of age-appropriate norms, resulting in significant functional impairment. Risperidone is licensed for the treatment of DBDs in children, adolescents, and adults in several countries. The aim of this study was to determine the effect of risperidone in a clinical setting on the symptom items of the Nisonger Child Behavior Rating Form (N-CBRF), used for the assessment of DBD patients. METHOD: Data from two 6-week, randomized, double-blind, placebo-controlled trials of risperidone oral solution (0.02-0.06 mg/kg/day) in children with DBDs and subaverage IQ (mild, moderate mental retardation and borderline IQ) were pooled for analysis. RESULTS: Risperidone produced improvement in both the Social Competence and the Problem Behavior N-CBRF subscales. Risperidone reduced symptoms in the Problem Behavior subscales (e.g., Conduct Problem, Insecure/Anxious) but also improved positive behaviors on the Social Competence subscales. Unlike most problem-behavior items, certain items reflecting "Affective insecurity" (e.g., shy, timid; clings to adults; crying, tearful episodes) failed to improve. This was also true of social disinterest and certain rituals. No items showed any worsening of symptoms with active medication. CONCLUSION: Whereas most categories of problem behavior improved with risperidone, items reflecting "affective insecurity" and some infrequently endorsed items were unaffected in these children with DBDs and subaverage IQ. These data may provide a more refined knowledge of risperidone's therapeutic effects in such children.