No abstract

Response to antipsychotics is highly variable, which may be due in part to differences in drug exposure. The goal of this study was to evaluate the magnitude and variability of concentration exposure of olanzapine. Patients with Alzheimer's disease (n = 117) and schizophrenia (n = 406) were treated with olanzapine as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Combined, these patients (n = 523) provided 1527 plasma samples for determination of olanzapine concentrations. Nonlinear mixed-effects modeling was used to determine the population pharmacokinetics of olanzapine, and patient-specific covariates were evaluated as potential contributors to variability in drug exposure. The population mean olanzapine clearance and volume of distribution were 16.1 L/h and 2150 L, respectively. Elimination of olanzapine varied nearly 10-fold (range, 6.66-67.96 L/h). Smoking status, sex, and race accounted for 26%, 12%, and 7% of the variability, respectively (P < .0001). Smokers cleared olanzapine 55% faster than non/past smokers (P < .0001). Men cleared olanzapine 38% faster than women (P < .0001). Patients who identified themselves as black or African American cleared olanzapine 26% faster than other races (P < .0001). Differences in olanzapine exposure due to sex, race, and smoking may account for some of the variability in response to olanzapine.

Serious infection due to strains of Pseudomonas aeruginosa that exhibit resistance to all common antipseudomonal antimicrobials increasingly is a serious problem. Colistin was used as salvage therapy for 23 critically ill patients with multidrug-resistant P. aeruginosa infection. Twenty-two patients who had septic shock (n=14) and/or renal failure (n=21) received mechanical ventilatory support at baseline. The most common types of infection were pneumonia (n=18) and intra-abdominal infection (n=5). Colistin was administered for a median of 17 days (range, 7-36 days). Seven patients died during therapy, at a median of 17 days (range, 4-26 days) after initiation of treatment. A favorable clinical response was observed in 14 patients (61%); only 3 patients experienced relapse. Bacteremia was the only significant factor associated with treatment failure (P=.02). One patient manifested diffuse weakness that resolved after temporary cessation of colistin therapy. Colistin provides an important salvage therapeutic option for patients with otherwise untreatable serious P. aeruginosa infection.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Risperidone metabolism is affected by blocking CYP2D6 and CYP3A4 (in CYP2D6 poor metabolizers) metabolizing enzymes.• Age affects risperidone disposition and renal function affects elimination of 9-hydroxy-risperidone (primary active metabolite). WHAT THIS STUDY ADDS• The detection of a systematic shift in estimated apparent clearance in the African-American population (it is not clear if there are biological or sociological contributors), and a shift in the clearance rate of risperidone based on concomitant administration of paroxetine, manifested as a change in assignment to a different metabolizer subpopulation group that may be primarily related to CYP2D6 metabolizer status. • The study shows an age-related decrement in 9-hydroxy-risperidone clearance across a wide range of ages.• Information on the nature of the pharmacokinetic variability with risperidone when used in a typical clinical patient population.• There are significant differences in the absolute values as well as the assignment to metabolizer status across race and concomitant paroxetine administration. AIMSTo characterize pharmacokinetic (PK) variability of risperidone and 9-OH risperidone using sparse sampling and to evaluate the effect of covariates on PK parameters. METHODSPK analysis used plasma samples collected from the Clinical Antipsychotic Trials of Intervention Effectiveness. A nonlinear mixed-effects model was developed using NONMEM to describe simultaneously the risperidone and 9-OH risperidone concentration-time profile. Covariate effects on risperidone and 9-OH risperidone PK parameters were assessed, including age, weight, sex, smoking status, race and concomitant medications. RESULTSPK samples comprised 1236 risperidone and 1236 9-OH risperidone concentrations from 490 subjects that were available for analysis. Ages ranged from 18 to 93 years. Population PK submodels for both risperidone and 9-OH risperidone with first-order absorption were selected to describe the concentration-time profile of risperidone and 9-OH risperidone. CONCLUSIONSA one-compartment mixture model with first-order absorption adequately described the risperidone and 9-OH risperidone concentrations. Age was identified as a significant covariate on 9-OH risperidone clearance in this study.

IMPORTANCE The shift toward value-based care has placed emphasis on preventive care and chronic disease management services delivered by multidisciplinary health care teams. Community pharmacists are particularly well positioned to deliver these services due to their accessibility. OBJECTIVE To compare the number of patient visits to community pharmacies and the number of encounters with primary care physicians among Medicare beneficiaries who actively access health care services.