Teresa A. O'Sullivan

Disposition of drugs in cystic fibrosis. IV. Mechanisms for enhanced renal clearance of ticarcillin

To investigate the hypothesis that renal secretion of penicillins is enhanced in cystic fibrosis the maximal tubular secretion rate (Tmax) of ticarcillin and the serum concentration of ticarcillin at half‐maximal secretion rate (TC50) were determined in patients with cystic fibrosis (n= 6) and control subjects (n= 6). Each subject received three consecutive constant‐rate intravenous infusions of ticarcillin (4, 13, and 70 mg/kg/hr; 21/2 hours each) simultaneously with a constant‐rate (30 mg/kg/hr) infusion of inulin. Urine samples were collected at 1/2‐hour intervals and serum samples at the midpoint of the urine collections. Ticarcillin and inulin concentrations in serum and urine were determined by high‐performance liquid chromatographic and a spectrophotometric method, respectively. Ticarcillin serum protein binding was determined by ultrafiltration. Steady‐state ticarcillin serum concentrations were achieved at all three infusion rates. The TC50 was significantly lower (p < 0.05) in patients with cystic fibrosis (33.7 ± 12.2 μg/ml) compared with that in control subjects (77.6 ± 38.4 μg/ml). In contrast, the Tmax was similar (cystic fibrosis, 0.25 ± 0.12 mg/min/kg; control, 0.22 ± 0.14 mg/min/kg; p> 0.05). These data indicate that renal clearance of penicillins is enhanced in cystic fibrosis because of greater affinity of the renal secretory system for these drugs.

Disposition of drugs in cystic fibrosis. V. In vivo CYP2C9 activity as probed by (S)-warfarin is not enhanced in cystic fibrosis.

Enhanced metabolism of theophylline in subjects with cystic fibrosis suggests that the activity of certain cytochrome P450 isoforms is affected in subjects with this genetic disease. To determine whether this effect on the P450 enzymes is selective, the in vivo activity of the cytochrome P450 isoform CYP2C9 was determined in adult subjects with cystic fibrosis (n= 6) and in control subjects (n= 8). Subjects were administered (S)‐warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 96 hours. Plasma (S)‐warfarin concentrations were determined by HPLC; urinary concentrations of (S)‐warfarin and its metabolites were determined by gas chromatography‐mass spectrometry. The total plasma clearance of (S)‐warfarin (subjects with cystic fibrosis, 3.6 ± 0.48 ml/hr/kg; control subjects, 3.82 ± 0.73 ml/hr/kg), elimination half‐life (subjects with cystic fibrosis, 29.5 ± 4.2 hours; control subjects, 25.9 ± 5.4 hours); and steady‐state volume of distribution (subjects with cystic fibrosis, 153 ± 18 ml/kg; control subjects, 138 ± 22 ml/kg) were similar in the two groups (p> 0.05). The metabolic clearance of (S)‐warfarin to its major metabolites mediated by CYP2C9, 6‐hydroxywarfarin and 7‐hydroxywarfarin, was not significantly (p> 0.05) different between the two groups (6‐hydroxywarfarin: subjects with cystic fibrosis, 0.33 ±0.1 ml/hr/kg; control subjects, 0.41 ± 0.1 ml/hr/kg; 7‐hydroxywarfarin: subjects with cystic fibrosis, 1.34 ± 0.49 ml/hr/kg; control subjects, 1.8 ± 0.45 ml/hr/kg). On the basis of these data, we conclude that the in vivo cytochrome P450 activity is selectively affected in persons with cystic fibrosis.

Disposition of drugs in cystic fibrosis. VI. In vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)‐warfarin (including P450 3A4) is not enhanced in cystic fibrosis

To determine whether the activity of cytochrome P450 isoforms involved in the metabolism of (R) ‐warfarin is enhanced in cystic fibrosis.

A Qualitative Analysis of Common Concerns about Challenges Facing Pharmacy Experiential Education Programs

Objective. To qualitatively analyze free-text responses gathered as part of a previously published survey in order to systematically identify common concerns facing pharmacy experiential education (EE) programs. Methods. In 2011, EE directors at all 118 accredited pharmacy schools in the US were asked in a survey to describe the most pressing issues facing their programs. Investigators performed qualitative, thematic analysis of responses and compared results against demographic data (institution type, class size, number of practice sites, number and type of EE faculty member/staff). Expert and novice investigators identified common themes via an iterative process. To check validity, additional expert and novice reviewers independently coded responses. The Cohen kappa coefficient was calculated and showed good agreement between investigators and reviewers. Results. Seventy-eight responses were received (66% response rate) representing 75% of publicly funded institutions and 71% of schools with class sizes 51-150. Themes identified as common concerns were site capacity, workload/financial support, quality assurance, preceptor development, preceptor stipends, assessment, onboarding, and support/recognition from administration. Good agreement (mean percent agreement 93%, ƙ range=0.59-0.92) was found between investigators and reviewers. Conclusion. Site capacity for student placements continues to be the foremost concern for many experiential education programs. New concerns about preceptor development and procedures for placing and orienting students at individual practice sites (ie, “onboarding”) have emerged and must be addressed as new accreditation standards are implemented.

Disposition of drugs in cystic fibrosis. II. Hepatic blood flow

To determine whether the increased clearance of high extraction‐ratio drugs in cystic fibrosis is caused by an increase in hepatic blood flow, the blood flow in main branches of the hepatic vein and portal vein was measured by use of noninvasive duplex ultrasound scanning in 10 adult subjects with cystic fibrosis and in 10 healthy age‐, gender‐, and height‐matched control subjects. No statistically significant differences between subjects with cystic fibrosis and control subjects were detected in either the hepatic vein (217 ± 103 ml/min for subjects with cystic fibrosis versus 211 ± 135 ml/min for control subjects) or the portal vein (205 ± 114 ml/min for subjects with cystic fibrosis versus 190 ± 101 ml/min for control subjects) blood flows. These data indicate that a large (≥100%) increase in the clearance of high extraction‐ratio drugs in patients with cystic fibrosis is unlikely to be primarily caused by an increase in hepatic blood flow. It is probable that alternative mechanisms such as enhanced secretory or metabolic pathways account in large part for increases in clearance of high extraction‐ratio drugs.

Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis

The objective of this study was to assess the pharmacokinetics of diclofenac sodium and its five metabolites following administration of a 150 mg oral dose to healthy subjects and patients with either chronic active hepatitis of varying morphology or alcoholic cirrhosis. Six healthy subjects, 6 chronic active hepatitis patients, and 6 alcoholic cirrhosis patients were enrolled in this prospective, open‐label, parallel study. Blood samples were drawn at 0, 0.25, 0.5, 0.75,1,2,4,6,8,12, 24, 48, 72, 144, 312, and 480 hours, and urine samples were collected for 144 hours after administration of a single oral dose of diclofenac sodium. The mean area under the serum concentration‐time curve extrapolated to infinity, oral clearance, half‐life, maximal concentration, and time to peak concentration for diclofenac and its metabolites were determined and compared using analysis of variance. Cirrhotics had a mean ± SD diclofenac AUC value (19,114 ± 6806ng•h/ml) significantly different (p < 0.02) from hepatitis patients (6071 ± 1867 ng•h/ml) and healthy subjects (7008 ± 2006 ng•hlml), whereas healthy subjects and hepatitis patients had similar values. Comparable results were found for 4′‐hydroxydiclofenac. The AUC values for 3′‐hydroxydiclofenac and 3′‐hydroxy‐4′methoxydiclofeanc were significantly different when healthy subjects were compared to cirrhotics. However, hepatitis subjects were not significantly different from either group. The results indicate that hepatitis does not alter the pharmacokinetics of diclofenac. Alcoholic cirrhosis increased the mean diclofenac AUC approximately three times compared to normal subjects, indicating that one‐third of the usual dose in cirrhotics would produce equivalent AUC values in normal subjects and subjects with alcoholic cirrhosis. However, since pharmacodynamic measurements were not made and no increase in untoward or side effects was noted in the alcoholic cirrhosis patients after a single dose, maintenance doses should be titrated to patient response.

Medical Literature Evaluation Education at US Schools of Pharmacy

Objective. To determine how medical literature evaluation (MLE) is being taught across the United States and to summarize methods for teaching and assessing MLE. Methods. An 18-question survey was administered to faculty members whose primary responsibility was teaching MLE at schools and colleges of pharmacy. Results. Responses were received from 90 (71%) US schools of pharmacy. The most common method of integrating MLE into the curriculum was as a stand-alone course (49%). The most common placement was during the second professional year (43%) or integrated throughout the curriculum (25%). The majority (77%) of schools used a team-based approach. The use of active-learning strategies was common as was the use of multiple methods of evaluation. Responses varied regarding what role the course director played in incorporating MLE into advanced pharmacy practice experiences (APPEs). Conclusion. There is a trend toward incorporating MLE education components throughout the pre-APPE curriculum and placement of literature review/evaluation exercises into therapeutics practice skills laboratories to help students see how this skill integrates into other patient care skills. Several pre-APPE educational standards for MLE education exist, including journal club activities, a team-based approach to teaching and evaluation, and use of active-learning techniques.

Student-Valued Measurable Teaching Behaviors of Award-Winning Pharmacy Preceptors

Objective. To identify specific preceptor teaching-coaching, role modeling, and facilitating behaviors valued by pharmacy students and to develop measures of those behaviors that can be used for an experiential education quality assurance program. Methods. Using a qualitative research approach, we conducted a thematic analysis of student comments about excellent preceptors to identify behaviors exhibited by those preceptors. Identified behaviors were sorted according to the preceptor’s role as role model, teacher/coach, or learning facilitator; measurable descriptors for each behavior were then developed. Results. Data analysis resulted in identification of 15 measurable behavior themes, the most frequent being: having an interest in student learning and success, making time for students, and displaying a positive preceptor attitude. Measureable descriptors were developed for 5 role-modeling behaviors, 6 teaching-coaching behaviors, and 4 facilitating behaviors. Conclusion. Preceptors may need to be evaluated in their separate roles as teacher-coach, role model, and learning facilitator. The developed measures in this report could be used in site quality evaluation.

Qualitative analysis of common definitions for core advanced pharmacy practice experiences.

Objective. To determine how colleges and schools of pharmacy interpreted the Accreditation Council for Pharmacy Education’s (ACPE’s) Standards 2007 definitions for core advanced pharmacy practice experiences (APPEs), and how they differentiated community and institutional practice activities for introductory pharmacy practice experiences (IPPEs) and APPEs. Methods. A cross-sectional, qualitative, thematic analysis was done of survey data obtained from experiential education directors in US colleges and schools of pharmacy. Open-ended responses to invited descriptions of the 4 core APPEs were analyzed using grounded theory to determine common themes. Type of college or school of pharmacy (private vs public) and size of program were compared. Results. Seventy-one schools (72%) with active APPE programs at the time of the survey responded. Lack of strong frequent themes describing specific activities for the acute care/general medicine core APPE indicated that most respondents agreed on the setting (hospital or inpatient) but the student experience remained highly variable. Themes were relatively consistent between public and private institutions, but there were differences across programs of varying size. Conclusion. Inconsistencies existed in how colleges and schools of pharmacy defined the core APPEs as required by ACPE. More specific descriptions of core APPEs would help to standardize the core practice experiences across institutions and provide an opportunity for quality benchmarking.

Diclofenac Kinetics in Patients with Liver Disease

Clinical Pharmacology & Therapeutics (1996) 59, 149–149; doi: 10.1038/sj.clpt.1996.94