Student Research Competition 2002

Faculty of Pharmaceutical Sciences University of British Columbia Alan C. Hayman Summer Student Research Competition 2002

Pharmacokinetics of mycophenolate in the early period following lung and heart transplantation

Leanne Kwan, Nilufar Partovi, Diane Decarie, Robert D. Levy, Guy Fradet, Andrew P. Ignaszewski, Mary H.H. Ensom. University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: The purpose of this pilot study was to evaluate the pharmacokinetics of mycophenolic acid (MPA) at 3 different times in the early period following lung or heart transplantation.

Methods: Nine patients were entered into this open-label study. Upon administration of a steady-state morning mycophenolate mofetil (MMF) dose, blood samples were collected at 0, 20, 40, 60, and 90 minutes and at 2, 4, 6, 8, 10, and 12 hours post-dose, at 3 different times in the early post-transplant period (targeted at post-transplant days 5-7, 20-40, and 60-80, respectively, and denoted as Sampling Periods 1, 2, and 3). Total MPA concentrations were measured by a validated high performance liquid chromatography (HPLC) method with ultraviolet detection and followed by ultrafiltration of pooled samples for free MPA concentrations. Pharmacokinetic parameters were calculated by traditional noncompartmental methods.

Results: Patient characteristics included: 7 males and 2 females; 5 lung and 4 heart transplant recipients; mean (±SD) age of 53±11 yr; and weight of 77±14 kg. All patients were on prednisone and cyclosporine (with the exception of 2 patients on tacrolimus during Sampling Periods 2 and 3). Sampling Periods 1, 2, and 3 occurred on post-transplant days 15+13, 56+33, and 125+73, respectively. Mean (±SD) parameters are as follows:

Sampling
Period
A LB

g/L

SrCr

mmol/L

Dosage Cmax

mg/mL

DN Cmax

mg/mL

T max h Cmin

mg/mL

AUC

mg*h/

mL

DN AUC

mg*h/mL

f % free AUC

mg*h/mL

 

mg/day mg/kg/day
1 32* (9) 129 (44) 2444 (527) 34.1 (11.4) 10.25 (7.86) 9.21 (7.99) 3.2 (4.01) 0.25 (0.52) 39.95 (44.86) 36.74 (44.81) 7.1 (3.6) 4.03 (6.62)
2 34 (5) 126 (53) 2500 (500) 36.8 (13.7) 8.83 (5.86) 7.18 (4.45) 0.8 (0.6) 0.34 (0.53) 25.24 (25.68) 20.72 (18.27) 4.3 (2.1) 1.14 (1.06)
3 37* (5) 134 (77) 2389 (486) 34.2 (10.9) 12.51 (9.53) 10.37 (7.74) 1.5 (1.2) 0.94 (1.63) 43.96 (38.67) 35.50 (27.17) 5.0 (2.9) 2.30 (3.10)

Conclusions: This is the first study to systematically evaluate MPA pharmacokinetics in thoracic transplant recipients at 3 different time points during the early post-transplant period. Wide inter-patient variability in MPA pharmacokinetics was observed, thus emphasizing the need to individualize dosing of MMF and to further evaluate important pharmacokinetic/pharmacodynamic parameters and endpoints that impact on clinical outcomes. Further studies involving more patients and pharmacodynamic outcomes are underway to help identify optimal MMF strategies.

Acknowledgements: BC Health Research Foundation/ BC Transplant Foundation; BC Research Institute for Children’s & Women’s Health; LK was supported by a CIHR Health Professional Student Research Award.

Psychiatric rating scales, side effects, compliance and other assessments of psychiatric inpatients: finding the correlation

Kaleena Patel, Ric M. Procyshyn, Deborah Thompson. Riverview Hospital, Port Coquitlam, British Columbia, Canada, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

Objective: To determine if there is a correlation between the various psychiatric rating scale scores and clinical pharmacist’s notes, medication side effects and compliance of psychiatric inpatients.

Methods: This retrospective study involved the review of clinical pharmacists’ notes of patients on their admission to the Refractory Psychosis Unit of Riverview Hospital, British Columbia. Psychiatric rating scales included the Drug Attitude Inventory to measure patient compliance, and the ESRS to identify movement disorders. The therapeutic category and total number of patient’s medications was recorded. Caffeine intake and nicotine use were also included. An analysis of the numerical data was performed, comparing one set of measurements against another to reveal correlations between any of these measurements.

Results: Data comparison identified two statistically significant correlations were found: patients who smoked tended to use more anticholinergic medications, and scored lower on the DAI .All other data was relatively similar between smoking and nonsmoking patients.

Conclusion: Two correlations may exist, indicated by higher anticholinergic medication use and lower DAI scores in smoking patients.. There may be several possible explanations for these trends, ranging from the chemical effects of nicotine at receptor sites to the inherent characteristics of addiction and addictive behaviour in these patients. Further research into the type and frequency of anticholinergic drug use, the accompanying side effects, patient-medication compliance, and the effects of smoking on all of these factors is required.

Medication specific predictors of adherence with Cardiovascular Regimens

Ivana Dojcinovic and Stephen Shalansky. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: The goal of this study was to identify medication specific predictors of adherence with cardiovascular regimens (e.g. frequency, medication class, etc.)

Methods: A survey was administered to 458 subjects who had taken a lipid lowering medication or an angiotensin converting enzyme (ACE) inhibitor for at least 3 months. Information was collected on non-prescription drug use, demographics, adverse effects, and use of adherence aids. Prescription medication use data over the previous 14 months was obtained for each subject from the Pharmanet, British Columbia prescription claims database. Adherence for each prescription medication was calculated based on prescription fill dates and number of days supplied. Univariate and multivariate analyses were used to identify medication specific predictors of adherence (<80%) with cardiovascular medications while controlling for individual patient characteristics.

Results: Of the 1543 drugs that were taken by 458 patients, 209 (13.5%) drugs were taken less than 80% of the time. Fifty-eight (12.7%) subjects were categorized as non-adherent. Medication class did not appear to independently predict adherence; however, adherence with cardiac glycosides was slightly higher than for other medication classes (95.3% ± 9.2% vs. 91.8% ± 14.1%, P<0.001). The majority of medications were taken once (74.1%) or twice daily (21.3%). Controlling for the effects of alternative medicine use, number of over-the-counter medications consumed, number of regular prescription medication consumed, use of adherence aids, living alone and clinic participation, adherence was less likely for drugs taken more often than once daily (OR 0.67, 95% CI 0.48-0.93, P=0.02). However, the clinical importance of this is questionable since there was little difference in the percent adherence between drugs taken = once per day, and those taken > once per day (92.5% ± 13.7% vs. 91.1% ± 14.1%, P=0.09). The use of adherence aids also appeared to be an independent predictor of adherence with individual medications (OR 1.48, 95% CI 1.06-2.05, P=0.02).

Conclusions: Within this study cohort, once daily dosing and use of adherence aids were found to be independent medication-specific predictors of adherence. However, though once daily dosing appears to have a statistically significant impact on adherence, the clinical impact is likely negligible.

Establishing a limited sampling strategy for cyclosporine (neoral™) in pediatric renal transplant patients

Joanne Li, Chris Cameron, Dawn Strong, David S. Lirenman, Mary H. H. Ensom. University of British Columbia and Children’s and Women’s Health Centre of British Columbia, Vancouver, BC, Canada.

Purpose: In pediatric renal transplant patients,

1) to define the optimal limited sampling strategy (LSS) for cyclosporine (CSA) (Neoral®) monitoring and to test its predictive performance, and

2) to characterize the pharmacokinetic parameters of Neoral®.

Methods: In Phase I, 11 pediatric renal transplant patients were entered into the study, following written informed consent. Upon administration of a steady-state morning Neoral® dose, blood samples were collected at 0, 0.5, 1, 2, 4, 6, and 8 hours post-dose. The whole blood samples were analyzed for CSA by fluorescence polarization immunoassay using a specific monoclonal antibody kit. Pharmacokinetic parameters were determined via non-compartmental analysis using WinNonlin® software. LSSs were determined by multiple regression analysis with forward stepwise elimination using Statistica® software. In Phase II, 16 patients underwent regular clinical monitoring of Neoral® and had blood collected and analyzed according to the above procedures. These data were used to test the predictive performance [measured by the coefficient of determination (r2), bias, and precision] of LSSs developed in Phase I.

Results: Data from Phase I patients were used to derive the following LSSs; the predictive performance of these equations, as tested in Phase II patients, is depicted below:

Area-under-the-curve (AUC) Equations

(mg*hr/L)

r2 Bias Precision
AUC = 6.98C2 – 964.51 0.84 0.21 0.32
AUC = 1.02C1 + 5.58C2 – 830.94 0.89 0.02 0.17
AUC = 3.18C0 + 5.69C2 – 535.20 0.83 0.15 0.23
AUC = 1.14C0.5 + 6.24C2 – 860.99 0.84 0.15 0.24

For Phase I patients, mean±SD AUCo-t was 4660±1849 mg*hr/L, Cmax was 1060±452 mg/L, Cmin was 164±101 mg/L, Tmax was 1.1±0.5 hours, and half-life was 5.0±1.8 hours.

Conclusions: The optimal and most clinically feasible LSS for pediatric renal transplant recipients 1) requiring one blood sample is AUC = 6.98C2 – 964.51; 2) requiring two blood samples is AUC = 1.02C1 + 5.58C2 – 830.94. This is based on patient wait time, number of blood samples required, coefficient of determination, bias, and precision. These are preliminary results as the final target for this study is n=25 for Phase I. Final study findings will be incorporated directly into clinical practice.

Acknowledgements: Elisa-Marie Babor, Dr. James Carter, Dr. Morrison Hurley, Dr. Colin White, Novartis Pharmaceuticals Canada Inc., and the BC Research Institute for Children’s and Women’s Health 2002 Summer Students’ Research Program.

Evaluating the implementation of a collaborative pharmacist research network

Peter Tong, David W. Fielding, Elan C. Paluck, Mary H.H. Ensom, Marc Levine, James P. McCormack, Judith A. Soon. CORxE UBC, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: To evaluate the implementation of a Collaborative Pharmacist Research Network (CPRxN) during its first year of operation, and to identify facilitators and barriers to the adoption and participation in the network’s first study, which examined the effectiveness of buproprion for smoking cessation in 200 patients over a one-year period.

Methods: A survey based on Roger’s Diffusion of Innovations Theory , and Roberts-Gray’s Systems Model of the Implementation Phase of Innovation and Planned Change , was developed and mailed to the 149 network pharmacists from 50 community pharmacies throughout British Columbia. The survey contained questions that measured the innovation characteristics of the CPRxN and of the buproprion study. To improve response rates, a phone call was made to each pharmacy prior to the survey mailing and 2 weeks after the survey was sent. In addition, pharmacists were permitted to complete the survey anonymously and a $10 cash honorarium was provided.

Results: Overall response rate was 75.9%, with 102 of 149 network pharmacists submitting completed surveys and an additional 11 pharmacists returning their surveys uncompleted with the $10 honorarium. Of the completed surveys, 82.4% of respective pharmacists participated in the buproprion study (i.e., recruited at least one patient). Major motivating factors for pharmacist participation included the opportunity to participate in research, interest in the use of buproprion for smoking cessation, and the desire to improve pharmacy practice. However, 91.7% of pharmacists experienced at least one problem with the buproprion study in regards to its complexity and compatibility with pharmacy procedures. Major barriers included insufficient staffing at pharmacies, low priority placed for the buproprion study, inability to incorporate CPRxN duties into pharmacy practice, and being discouraged by a poor initial response from eligible patients. In addition, 32.8% of respective pharmacists believed the honorarium for patient enrollment should be at least double that used for the buproprion study. The lack of new prescriptions for buproprion as a smoking cessation aid also made patient enrollment difficult. Furthermore, respondents identified team building, training, monitoring, and funding as areas where additional support could help in future studies.

Conclusions: The barriers to enrolling patients in the buproprion study stemmed mainly from the complexity and compatibility of the expected CPRxN duties. While some barriers are project-specific and out of the control of researchers, such as the decreasing number of buproprion prescriptions since 2000, others were related to CPRxN operation and can be managed by increased implementation support.

Acknowledgements: Funding provided by the BC Medical Services Foundation.

Student data analysis of a cross-disciplinary, case-based problem using the web-based learning centre in a large pharmaceutics class

Philip Hui, Simon P. Albon, Lynda Eccott. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.

Background: An online, cross-disciplinary case-based problem was created and implemented during the 2001-2002 academic year. The problem was implemented in Pharmacy 311 (Drug Delivery Systems I) using the Web-Based Learning Centre as the delivery platform. Student feedback data was collected and analyzed toevaluate the effectiveness of this learning activity.

Methods: Following the four-week implementation of the problem, an online student survey was administered to the students. The survey included 26 multiple-choice questions and 3 open-ended questions. The multiple-choice questions utilized the Likert scale to quantify student opinions. All multiple-choice questions were analyzed for reliability using the Wilcoxin signed-rank test with an alpha level of 0.05. Chi-square contingency analysis was conducted on 9 pairs of survey questions in an attempt to establish correlation among student responses.

Results: A total of 125 students responded to the survey for a 94 percent response rate. The overall rating of the online problem ranged from 1 (poor) to 5 (excellent), with an average rating of 2.18. The overall rating for the learning activity was “fair”. Nine pairs of correlation results were summarized as follows:

Major correlation

Question # Question # p-value
26  

Overall rating

03 Comfort in contributing online <0.0001
04 Depth of understanding 0.0003
05 Teaching support 0.0013
20 Inadequate time <0.0001
22 Having student answer all questions 0.0004
04 Depth of learning 20 Inadequate time <0.0001
10 Teaching support 0.2974
26 Overall rating 21 Student previous knowledge 0.0577
06 Technical support 0.1242

Discussion: Students preferred to work on the online problem earlier during the term, and to have more time to research the guiding questions. Tutor support was perceived to be insufficient, suggesting that student learning environment had not been optimized. Students complimented the flexibility and accessibility of the online problem. However, they also commented that online tutorial sessions are inefficient compared to face-to-face tutorial sessions. Furthermore, students felt that the depth of understanding of materials was not as deep as the face-to-face mode of delivery. This is contradictory to established literature.

Conclusion: An online, cross-disciplinary case-based problem was created and implemented in a large pharmaceutics class. This new learning activity has the potential to enhance student cross-disciplinary thinking. Feedback data showed that online delivery of tutorial problems using the Web-Based Learning Centre is feasible. While students rated the online problem as “fair”, Likert-scale data as well as written comments provided useful information for future implementation.

The impact of complementary and alternative medicine use on warfarin-related adverse outcomes

Stephen J. Shalansky,Esther A. Abd-Elmessih, Rudy C. Sedlak, Larry Lynd.  Faculty of Pharmaceutical Sciences, The University of British Columbia, St. Paul’s Hospital, Vancouver, British Columbia, Canada.

Purpose: The purpose of this study was to identify the prevalence of complementary and alternative medicine (CAM) use and its associated adverse outcomes (INR ³ 4 or bleed) amongst a cohort of patients taking warfarin. In addition, exposure patterns to prescription medications, over-the-counter medications, vitamins and supplements were also identified.

Methods: Patients taking warfarin were identified through a review of pharmacy, cardiac rehabilitation clinic, anticoagulation clinic, and atrial fibrillation clinic records. Those patients consenting to participate were administered a cross-sectional standardized survey. Patients were queried as to their daily dose of warfarin, information regarding minor bleeding episodes, acute illness, alcohol consumption, hospitalization, and prescription and OTC drug use. Patients were also questioned regarding vitamin K-containing food consumption and CAM use. British Columbia’s provincial prescription database (Pharmanet) was accessed, with patients’ consent, providing information on prescription medication used for the three month period prior to the survey date. Patient INR values were obtained from medical laboratories when such data were available.

Results: The survey was completed by 156 patients, 71 (46%) of whom reported CAM use over the month prior to survey including 51 (33%) who had used at least one CAM reported to potentially increase the risk of bleeding or an INR outside of the therapeutic range. The most common potentially interacting CAMs were vitamin E (26%), garlic (10%), chamomile (6%) and coenzyme Q10 (5%). Sixty-nine patients (44%) reported bleeding events in the past month. Of the 146 patients for whom INR results were available, 19 (12%) had INRs = 4 and 52 (33%) had INR < 2 during the month prior to survey. Comparing patients who did and did not report the use of a CAMs that could potentially increase the risk an elevated INRs, there was an unexpected trend towards CAM users having lower incidence of an INR > 4.0 (16% versus 5% respectively, P=0.06). Comparing patients who did and did not use a CAM that could increase the risk of bleeding through anti-platelet effects, there was a similar trend towards CAM users being less likely to report bleeding events over the past month (48% versus 38% respectively, p=0.22), although the difference was not statistically significant for either comparison.

Conclusions: While the use of potentially interacting CAM was common amongst this cohort of warfarin patients, it did not appear to increase the risk of bleeding or having an elevated INR.

Acknowledgments: Erin Neall, Melissa Lo, Biljana Radulovic.  Faculty of Pharmaceutical Sciences, The University of British Columbia, St. Paul’s Hospital, Vancouver, British Columbia, Canada.

Physician dispensing of non-prescribed emergency contraceptive pills in women in british columbia

Rita H.W. Lung, Judith A. Soon, Marc Levine.  Collaboration for Outcomes Research and Evaluation (CORxE), Faculty of Pharmaceutical Sciences, The University of British Columbia,  Vancouver, British Columbia, Canada.

Purpose: Emergency Contraceptive Pills (ECPs) are accessed through various sources in British Columbia, one of which is physicians. While physician prescribing of ECP is well recorded, “out-of-cupboard” ECP provision has not been well documented. However, out-of-cupboard provision has been estimated to be as high as 35% of the total number of ECP treatments distributed throughout BC. The purpose of this study was to quantify the “out-of-cupboard” dispensing from GP offices/clinics and to identify the prescribing and dispensing patterns of ECP by GPs.

Methods: The College of Physicians & Surgeons registry database was obtained. All apparent GPs were selected, then stratified by health region and randomized. Calculations performed in a prior pilot study determined the sample size for a full study. A 10% sample of registered GPs (373 physicians) was extracted from the database and the physicians were invited to participate in the study. Physician offices were initially contacted by telephone and advised that a cover letter and one-page survey would be faxed. After completing the 10-item survey, the physician was requested to fax the document back to the research group. Non-responders were contacted by telephone twice, at a 2-week interval. Surveys were mailed to physicians without facsimile access.

Results: The response rate was 46% (173 completed surveys evaluated.) Respondents were 68% male, 60% were in group practices, and 68% were full-time physicians. In the previous 12 months, 68% of respondents provided ECPs without a prescription. During this period, respondents provided ECPs a mean of 25.6 times (range 1-260.) Ovral® was the ECP agent most often distributed by physicians, both through written prescriptions (83%) and out-of-cupboard sources (99%). Plan B™ was most often prescribed by 25% of respondents and most often provided by 7%. GPs in BC provided 4.00 ± 0.36 tablets per non-prescribed ECP treatment. Extrapolation of the data suggests that out-of-cupboard ECP provision is projected to be more than 196,000 Ovral® tablets per year. This represents a substantial proportion of Ovral® sales not previously captured by PharmNet, Planned Parenthood, and youth clinic data. Of physicians who provided out-of-cupboard ECPs, 15% reported providing them to patients for future use and 66% provided antiemetic tablets with the ECP treatment.

Conclusions: Out-of-cupboard ECP provision from physician offices is a substantial source of ECP distribution, which contributes considerably to the impact of ECP treatments on pregnancy and abortion rates in BC.

Acknowledgements: This study was funded by BC Ministry of Health Planning, BC Women’s Hospital and Health Centre, and an AFPC/Apotex PACE Studentship.

Analyzing the prevalence and outcome of pharmaceutical industry sponsored clinical studies involving risperidone or olanzapine (an interim analysis)

Anthony Chau, Ric M. Procyshyn, Willough Jenkins, Patricia Fortin. Faculty of Pharmaceutical Sciences, The University of British Columbia and Riverview Hospital, Vancouver, BC, Canada.

Purpose: The purpose of this study is two-fold:

1. To investigate the prevalence of sponsorship in psychiatric literature involving two atypical antipsychotics: risperidone and olanzapine.

2. To determine the outcomes of clinical trials that are sponsored by pharmaceutical industry.

Methods: Both antipsychotics were initially searched by subject and keyword between the years 1990 and 2002. Following this, “schizophrenia and disorders with psychotic features” was exploded in Medline. This search was next limited to the different types of clinical trials (i.e., phase I, II, III, IV, controlled, multicenter and randomized). A final limit by Human and English language was then performed. All studies found within the search were compiled. Excluded were review articles, letters and meta-analyses. Data collected included the following parameters: Disclosure of any financial support, author(s) employed by the industry, comparator drug(s) within the trial, sample size, blinding, placebo controlled, and outcome (if the study was sponsored).

Results: The literature search captured a total of 347 published journal articles of which 198 met the inclusion criteria for our study. Ninety-five (48%) of these studies were Industry sponsored (56 by Eli Lilly and 39 by Janssen). Regarding authorship, industry-employed authors was significantly higher for the studies funded by Eli Lilly compared to Janssen (76.8% vs. 23.1% respectively, p<0.05). However, significantly more of the Eli Lilly sponsored studies compared their antipsychotic (olanzapine) to at least on other atypical antipsychotic (28.6 vs. 10.3% for Janssen sponsored studies, p<0.05). Overall, no significant difference was noted for positive outcomes reported in the industry sponsored studies (91.1% vs. 79.5 for Eli Lilly and Janssen sponsored studies respectively). What’s more, no negative results were reported in any of the funded studies. The major difference between the non sponsored studies and the industry sponsored studies is that the latter were more likely to be blinded and placebo controlled.

Conclusions: Almost 50% of published clinical trials involving olanzapine or risperidone have been funded by their respective manufacturer. Furthermore, the reported outcomes of the sponsored studies are highly in favor of their respective product.

Acknowledgements: Funding for this project was provided by the Canadian Institute of Health Research.

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