A Simple and Flexible Model to Calculate Annual Merit Raises for Health Sciences Faculty

Purpose The objective of this study was to develop and implement a simple and flexible mathematical model to generate merit-based salary increases as a percentage of the faculty base salaries, with the flexibility to choose the range of merit raises. Methods Annual faculty performance scores, faculty base salaries, and available salary increase pool were used in a relatively simple linear model to determine the individual faculty merit raises as a percentage of their base salary. The core model allows the selection of a slope value that determines how steeply the merit raise changes with a change in the performance score. The application of the method to different scenarios, including random and non-random distribution of salaries and performance scores, was also tested. More advanced versions of the core model, where the slope value is calculated based on various criteria, are presented in an appendix. The models were incorporated into spreadsheets, which automatically calculate percent merit raises for different input scenarios. Results The developed method successfully estimates percent merit raises for individual faculty to precisely match the available merit pool fund. Additionally, merit raises simulated for scenarios with different slopes indicate that the range of distribution of percent merit raise is directly proportional to the slope, i.e., doubling the slope doubles the difference in the percent merit raises for the faculty with the lowest and highest performance scores. The application of the method to different scenarios indicates that the method is robust and independent of the available merit raise pool or distribution patterns of the salaries and performance scores among faculty. Conclusion Faculty merit raises may be easily calculated using a relatively simple model, which may be applied to a variety of cases where flexibility in the degree of distribution of raises is desired

Modulation of the Pharmacokinetics and Pharmacodynamics of Proteins by Polyethylene Glycol Conjugation

With the rapid advances in the field of biotechnology during the last decade, many peptides and proteins have been produced and evaluated for therapy of various diseases, including cancer. However, rapid clearance and the possibility of immunogenicity after the in vivo administration of these biotechnology-driven products have impeded their marketing. To circumvent these problems, synthetic and natural polymers such as polyethylene glycol (PEG) and dextrans, respectively, have been covalently attached to proteins, and some of these protein-polymer conjugates have shown promising therapeutic results. The conjugation of proteins with polymers usually causes a reduction in the recognition of the protein by the immune system, resulting in a decrease in protein clearance and immunogenicity. Most of the protein-polymer conjugates retain the pharmacologic activity of the protein, although to a lesser extent than the native protein. Additionally, in most of the examples in the literature, a significant increase in the plasma half life of the protein more than compensates for any reduction in the pharmacologic effects of the polymer-protein conjugates. Therefore, polymer conjugation in most cases would result in a net increase in the pharmacologic activity of the protein. The intent of this article is to review the pharmacokinetics and pharmacodynamics of proteins conjugated to PEG which is one of the most widely used synthetic polymers for protein conjugation

On-Line, Individualized, and Interactive Pharmacokinetic Scenarios with Immediate Grading and Feedback and Potential for Use by Multiple Instructors

On-line (web-based) pharmacokinetic modules were developed for 25 topics in basic and clinical pharmacokinetics. The modules consist of spreadsheet files, relational databases, and dynamic web. Instructors use a web browser to set up their class list, set/edit preferences (e.g, due date) for each module, and create on-line and e-mail reports of their students\u27 works. Students use a web browser to create an individualized assignment (scenarios without solutions) and unlimited practice problems (scenarios with solutions and graphs) and to submit their answers and receive immediate feedback. A test of the effect of innovation on students\u27 learning in a basic pharmacokinetics course indicated that the innovation caused a significant improvement in learning (similar to 10 percent), compared with traditional use of assignments in a paper format. Additionally, students\u27 evaluations of the innovation were extremely positive. The innovation was also successfully used by instructors and students in two other sites. The innovation may be used as a tool in active learning strategies in pharmacokinetics courses, without a significant time burden for the instructor

Application of Organ Clearance to Estimation of the In Vivo Hepatic Extraction Ratio

Organ clearance, which has been derived from the organ blood flow and extraction ratio (E), has been extensively used by clinical pharmacologists to explain the pharmacokinetics of many drugs in health and disease. For example, the extent of hepatic clearance or E (Eh) of drugs would determine their response to changes in the liver blood flow and/or activities of the metabolizing enzymes. Although Eh may be obtained directly by cannulating internal blood vessels, the method is invasive. Therefore, indirect methods have been used to estimate Eh from the peripheral blood concentration-time data after intravascular administration of drugs. Additionally, these indirect methods require an estimate of the liver blood flow in the patients or animals. However, some investigators use plasma concentrations and/or liver plasma flow for the estimation of Eh, which could potentially result in significant errors. It is shown here that when plasma concentrations are used along with liver blood flow, an overestimation or underestimation of the true value will result if the blood: plasma concentration (B:P) ratio is \u3e1 or \u3c 1, respectively, with the estimated Eh being different from the true value by a factor equal to the B:P ratio. On the other hand, the use of plasma concentrations and plasma liver flow will always result in an overestimation of the true Eh unless the drug does not penetrate the red blood cells. It is concluded that for the accurate estimation of Eh from the in vivo data, the blood concentration and blood flow should be used

Effects of Simulations on the Learning of Pharmacokinetic Concepts

Objective: Although the use of computer simulations in pharmacokinetics courses is not new, the data on the effects of simulation on student learning are scarce. The objective of this study was to design and evaluate the use of Web-based simulations on the learning of pharmacokinetic concepts by doctor of pharmacy (PharmD) students. Method: Six online modules were designed to allow the instructor and students to use “what-if” scenarios for understanding the effects of various dosage regimens and/or pharmacokinetic parameters on the plasma concentration-time courses of drugs. The designed modules were intravenous and oral pharmacokinetic concepts, bioavailability, intravenous infusion, multiple dosing, nonlinear pharmacokinetics, and hepatic clearance. The effects of simulation modules on student learning were tested in pre/post tests for the multiple dosing module and in mid-term assessments for the hepatic clearance concepts. Additionally, the students’ perceptions of the effectiveness of the modules were determined using a survey. Results: Compared with a pretest, a 10-min use of the multiple dosing module in class by students resulted in a 21% improvement in the performance of the students in a posttest. Additionally, the use of the hepatic clearance module outside the classroom was associated with a 16% improvement in their performance in a mid-term assessment. Finally, the students’ responses to an attitudinal survey indicated that students believe the use of modules improves their learning of pharmacokinetic concepts. Conclusions: Online simulation modules dealing with pharmacokinetic concepts improve student learning of pharmacokinetics

The Importance of Active Learning and Practice on the Students\u27 Mastery of Pharmacokinetic Calculations for the Intermittent Intravenous Infusion Dosing of Antibiotics

Estimation of pharmacokinetic parameters after intermittent intravenous infusion (III) of antibiotics, such as aminoglycosides or vancomycin, has traditionally been a difficult subject for students in clinical pharmacology or pharmacokinetic courses. Additionally, samples taken at different intervals during repeated dose therapy require manipulation of sampling times before accurate calculation of the patient-specific pharmacokinetic parameters. The main goal of this study was to evaluate the effectiveness of active learning tools and practice opportunities on the ability of students to estimate pharmacokinetic parameters from the plasma samples obtained at different intervals following intermittent intravenous infusion

Interdependency of Pharmacokinetic Parameters: A Chicken-and-Egg Problem? Not!

Pharmacokinetic (PK) software packages are widely used by scientists in different disciplines to estimate PK parameters. However, their use without a clear understanding of physiological parameters affecting the PK parameters and how different PK parameters are related to each other may result in erroneous interpretation of data. Often, mathematical relationships used for the estimation of PK parameters obscure the true physiological relationships among these parameters, prompting a discussion of which parameter came first and giving the appearance of the-chicken-and-the-egg dilemma. In this article, the author attempts to show how different PK parameters are related to physiological parameters and each other by using various scenarios and examples. In particular, the relationship between clearance and the rate of elimination and that among the other major PK parameters are explored. It is concluded that there is no dilemma in interdependency of the PK parameters, and the relationships among the PK parameters and between PK and physiological parameters are clear

Kinetics of Hepatic Accumulation of Dextrans in Isolated Perfused Rat Livers

The role of various processes (uptake, release, metabolism, and excretion) in the hepatic accumulation of dextrans was investigated in isolated perfused rat livers (IPRLs). Single-pass IPRLs were infused with fluorescein-dextran (FD) with a molecular weight (MW) of 70,000 (FD-70) for 15, 30, 45, or 60 min, and inlet and outlet samples and livers were collected. In addition, two groups of livers were infused with FD-70 for 60 min, followed by 30 or 60 min of drug-free perfusion. The concentrations of the macromolecule in the samples were measured by a size exclusion chromatographic method. Similar, but limited, experiments were also conducted for FDs with MWs of 4,000 (FD-4) and 150,000 (FD-150). In addition, the metabolism of all three FDs were investigated using liver homogenates. Because of low hepatic extraction, the concentrations of dextrans in the inlet and outlet perfusates were almost the same during the entire perfusion. However, liver concentrations increased almost linearly during the infusion of FD-70 (0–60 min) and declined slowly thereafter (60–120 min). The apparent hepatic extraction ratio (Eapp) values, estimated directly from the concentrations of FDs in the liver, were MW dependent; Eapp of FD-4 (0.124% ± 0.015%) was significantly (p \u3c 0.05) less than that for FD-70 (0.677% ± 0.193%) or FD-150 (0.711% ± 0.022%). The metabolism and biliary excretion of all FDs were negligible during the perfusion time. The mean residence time of FD-70 in the liver, estimated by nonlinear regression analysis of experimental data, was 248 min. These studies define the role of various processes involved in the slow (but substantial) and MW dependent hepatic accumulation of dextrans

Clearance Concepts: Fundamentals and Application to Pharmacokinetic Behavior of Drugs

Clearance concepts were introduced into the pharmacokinetics discipline in the 1970s and since then have played a major role in characterization of the pharmacokinetic behavior of drugs. These concepts are based on the relationship between organ extraction ratio or clearance and physiologic parameters such as the organ blood flow and the intrinsic capability of the eliminating organ to remove the free (unbound) drug from the body. Several theoretical models have been developed, which define these relationships and may be used to predict the effects of changes in the physiological parameters on various pharmacokinetic parameters of drugs, such as drug clearance. In this communication, the fundamentals of the two most widely used models of hepatic metabolism, namely the well-stirred (venous equilibrium) and parallel-tube (sinusoidal perfusion) models, are reviewed. Additionally, the assumptions inherent to these models and the differences between them in terms of their predictive behavior are discussed. The effects of changes in the physiologic determinants of clearance on the blood concentration-time profiles of drugs with low and high extraction ratio are also presented using numerical examples. Lastly, interesting and unusual examples from the literature are provided where these concepts have been applied beyond their widely known applications. These examples include estimation of the oral bioavailability of drugs in the absence of otherwise needed intravenous data, differentiation between the role of liver and gut in the first-pass loss of drugs, and distinction between the incomplete absorption and first-pass metabolism in the gastrointestinal tract after the oral administration of drugs. It is concluded that the clearance concepts are a powerful tool in explaining the pharmacokinetics of drugs and predicting the changes in their blood concentration-time courses when the underlying physiologic parameters are altered due to age, disease states, or drug interactions

Hepatic Disposition of Cyclosporine A in Isolated Perfused Rat Livers

PURPOSE. To develop an isolated perfused rat liver model to study the hepatic disposition of cyclosporine A (CyA) in both sexes. METHODS. Livers were isolated from male (n = 6) and female (n = 7) rats and perfused with a physiological buffer in a single-pass manner. A bolus 1-mg dose of CyA was injected into the inlet catheter and periodical samples (0-15 min) were collected from the outlet perfusate. The concentrations of CyA in the outlet perfusate, collected bile (0-15 min), and liver tissue (at the end of perfusion) were quantitated by HPLC and subjected to statistical moment analysis. RESULTS. The dilution curves of CyA in the outlet perfusate exhibited unusually long terminal phases due to large volume of distribution of the drug (~100 mL/g) and its slow release from binding sites in the liver (net release rate constant of ~0.020 min-1 ). This was in contrast to the rapid uptake of the drug, indicated by significant amounts of the intact drug (\u3e40%) taken up during one single pass through the liver. Consequently, the liver tissue:perfusate distribution ratio of CyA was very high (~220). No significant differences were found between the male and female livers in any of the estimated parameters. CONCLUSIONS. The tissue binding of cyclosporine A is substantial, slowly reversible, and gender-independent in isolated perfused rat livers