by Dr. Ray Nims
In a previous posting, Leah Choi described her frustration over the lack of specific training, received during her undergraduate schooling, in aspects germane to the realities of employment within the biopharmaceutical industry. Employment in the highly regulated world of biopharmaceutical manufacturing, Quality, and Quality Control (biopharmaceutical operations) requires different skills and employee temperaments compared to employment within the research and development (R&D) world. The academic institutions would do well to consider this during the preparation of students for eventual life in the working world.
What do we mean by different skills and employee temperaments? Most of us are familiar with the Myers and Briggs personality typing instrument which looks at attibutes like intro/extraversion, sensing, intuition, etc. This instrument provides interesting and revealing information about how different people deal with the world. In addition to the qualities addressed by Myers & Brigg, however, there is a personality spectrum which I will refer to as Innovation ↔ Perfection.
In the R&D world, technical knowledge, mastery of the literature concerning a subject, and most importantly, innovation are the attributes which are essential for success. A researcher must long to travel untraveled paths, to uncover new ground, to learn and often develop methods where such may not have existed previously (i.e., to go where no man has gone before). Those who are well suited to this environment we refer to as innovators. The academic institutions are pretty good at fostering these attributes in students.
On the other hand, the highly regulated areas of biopharmaceutical operations require individuals who are capable of following set instructions time after time, documenting their work in a precise and strictly controlled manner. Innovation, improvisation, and experimentation with mature methodologies and standard operating procedures are not encouraged. A mind-set which is compatible with achieving perfect compliance with documented procedures is the key to success in this environment. Such individuals we refer to as perfectionists, as they are motivated by the desire (or if not desire, at least the requirement) to conduct their work exactly as proscribed. It is this particular set of attributes which many academic programs fail to address adequately. This leaves employers with the task of training their entry-level staff in such matters, and (as Leah mentioned in her posting) students with the sometimes shocking revelation that they are poorly prepared for this type of employment.
Are there individuals who can be successful both as “innovators” and as “perfectionists”? Undoubtedly so! It is more likely, however, that most people fit within a spectrum falling between the two temperaments. I, for instance, have always regarded myself more of a perfectionist than an innovator, happily conducting the same assay the 100th time and still trying to do a better job than the last time. I know of others who, as soon as they learn a method, are bored with it and anxious to move on to something new. These temperaments may be determined by our personalities and may not be subject to alteration. It would appear to be valuable for academic programs to try, therefore, to determine the temperaments of their students, and to provide training suitable and appropriate for both the innovators and the perfectionists. Both the students as well as the biomedical industry would benefit from a little temperament triage and curriculum adjustment done at the undergraduate level.
Showing posts with label GLP. Show all posts
Showing posts with label GLP. Show all posts
Tuesday, March 23, 2010
Friday, November 6, 2009
Enzyme induction…done pharmacodynamically
By Ray Nims
Pharmacodynamics is the study of a specific effect of a drug as related to drug concentration at the putative active-site for that effect. Pharmacodynamics is sometimes used to model quantitatively the effect of a drug over time as drug concentration at the active-site rises and falls. Another type of pharmacodynamic study entails exposing the animal or in vitro system to graded doses of a drug and monitoring the effect associated with each active-site concentration. From the latter type of study, one is able to estimate both potency for the effect (given in terms of the active-site drug concentration at the half-maximal effect for that drug, or EC50) and its efficacy (given in terms of percentage of maximal response compared to other drugs causing the same effect through the same mechanism). In receptor theory, EC50 is considered to reflect the affinity of the drug for a receptor, while efficacy is a measure of the bound drug’s ability to cause the specific response.
The induction of drug-metabolizing enzymes, such as the cytochromes P450, may be considered to represent an effect of a drug or xenobiotic. It is common for investigators to measure such induction at one or a few dose levels and to compare the resulting enzyme induction with that of a prototype inducer. These comparisons are sometimes described in terms of the test xenobiotic causing “strong” (“potent”) or “weak” induction in comparison with the prototype inducer. As already pointed out quite elegantly by D. A. Smith and coworkers (Letter to the Editor: The Time to Move Cytochrome P450 Induction into Mainstream Pharmacology is Long Overdue. Drug Metab. Dispos. 35:697-698, 2007; http://dmd.aspetjournals.org/cgi/content/full/35/4/697), such statements are both misleading and inaccurate. As with any drug effect, enzyme induction must be described in terms of both potency and efficacy. It is possible for an inducer to be very potent but to display little efficacy. In fact, a xenobiotic having high potency and little or no induction efficacy might represent a competitive inhibitor for this effect. In contrast, there may be inducers which are very effective, but not very potent.
It is possible for efficacy and potency for enzyme induction to be estimated on the basis of studies using intact animals, provided that certain assumptions are made (e.g., that total plasma drug concentration is a suitable proxy for drug concentration at the induction active site, which cannot be sampled directly). An example of such a study is that of R.W. Nims and coworkers (Comparative Pharmacodynamics of Hepatic Cytochrome P450 2B Induction by 5,5-Diphenyl- and 5,5-Diethyl-substituted Barbiturates and Hydantoins in the Male F344/NCr Rat. J. Pharmacol. Exp. Therap. 270: 348-355, 1994; http://jpet.aspetjournals.org/cgi/content/abstract/270/1/348). A more straightforward approach is offered through in vitro enzyme induction studies, in which enzyme induction can be related to drug concentration in the culture medium (e.g., Kocarek and coworkers: Differentiated Induction of Cytochrome P450b/e and P450p mRNAs by Dose of Phenobarbital in Primary Cultures of Adult Rat Hepatocytes. Mol. Pharmacol. 38:440-444, 1990; http://molpharm.aspetjournals.org/cgi/content/abstract/38/4/440).
Measurement of the induction of the cytochromes P450 and other drug-metabolizing enzymes following drug treatment in animals and humans is an important aspect of drug characterization. The studies should be performed and reported in a manner consistent with other drug effects, that is, in a manner consistent with the principles of pharmacology.
Pharmacodynamics is the study of a specific effect of a drug as related to drug concentration at the putative active-site for that effect. Pharmacodynamics is sometimes used to model quantitatively the effect of a drug over time as drug concentration at the active-site rises and falls. Another type of pharmacodynamic study entails exposing the animal or in vitro system to graded doses of a drug and monitoring the effect associated with each active-site concentration. From the latter type of study, one is able to estimate both potency for the effect (given in terms of the active-site drug concentration at the half-maximal effect for that drug, or EC50) and its efficacy (given in terms of percentage of maximal response compared to other drugs causing the same effect through the same mechanism). In receptor theory, EC50 is considered to reflect the affinity of the drug for a receptor, while efficacy is a measure of the bound drug’s ability to cause the specific response.
The induction of drug-metabolizing enzymes, such as the cytochromes P450, may be considered to represent an effect of a drug or xenobiotic. It is common for investigators to measure such induction at one or a few dose levels and to compare the resulting enzyme induction with that of a prototype inducer. These comparisons are sometimes described in terms of the test xenobiotic causing “strong” (“potent”) or “weak” induction in comparison with the prototype inducer. As already pointed out quite elegantly by D. A. Smith and coworkers (Letter to the Editor: The Time to Move Cytochrome P450 Induction into Mainstream Pharmacology is Long Overdue. Drug Metab. Dispos. 35:697-698, 2007; http://dmd.aspetjournals.org/cgi/content/full/35/4/697), such statements are both misleading and inaccurate. As with any drug effect, enzyme induction must be described in terms of both potency and efficacy. It is possible for an inducer to be very potent but to display little efficacy. In fact, a xenobiotic having high potency and little or no induction efficacy might represent a competitive inhibitor for this effect. In contrast, there may be inducers which are very effective, but not very potent.
It is possible for efficacy and potency for enzyme induction to be estimated on the basis of studies using intact animals, provided that certain assumptions are made (e.g., that total plasma drug concentration is a suitable proxy for drug concentration at the induction active site, which cannot be sampled directly). An example of such a study is that of R.W. Nims and coworkers (Comparative Pharmacodynamics of Hepatic Cytochrome P450 2B Induction by 5,5-Diphenyl- and 5,5-Diethyl-substituted Barbiturates and Hydantoins in the Male F344/NCr Rat. J. Pharmacol. Exp. Therap. 270: 348-355, 1994; http://jpet.aspetjournals.org/cgi/content/abstract/270/1/348). A more straightforward approach is offered through in vitro enzyme induction studies, in which enzyme induction can be related to drug concentration in the culture medium (e.g., Kocarek and coworkers: Differentiated Induction of Cytochrome P450b/e and P450p mRNAs by Dose of Phenobarbital in Primary Cultures of Adult Rat Hepatocytes. Mol. Pharmacol. 38:440-444, 1990; http://molpharm.aspetjournals.org/cgi/content/abstract/38/4/440).
Measurement of the induction of the cytochromes P450 and other drug-metabolizing enzymes following drug treatment in animals and humans is an important aspect of drug characterization. The studies should be performed and reported in a manner consistent with other drug effects, that is, in a manner consistent with the principles of pharmacology.
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