The Potential of Population Pharmacokinetics in Drug Regulation - Essay Example

The Potential of Population Pharmacokinetics in Drug Regulation 0 Introduction Given a rapidly increasing global population, and the continued prevalence of debilitating disease affect every sector of society. the need for therapeutic options continues to be at the forefront of modern medicine. One such approach lies in population pharmacokinetics analysis as a methodology designed to obtain critical and lifesaving pharmacodynamic and pharmacokinetic information. This information can be gleaned from data sets that are often observed and realised during phase II and phase III clinical study (Baksh, Edelman, & Sausville, 2013). It should be noted, however, that such studies typically have numerous patients, yet few observations per patient are actually ever recorded. For medical studies where it is not possible to conduct intensive blood sampling on patients, the benefits of population pharmacokinetics is becoming even more apparent. For this, one just has to consider children and patients currently living with cancer or the AIDS virus (Chan, Morris, Llett, & Tett, 2011). Both of these will be discussed in this report. While the concept of population pharmacokinetics was first introduced into the medical community over 50 years ago by Sheiner and Beal, it was not until the late 1980s that the approach had gained traction. At that time, medical researchers began to embrace population pharmacokinetics as a viable therapeutic option for many critically ill patients, and the movement at that point gained appreciable momentum (Bigos, Bies, & Pollock, 2006). In the modern era, countless pharmaceutical companies spanning the globe now embrace the population pharmacokinetic approach on a routine basis, to varying degrees, during their research and development process for new and potentially life saving drugs. This approach has since received recognition from numerous pharmaceutical related governing boards around the world. In 1999, for example, the Food and Drug Administration in the United States issued their own publication entitled ‘Guidance for Industry: Population Pharmacokinetics’. This well organised document sets out the mechanisms and philosophy inherent with population pharmacokinetics, and it issues policy directives related to its important and vital role in current drug development endeavours. The acceptance of this approach by the U.S. Food and Drug Administration, in addition to other governmental agencies throughout the globe, has encouraged an enhanced screening process during Phase II and Phase III studies (Colucci, 2011). As this has occurred, more and more drug companies have come on board into the realisation of today’s widespread adoption of this innovative and methodologically sound approach. A secondary factor mitigation this acceptance has been the growing awareness that population pharmacokinetics provides a cost effect approach that can reveal clinically critical information about the determinants of certain inter-patient pharmacokinetic and pharmacodynamic variability inherent in treated patients, particularly those with critical and debilitating diseases (Cox, 2011). Even with all of these advantages and hopeful results, however, the population pharmacokinetic approach still has not been universally adopted, and there are still some unresolved issues conceding the methodology that must be resolved moving forward. That forms the basis for the ensuing review of relevant literature in this field. 2.0 Literature Review 2.1 Population Pharmacokinetics Quite simply, pharmacokinetics is a branch of pharmacology that has its chief aim and objective to determine that actual efficacy of certain substances that are externally administrated externally to any given living organism. The literature currently available has been in development for the past 30 years and is aimed at better understanding how life saving treatments can better be administered to critically ill patients (Dodds, Hooker, & Vicini, 2005). Of particular interest are pharmaceutical agents, hormones, toxins, and nutrients that naturally and synthetically occur throughout this process. Taking those four components of the pharmaceutical industry itself, pharmacokinetics involves a mechanism by which researchers aim to discover the efficacy of a drug from the very moment that it is administered to a patient until it eventually exits the body via some method of elimination (Dirks & Meibohm, 2010). More specifically, it is important to determine how the body reacts after a certain drug is administered by specifically examining how the components of the drug are both absorbed and distributed within the body. In addition, a focus is placed on analysing the chemical changes that occur within the body as a result of the substances that have been administered. Examples of these that are of particular concern to medical researchers include metabolic enzymes, such as cytochrome P450 and glucuronosyltransferase enzymes (Dodds, Hooker, & Vicini, 2005). Upon examining these particular enzymes, researchers concern themselves with looking at the effects that the various routes of excretion within the body itself that occur as the drug is metabolised. It has been determined that the pharmacokinetic properties of these drugs may, in the end, be impacted by certain external factors. These factors include the actual location where the drug is administered to the body, and the dosage amount that is given. Each of these factors, and others, have been shown to impact that actual rate of absorption, which can mean the different between a drug being highly effective, and completely ineffective (Doh, Woo, & Hur, 2010). For these reasons, the information gathered from the population pharmacokinetics methodological approach can provide critical towards the further development of life saving drugs that can be beneficial for critically ill patients. Population pharmacokinetics itself is a rather complex approach. To begin, a variety of different models have already been created that are designed to simplify the conceptualisation process regarding the plethora of different process that are known to occur when a drug begins to interact with a living organism (Ette & Williams, 2012). The studies contained under the scope of this literature review appear to focus heavily upon the multi-compartment model. This particular scientific model gives results that are the best possible approximations to reality. The drawback, however, is that the model is extremely complex, necessitating the more easily digestible monocompartmental and two compartmental models to be more frequently incorporated into the popular pharmacokinetics process (Han & Paillai, 2013). Within these models, different compartments are enhanced into an ADME scheme in order to make the results more clear to the medical research team. Most studies look at five main components under this scheme, described below. Liberation - The liberation process occurs when the drug is released from its initial pharmaceutical formulation and is free to invade the living organism to work its intended function within the body (Kolesar & Brundage, 2011). Absorption - This involves the process of the substance in question actually entering into the blood supply of the living organism (Kolesar & Brundage, 2011). Distribution - Once absorption has taken place, the process of distribution enables the vital substances from the drug to be dispersed through various fluids and tissues within the body itself (Kolesar & Brundage, 2011). Metabolisation - This process occurs when the organism recognises the presence of a foreign substance. At this point, an irreversible transformation of parent compounds forming into different related metabolites is to take place in order for the drug to maintain its efficacy (Kolesar & Brundage, 2011). Excretion - At this last stage, excretion involves the removal of substances from the drug out of the body (Kolesar & Brundage, 2011). Some studies actually link metabolisation and excretion under one stage, that being elimination. Individuals who study these phases of the process actually begin to manipulate various concepts in order to better understand the dynamics of drugs, and their various substances, as their way is made through the blood stream of a living organism. As a result, the kinetics of the drug in question is vital in order to understand how to maximise it efficacy once administered to a human (Lohar & Rathore-Arvind, 2012). While not everyone is sold on the success and viability of population pharmacokinetics, its intended objective certainly appears too solid. As we know, drugs administered in too high a dose can be lethal in humans. Too little of a dosage will render it ineffective. Pharmacokinetics is much more than getting the dosage level correct, however, as it is more concerned with what the body actually does with the substances once inside the blood stream. Examined closely is the path that the drug takes, how effective the substance is at impacting the parts of the body that need assistance, and the rate at which the drug is excreted from the body, thereby necessitating another potentially life saving administration (Punyawudho & Ramsay, 2012). Combining all of this information, one can visualise that population pharmacokinetics is more concerned to studying the various sources and correlations related to the variability that exists in terms of the concentrations of a drug administered to different individuals with a given target population. These patients would receive doses of the drug that are considered to be clinically relevant within the context of the particular drug itself. It is only through this type of study that researchers in the field of medical science can begin to determine how to more effectively administer drugs to critically ill patients in a timely and relevant manner (Purwonugroho, 2012). What makes this process unique, and the reason an entire different set of procedures is implanted into its design, is that it takes into account unique patient demographic information in order to determine that best path for the drug to take. This is pathophysiological and therapeutic features of the patient. Among the factors considered include body weight, the excretory and metabolic capabilities of the individual, and whether or not other therapies are also being considered (Xu & Smith, 2010). Each of the demographic characteristics can significantly affect the eventual efficacy of any given drug, so population pharmacokinetics is an attempt to determine these relationships, document them, and move towards to a more individualised system of monitoring drug intake in critically ill patients. (Sherwin, Wead, & Stockmann, 2014) One study in particularly was commissioned, as an example, to examine the steady state concentrations of any given drug that is eliminated almost entirely by the kidney, and how this result is usually greater in patients that are suffering from some type of acute renal failure. This is then compared with levels found in individuals with normal renal function, while receive exactly the same dosage of the same drug. Studies also remind us that the process of population pharmacokinetics has as one of its core objectives the goal of identifying certain pathophysiological factors that can be measured in terms of their ability to cause changes in the dosage and concentration of the drug being administrated (Zuo, Li, & Sun, 2014). When comparing this with any clinically significant changes what are noted within the therapeutic index, the dosage levels can then be appropriately modified as necessary. Another advantages of modeling this process by using population pharmacokinetics is that the approach allows researcher to analyze data sets that are quite sparse, often measurable as only one unit of concentration per individual patient) (Schuttler & Ihmsen, 201). Naturally, all of this data can be difficult to interpret without measurable technological assistance, such as that found with NONMEM software. 2.2 NONMEM NONMEM software packages are quite useful within the context of population pharmacokinetics modeling. The software itself was actually developed at UCSF, and newer versions have been created to incorporate GUIs, such as Monlix, in addition to certain graphical tools designed to build models, such as the Phoenix NLME. The NONMEM software product is trademarked, and is designed to be a nonlinear mixed effects modeling tool that is useful in the analysis of population pharmacokinetics. The program itself remains the property of the Regents of the University of California, but the university has granted exclusive rights for the licensing of the product to ICON Development Solutions. The current version in use today that is most helpful to those analyzing drug efficacy by incorporating population pharmacokinetics is 7.2. The NONMEM program actually consists of three main parts. The software was designed to a non-interactive and quite general model analysis program that can prove useful as a mechanism to fit the models of numerous types of data. The latest version now enable both Monte Carol expectation-maximization and Markov Chain Monte Carlo Bayesian methods. Both of these techniques add to the more classical methodologies employed by earlier version of NOMEM. Another useful feature is PREDPP, which contains a package of subroutines that are utilised by NONMEM to actually computer predictions for population pharmacokinetics and its associated pharmacodynamic data. Using PREDPP means that user must code kinetic-type equations, but it also enables more complicated patient-type data to be more readily available and easily used. In addition, users of PREDPP can work directly with coded prediction-types and analyse the likelihood of 2 log likelihood equations. This process, int he end, enables a greater variety of different types of models to be useful within the scheme of population of pharmacokinetics (Sandeep, Santhosh, & Srikanth, 2013). Finally, NM-TRAN is another feature of NONMEM. This is a non-interactive processor that allows control and other necessary inputs to be specified by the program in a much more user friendly and understandable manner. This enables the user to quickly and quite comprehensively detect a variety of errors that might have been made throughout the entire process, thereby increasing the results that are achieved. It should be noted that NONMEM is quite complex and results can take a long to generate, often up to several days. As a result, it is recommended that users of the program have a fast computer and a great deal of available memory in order to get the maximum use out of the software. In the end, this software makes the process of population pharmacokinetics much more manageable, and allows users to more quickly achieve the objective of finding the best delivery method of lifesaving drugs and substances into living organisms (Sandeep, Santhosh, & Srikanth, 2013). 2.3 Drug Regulation Naturally, governing bodies the world over are concerned about the regulation of drugs. This is particularly important in critically ill patents, as the wrong drug administrated improperly, or with an incorrect dose, can quickly become lethal. When utilising the methodological approach found in population pharmacokinetics, the U.S. Food and Drug Administration, in addition to similar governmental agencies in the develop world, have worked to implement policies aimed at the better regulation of key drugs and other substances designed to heal and treat the human body. As mentioned by Sun (1999), “The application of population pharmacokinetics approach to drug development is recommended in several US Food and Drug Administration (FDA) guidance documents” (p. 41). This illustrates the importance of going through proper procedures in the research stage for any drug falling under the scope of population pharmacokinetics, and to implement correct protocol in ensuring that the efficacy and absorption rates of any drug in question is accurate and beneficial. The techniques incorporated by population pharmacokinetics enable the ready identification of inter and intra-individual variability that can often encroach the safety of a drug, and its eventual efficacy. This includes the discovery of any potential impediments that can impact the overall effectiveness of the drug, particularly when considering critical illnesses for which there is no known cure, or where cure rates are extremely low. The 2-stage approach to drug regulation is most commonly alluded to in literature as being not only useful to the population pharmacokinetics process, but also one that is more readily accepted by governing agencies and regulatory bodies. This approach aims to estimate existent parameters in the population pharmacokinetics technique, and it necessitates certain serial measurements to be conducted numerous times on each participant in any test of a drugs efficacy (Baksh, Edelman, & Sausville, 2013). The reviews that are compiled during this approach are comprehensive in nature an incorporate a non-linear mixed-effects methodology to the modelling that is generated. This can then be applied to varying situations where a great deal of sampling is not necessary, nor conducted, on any of the participants, or if they are, where only a small sampling size becomes necessary. In conducting a population pharmacokinetics study, there is a certain amount of preliminary information that must be compile from the outset. Some of this necessary information includes the compartment model that will be utilised within the scope of the description of the pharmacokinetics of the drug that is to be studied (Baksh, Edelman, & Sausville, 2013). The medical research team must also concern themselves with the practical design that will be incorporated into the study itself, such as the location of the sampling, sampling time frames, the number of samples to be gathered, the number of participants to be included in the scope of the study, and how many times a sample will need to be taken from each participant. Because of these many factors that must be considered, it is recommended that a simulation of the model be conducted before hand in order to determine whether or not the intended objectives of the planned study will be met by the particular approach being considered by the research team (Baksh, Edelman, & Sausville, 2013). This will also enable the team to enhance their list of objectives for the study and to make modifications as deemed necessary. When considering drug regulation, it is also important to bear in mind that the primary stated objectives of a population pharmacokinetics study might actually end up becoming secondary to the stated objectives of the overall primary clinical study (Chan, Morris, Llett, & Tett, 2011). When this occurs, the United States Food and Drug Administration recommends that a population pharmacokinetic protocol actually be implemented, or potentially even the incorporation of a stand alone protocol could prove to be necessary. Such protocols being incorporated into population pharmacokinetics ends up becoming a critical component of a solid and methodologically sound study (Chan, Morris, Llett, & Tett, 2011). In addition, it is important to assemble dealt time data and to analyse it effective by allowing for an ongoing evaluation of the work and lab sites to ensure that they are in compliance with the protocols implemented into the scope of the study itself. Following this advice will allow the research to correct any violations that might have crept into the design of the study and to correct any procedures related to the entire process that might need to be modified, but simply was not caught by the research team themselves due to their intimate involvement with the study. These steps are critical to the drug regulation process, and without them, eventual approval of the population pharmacokinetics study might be hard to obtain (Chan, Morris, Llett, & Tett, 2011). Keeping the above discussion in mind, population pharmacokinetics studies must have proper polices and procedures in place. This is critical in order to ensure that any such blind study can be properly maintained and executed, and that conclusions will generally be accepted by the larger medical and scientific community (Chan, Morris, Llett, & Tett, 2011). The assembly of data in real time also provides researchers with the possibility of detecting, and subsequently correcting, any errors that might present themselves in terms of concentration time data, any issues with the actual administration of the drug itself and the history of said administration, and the covariate data that is recorded. population pharmacokinetics analysis is generally completed by going through a series of three steps that interconnected with one another. These steps are typically labeled as exploratory data analysis, model developments, and then model validation (Bigos, Bies, & Pollock, 2006). The step involving model validation is referred to by many scholars as predictive performance. During each of these steps, in order for the drug regulation process to truly take hold, accurate and detailed documentation should be compiled, organised, and maintained. This should most certainly also include a complete and precise inventory of the key steps and methodologies that were incorporated into the design stage of the study, and this documentation should be inclusive of understandable and relevant flow diagrams when at all possible. All of this should be accompanied by a detailed and written account of the objectives for the study, in addition to a statement of any underlying assumptions made by the researchers in regards to the hypothesis for the study (Bigos, Bies, & Pollock, 2006). The Food and Drug Administration also recommends that the population pharmacokinetics study design include a diagnostic analyses of goodness of fit as further proof that the results achieved are both valid and reliable. When all of this has been accomplished, there still may be further stability testing and or model validation that may be requested depending on what claims are desired to be placed upon the drug label itself (Bigos, Bies, & Pollock, 2006). 2.4 Key Studies Let us begin by looking at studies in population pharmacokinetics using a multi-compartmental model. These models aim to graph the non-linear relationship that exists between various factors in determining the efficacy of the drug in question. These factors are then represented by a curve which illustrates how the calculation of dimensions of each of the areas under the curve were calculated. Such a model has proven useful in non linear pharmacokinetics and are based upon the Michaelis Menten kinetics mindset (Colucci, 2011). The factors the react in such a non linear fashion are typically represented by either multi phasic absorption, the alpha phase, or the beta phase. Multiphasic absorption is representative of drugs being inject intravenously into the patent and then being removed from the plasma. This occurs in two main ways. The first is by distributing the drug directly to various tissues within the living and organism. The second way is to examine the metabolism of the patient combine with the manner and rate at which the drug is actually extorted from the body (Cox, 2011). As this occurs, the drug’s actual plasma concentration should decrease, largely represent via a biphasic pattern. The alpha phase occurs during the initial stages of a rapid decrease in plasma concentration on the patient. Studies have revealed that this decrease in plasma is usually the result of the drug being distributed from the central compartment, via the process of circulation, in the more peripheral compartments of the body via tissues in the living organism. The alpha phase actually comes to an end when a pseudo equilibrium of the concentration of the drug that has been administered to the patent becomes established between both the central and peripheral compartments, as discussed previously. Finally, the beta phase is represented by a gradual decrease in the concentration of plasma that begins to occur directly following the alpha phase. Studies do reveal that this decrease usually occurs as a result of the way that the drug that was administered metabolising in the body and then eventually being excreted (Blanco, 2009). To this point, studies in population pharmacokinetics has noted that the characteristics represented by any given drug can distinguish between tissues within a living organism, as well as noting any differences between high and low blood flow. In addition, enzymatic saturation is known to occur when the dose of a drug is dependent upon a certain biotransformation taking place before the drug can be eliminated from the body. As a result, it has been noted that there is an increase above a certain benchmark that occurs, as the enzymes responsible for a drugs actual rate of metabolism becomes saturated within the body (Dirks & Meibohm, 2010). It is at this point that the concentration of the plasma within the drug will begin to increase at a disproportionate rate, losing its constant state, and thereby becoming eliminated within the organism itself. Studies in population pharmacokinetics have also revealed the process of induction or enzymatic inhibition that takes place within the body as well. This occurs with certain drugs that appear to have developed the capacity to actually inhibit or stimulate their very own metabolism. This can result in either positive or negative feedback reactions (Dirks & Meibohm, 2010). These reactions have been most commonly seen in fluvoxamine, fluoxetine, and phenytoin. Some studies have analysed larger doses of certain drugs. It has been found that, as larger does of the aforementioned drugs are administered, the concentrations of plasma within the unmetabolised drug actually increases. At this same time, the elimination half life increases as well. As a consequence, it has been determined that the dose should be adjusted under these circumstances, or other treatment parameters should be altered when a higher dosage of the drug is evidently necessary. It has also been determined that the kidneys within the body can also serve as a mechanism to eliminate some drugs from the living organism. This phenomenon has been observed to occur independent of the concentrations of plasm that are in the body (Dodds, Hooker, & Vicini, 2005). Some studies actually link metabolisation and excretion under one stage, that being elimination. Individuals who study these phases of the process actually begin to manipulate various concepts in order to better understand the dynamics of drugs, and their various substances, as their way is made through the blood stream of a living organism. As a result, the kinetics of the drug in question is vital in order to understand how to maximise it efficacy once administered to a human (Lohar & Rathore-Arvind, 2012). While not everyone is sold on the success and viability of population pharmacokinetics, its intended objective certainly appears too solid. As we know, drugs administered in too high a dose can be lethal in humans. Too little of a dosage will render it ineffective. Pharmacokinetics is much more than getting the dosage level correct, however, as it is more concerned with what the body actually does with the substances once inside the blood stream. Examined closely is the path that the drug takes, how effective the substance is at impacting the parts of the body that need assistance, and the rate at which the drug is excreted from the body, thereby necessitating another potentially life saving administration (Punyawudho & Ramsay, 2012). Combining all of this information, one can visualise that population pharmacokinetics is more concerned to studying the various sources and correlations related to the variability that exists in terms of the concentrations of a drug administered to different individuals with a given target population. These patients would receive doses of the drug that are considered to be clinically relevant within the context of the particular drug itself. It is only through this type of study that researchers in the field of medical science can begin to determine how to more effectively administer drugs to critically ill patients in a timely and relevant manner (Purwonugroho, 2012). What makes this process unique, and the reason an entire different set of procedures is implanted into its design, is that it takes into account unique patient demographic information in order to determine that best path for the drug to take. This is pathophysiological and therapeutic features of the patient. Among the factors considered include body weight, the excretory and metabolic capabilities of the individual, and whether or not other therapies are also being considered (Xu & Smith, 2010). Each of the demographic characteristics can significantly affect the eventual efficacy of any given drug, so population pharmacokinetics is an attempt to determine these relationships, document them, and move towards to a more individualised system of monitoring drug intake in critically ill patients. (Sherwin, Wead, & Stockmann, 2014) 3.0 Conclusion To conclude, it is helpful to remember that pharmacokinetics is a branch of pharmacology that has its chief aim and objective to determine that actual efficacy of certain substances that are externally administrated externally to any given living organism. The literature discussed in this report has been in development for the past 30 years and is aimed at better understanding how life saving treatments can better be administered to critically ill patients. Of particular interest are pharmaceutical agents, hormones, toxins, and nutrients that naturally and synthetically occur throughout this process. Taking those four components of the pharmaceutical industry itself, pharmacokinetics involves a mechanism by which researchers aim to discover the efficacy of a drug from the very moment that it is administered to a patient until it eventually exits the body via some method of elimination. More specifically, it is important to determine how the body reacts after a certain drug is administered by specifically examining how the components of the drug are both absorbed and distributed within the body. In addition, a focus is placed on analysing the chemical changes that occur within the body as a result of the substances that have been administered. Examples of these that are of particular concern to medical researchers include metabolic enzymes, such as cytochrome P450 and glucuronosyltransferase enzymes. Upon examining these particular enzymes, researchers concern themselves with looking at the effects that the various routes of excretion within the body itself that occur as the drug is metabolised. It has been determined that the pharmacokinetic properties of these drugs may, in the end, be impacted by certain external factors. These factors include the actual location where the drug is administered to the body, and the dosage amount that is given. Each of these factors, and others, have been shown to impact that actual rate of absorption, which can mean the different between a drug being highly effective, and completely ineffective. For these reasons, the information gathered from the population pharmacokinetics methodological approach can provide critical towards the further development of life saving drugs that can be beneficial for critically ill patients. Population pharmacokinetics itself is a rather complex approach. To begin, a variety of different models have already been created that are designed to simplify the conceptualisation process regarding the plethora of different process that are known to occur when a drug begins to interact with a living organism. The models have been discussed in detailed, and their relevance to the population pharmacokinetics process explained. The studies contained under the scope of this literature review appear to focus heavily upon the multi-compartment model. This particular scientific model gives results that are the best possible approximations to reality. The drawback, however, is that the model is extremely complex, necessitating the more easily digestible monocompartmental and two compartmental models to be more frequently incorporated into the popular pharmacokinetics process. Within these models, different compartments are enhanced into an ADME scheme in order to make the results more clear to the medical research team. This is an area of medical science that continues to be developed, and is gaining more and more supporters every year. While some would argue the methodology, few would question the notion that the objective of the approach is based solely on finding cures for debilitating, crippling, and terminal illnesses. References Baksh, C., Edelman, M., and Sausville, E. (2013). Population pharmacokinetics. Journal of Cancer Therapy, 4(10), 1513-1519. Bigos, K., Bies, R., and Pollock, B. (2006). Population pharmacokinetics in geriatric psychiatry. The American Journal of Geriatric Psychiatry, 14(12), 993-1003. Blanco, S. (2009). Valproate population pharmacokinetics in children. Journal of Clinical Pharmacy and Therapeutics, 24(1), 73-80. Borghorst, S. (2012). Population pharmacokinetics of native escherichia coli asparaginase. Pediatric Hematology and Oncology, 29(2), 154. Chan, V., Morris, R., Llett, K., and Tett, S. (2011). Population pharmacokinetics of lamotrigine. 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