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75-441: Pharmacokinetics : A number of phases occur once the drug enters into contact with the organism, these are described using the acronym ADME (or LADME if liberation is included as a separate step from absorption): Some textbooks combine the first two phases as the drug is often administered in an active form, which means that there is no liberation phase. Others include a phase that combines distribution, metabolism and excretion into

150-507: A {\displaystyle Va} is the drug's rate of administration and τ {\displaystyle \tau } is the rate at which the absorbed drug reaches the circulatory system. Finally, using the Henderson-Hasselbalch equation , and knowing the drug's p K a {\displaystyle pKa\,} ( pH at which there is an equilibrium between its ionized and non-ionized molecules), it

225-407: A blood plasma concentration of 80 mg that has the capacity to have a pharmaceutical effect. This concept depends on a series of factors inherent to each drug, such as: These concepts, which are discussed in detail in their respective titled articles, can be mathematically quantified and integrated to obtain an overall mathematical equation: where Q is the drug's purity. where V

300-424: A concentration-time profile. Chemical techniques are employed to measure the concentration of drugs in biological matrix , most often plasma. Proper bioanalytical methods should be selective and sensitive. For example, microscale thermophoresis can be used to quantify how the biological matrix/liquid affects the affinity of a drug to its target. Pharmacokinetics is often studied using mass spectrometry because of

375-555: A corresponding graphical representation . The use of these models allows an understanding of the characteristics of a molecule , as well as how a particular drug will behave given information regarding some of its basic characteristics such as its acid dissociation constant (pKa), bioavailability and solubility , absorption capacity and distribution in the organism. A variety of analysis techniques may be used to develop models, such as nonlinear regression or curve stripping. Noncompartmental methods estimate PK parameters directly from

450-413: A disposition phase. Other authors include the drug's toxicological aspect in what is known as ADME-Tox or ADMET . The two phases of metabolism and excretion can be grouped together under the title elimination . The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason, in order to fully comprehend the kinetics of

525-401: A drug can be used in industry (for example, in calculating bioequivalence when designing generic drugs) or in the clinical application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in veterinary medicine . Models generally take the form of mathematical formulas that have

600-410: A drug is eliminated (that is, cleared and excreted ) from an organism either in an unaltered form (unbound molecules) or modified as a metabolite. The kidney is the main excretory organ although others exist such as the liver , the skin , the lungs or glandular structures, such as the salivary glands and the lacrimal glands . These organs or structures use specific routes to expel a drug from

675-406: A drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients , the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug. The following are the most commonly measured pharmacokinetic metrics: The units of

750-413: A drug to reach C max . While the mechanisms by which a formulation affects bioavailability and bioequivalence have been extensively studied in drugs, formulation factors that influence bioavailability and bioequivalence in nutritional supplements are largely unknown. As a result, in nutritional sciences, relative bioavailability or bioequivalence is the most common measure of bioavailability, comparing

825-415: A drug's bioavailability and the apparent volume of distribution . For elimination via bile please see: Estimation of Biliary Excretion of Foreign Compounds Using Properties of Molecular Structure. 2014. Sharifi M., Ghafourian T. AAPS J. 16(1) 65–78. Bioavailability In pharmacology , bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches

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900-428: A drug's toxic effects . For this reason it is important to know if a drug is likely to be eliminated from a woman's body if she is breast feeding in order to avoid this situation. Pharmacokinetics studies the manner and speed with which drugs and their metabolites are eliminated by the various excretory organs. This elimination will be proportional to the drug's plasmatic concentrations. In order to model these processes

975-424: A drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (iv) and extravascular (non-intravenous, i.e., oral) administration. The absolute bioavailability is the dose-corrected area under curve ( AUC ) non-intravenous divided by AUC intravenous. The formula for calculating the absolute bioavailability, F , of a drug administered orally (po)

1050-442: A more rapid distribution, comprising organs and systems with a well-developed blood supply; and a peripheral compartment made up of organs with a lower blood flow. Other tissues, such as the brain, can occupy a variable position depending on a drug's ability to cross the barrier that separates the organ from the blood supply. Two-compartment models vary depending on which compartment elimination occurs in. The most common situation

1125-435: A practical level, a drug's bioavailability can be defined as the proportion of the drug that reaches the systemic circulation. From this perspective the intravenous administration of a drug provides the greatest possible bioavailability, and this method is considered to yield a bioavailability of 1 (or 100%). Bioavailability of other delivery methods is compared with that of intravenous injection (absolute bioavailability) or to

1200-473: A single pharmaceutical in the samples. The samples represent different time points as a pharmaceutical is administered and then metabolized or cleared from the body. Blank samples taken before administration are important in determining background and ensuring data integrity with such complex sample matrices. Much attention is paid to the linearity of the standard curve; however it is common to use curve fitting with more complex functions such as quadratics since

1275-400: A standard value related to other delivery methods in a particular study (relative bioavailability). Once a drug's bioavailability has been established it is possible to calculate the changes that need to be made to its dosage in order to reach the required blood plasma levels. Bioavailability is, therefore, a mathematical factor for each individual drug that influences the administered dose. It

1350-413: A table of concentration-time measurements. Noncompartmental methods are versatile in that they do not assume any specific model and generally produce accurate results acceptable for bioequivalence studies. Total drug exposure is most often estimated by area under the curve (AUC) methods, with the trapezoidal rule ( numerical integration ) the most common method. Due to the dependence on the length of x in

1425-399: A weak acid, rather than it getting reabsorbed. As the acid is ionised , it cannot pass through the plasma membrane back into the blood stream and instead gets excreted with the urine. Acidifying the urine has the same effect for weakly basic drugs. On other occasions drugs combine with bile juices and enter the intestines. In the intestines the drug will join with the unabsorbed fraction of

1500-426: A working definition is required for some of the concepts related to excretion. The plasma half-life or half life of elimination is the time required to eliminate 50% of the absorbed dose of a drug from an organism. Or put another way, the time that it takes for the plasma concentration to fall by half from its maximum levels. The difference in a drug's concentration in arterial blood (before it has circulated around

1575-400: Is a critical measurement used to assess the bioavailability differences from patient to patient in order to ensure predictable dosing. ^   TH:  One of the few exceptions where a drug shows F of over 100% is theophylline . If administered as an oral solution F is 111%, since the drug is completely absorbed and first-pass metabolism in the lung after intravenous administration

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1650-429: Is given below (where D is dose administered). Therefore, a drug given by the intravenous route will have an absolute bioavailability of 100% ( f = 1), whereas drugs given by other routes usually have an absolute bioavailability of less than one. If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability. Although knowing

1725-431: Is possible to calculate the amount of a drug in the blood plasma that has a real potential to bring about its effect using the formula: where De is the effective dose , B bioavailability and Da the administered dose. Therefore, if a drug has a bioavailability of 0.8 (or 80%) and it is administered in a dose of 100 mg, the equation will demonstrate the following: That is the 100 mg administered represents

1800-446: Is possible to calculate the non-ionized concentration of the drug and therefore the concentration that will be subject to absorption: When two drugs have the same bioavailability, they are said to be biological equivalents or bioequivalents. This concept of bioequivalence is important because it is currently used as a yardstick in the authorization of generic drugs in many countries. Bioanalytical methods are necessary to construct

1875-493: Is represented by a curve ; the relationships between the factors can then be found by calculating the dimensions of different areas under the curve. The models used in non-linear pharmacokinetics are largely based on Michaelis–Menten kinetics . A reaction's factors of non-linearity include the following: It can therefore be seen that non-linearity can occur because of reasons that affect the entire pharmacokinetic sequence: absorption, distribution, metabolism and elimination. At

1950-555: Is that elimination occurs in the central compartment as the liver and kidneys are organs with a good blood supply. However, in some situations it may be that elimination occurs in the peripheral compartment or even in both. This can mean that there are three possible variations in the two compartment model, which still do not cover all possibilities. In the real world, each tissue will have its own distribution characteristics and none of them will be strictly linear. The two-compartment model may not be applicable in situations where some of

2025-452: Is the ability to modify parameters and to extrapolate to novel situations. The disadvantage is the difficulty in developing and validating the proper model. Although compartment models have the potential to realistically model the situation within an organism, models inevitably make simplifying assumptions and will not be applicable in all situations. However complicated and precise a model may be, it still does not truly represent reality despite

2100-407: Is the direct application to a therapeutic situation of knowledge regarding a drug's pharmacokinetics and the characteristics of a population that a patient belongs to (or can be ascribed to). An example is the relaunch of the use of ciclosporin as an immunosuppressor to facilitate organ transplant. The drug's therapeutic properties were initially demonstrated, but it was almost never used after it

2175-436: Is the fraction of exposure to a drug (AUC) through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be dose normalized (e.g., account for different doses or varying weights of the subjects); consequently, the amount absorbed is corrected by dividing the corresponding dose administered. In pharmacology, in order to determine absolute bioavailability of

2250-437: Is the necessity to conduct preclinical toxicity tests to ensure adequate safety, as well as potential problems due to solubility limitations. These limitations may be overcome, however, by administering a very low dose (typically a few micrograms) of an isotopically labelled drug concomitantly with a therapeutic non-isotopically labelled oral dose (the isotopically labelled intravenous dose is sufficiently low so as not to perturb

2325-502: Is the organ's clearance rate, C A {\displaystyle C_{A}} is the drug's plasma concentration in arterial blood, C V {\displaystyle C_{V}} is the drug's plasma concentration in venous blood and Q {\displaystyle Q} an organ's blood flow. Each organ will have its own specific clearance conditions, which will relate to its mode of action. The «renal clearance» rate will be determined by factors such as

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2400-531: Is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest. Certain patient demographic, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-concentration relationships and can explain variability in exposures. For example, steady-state concentrations of drugs eliminated mostly by

2475-431: Is usually the easiest to obtain and the most reliable. The main reasons for determining a drug's plasma concentration include: Ecotoxicology is the branch of science that deals with the nature, effects, and interactions of substances that are harmful to the environment such as microplastics and other biosphere harmful substances. Ecotoxicology is studied in pharmacokinetics due to the substances responsible for harming

2550-401: The brain tissue) that present a real barrier to the distribution of drugs, that can be breached with greater or lesser ease depending on the drug's characteristics. If these relative conditions for the different tissue types are considered along with the rate of elimination, the organism can be considered to be acting like two compartments: one that we can call the central compartment that has

2625-405: The multi-compartment model with a number of curves that express complicated equations in order to obtain an overall curve. A number of computer programs have been developed to plot these equations. The most complex PK models (called PBPK models) rely on the use of physiological information to ease development and validation. The graph for the non-linear relationship between the various factors

2700-451: The systemic circulation . By definition, when a medication is administered intravenously , its bioavailability is 100%. However, when a medication is administered via routes other than intravenous, its bioavailability is lower due to intestinal epithelium absorption and first-pass metabolism . Thereby, mathematically, bioavailability equals the ratio of comparing the area under the plasma drug concentration curve versus time (AUC) for

2775-478: The administered dose and be eliminated with the faeces or it may undergo a new process of absorption to eventually be eliminated by the kidney. The other elimination pathways are less important in the elimination of drugs, except in very specific cases, such as the respiratory tract for alcohol or anaesthetic gases. The case of mother's milk is of special importance. The liver and kidneys of newly born infants are relatively undeveloped and they are highly sensitive to

2850-510: The bioavailability of one formulation of the same dietary ingredient to another. The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e., F < 100%). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation. Whether a drug is taken with or without food will also affect absorption, other drugs taken concurrently may alter absorption and first-pass metabolism, intestinal motility alters

2925-708: The body) and venous blood (after it has passed through the body's organs) represents the amount of the drug that the body has eliminated or cleared . Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance . Clearance is therefore expressed as the plasma volume totally free of the drug per unit of time, and it is measured in units of volume per units of time. Clearance can be determined on an overall, organism level («systemic clearance») or at an organ level (hepatic clearance, renal clearance etc.). The equation that describes this concept is: Where: C L o {\displaystyle CL_{o}}

3000-531: The body, these are termed elimination pathways : Drugs are excreted from the kidney by glomerular filtration and by active tubular secretion following the same steps and mechanisms as the products of intermediate metabolism. Therefore, drugs that are filtered by the glomerulus are also subject to the process of passive tubular reabsorption . Glomerular filtration will only remove those drugs or metabolites that are not bound to proteins present in blood plasma (free fraction) and many other types of drugs (such as

3075-417: The complex nature of the matrix (often plasma or urine) and the need for high sensitivity to observe concentrations after a low dose and a long time period. The most common instrumentation used in this application is LC-MS with a triple quadrupole mass spectrometer . Tandem mass spectrometry is usually employed for added specificity. Standard curves and internal standards are used for quantitation of usually

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3150-463: The degree of plasma protein binding as the drug will only be filtered out if it is in the unbound free form, the degree of saturation of the transporters (active secretion depends on transporter proteins that can become saturated) or the number of functioning nephrons (hence the importance of factors such as kidney failure ). As «hepatic clearance» is an active process it is therefore determined by factors that alter an organism's metabolism such as

3225-477: The deviation range is employed to represent real bioavailability and to calculate the drug dose needed for the drug taker to achieve systemic concentrations similar to the intravenous formulation. To dose without knowing the drug taker's absorption rate, the bottom value of the deviation range is used in order to ensure the intended efficacy, unless the drug is associated with a narrow therapeutic window . For dietary supplements , herbs and other nutrients in which

3300-472: The dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora. Disease states affecting liver metabolism or gastrointestinal function will also have an effect. Other factors may include, but are not limited to: Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). In clinical trials , inter-individual variation

3375-593: The dose in the table are expressed in moles (mol) and molar (M). To express the metrics of the table in units of mass, instead of Amount of substance , simply replace 'mol' with 'g' and 'M' with 'g/L'. Similarly, other units in the table may be expressed in units of an equivalent dimension by scaling. where C av , ss = A U C τ , ss τ {\displaystyle C_{{\text{av}},{\text{ss}}}={\frac {AUC_{\tau ,{\text{ss}}}}{\tau }}} In pharmacokinetics, steady state refers to

3450-403: The drug are the only information needed to determine the drug's concentration in other fluids and tissues. For example, the concentration in other areas may be approximately related by known, constant factors to the blood plasma concentration. In this one-compartment model, the most common model of elimination is first order kinetics , where the elimination of the drug is directly proportional to

3525-455: The drug be given intravenously. Intravenous administration of a developmental drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution ( V ) and clearance ( CL ). In pharmacology, relative bioavailability measures the bioavailability (estimated as the AUC ) of a formulation (A) of a certain drug when compared with another formulation (B) of

3600-542: The drug's concentration in the organism. This is often called linear pharmacokinetics , as the change in concentration over time can be expressed as a linear differential equation d C d t = − k el C {\textstyle {\frac {dC}{dt}}=-k_{\text{el}}C} . Assuming a single IV bolus dose resulting in a concentration C initial {\displaystyle C_{\text{initial}}} at time t = 0 {\displaystyle t=0} ,

3675-669: The drug. Beyond AUC exposure measures, parameters such as Cmax (maximum concentration), Tmax (time to maximum concentration), CL and Vd can also be reported using NCA methods. Compartment models methods estimate the concentration-time graph by modeling it as a system of differential equations. These models are based on a consideration of an organism as a number of related compartments . Both single compartment and multi-compartment models are in use. PK compartmental models are often similar to kinetic models used in other scientific disciplines such as chemical kinetics and thermodynamics . The advantage of compartmental over noncompartmental analysis

3750-516: The effort involved in obtaining various distribution values for a drug. This is because the concept of distribution volume is a relative concept that is not a true reflection of reality. The choice of model therefore comes down to deciding which one offers the lowest margin of error for the drug involved. The simplest PK compartmental model is the one-compartmental PK model. This models an organism as one homogenous compartment. This monocompartmental model presupposes that blood plasma concentrations of

3825-457: The environment such as pesticides can get into the bodies of living organisms. The health effects of these chemicals is thus subject to research and safety trials by government or international agencies such as the EPA or WHO . How long these chemicals stay in the body , the lethal dose and other factors are the main focus of Ecotoxicology. All model based software above. Global centres with

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3900-446: The environment when they are adsorbed to soil minerals or partition into hydrophobic organic matter. Absolute bioavailability compares the bioavailability of the active drug in systemic circulation following non- intravenous administration (i.e., after oral , buccal, ocular, nasal, rectal, transdermal , subcutaneous , or sublingual administration), with the bioavailability of the same drug following intravenous administration. It

3975-445: The enzymes responsible for metabolizing the drug become saturated, or where an active elimination mechanism is present that is independent of the drug's plasma concentration. If we label the drug's volume of distribution within the organism Vd F and its volume of distribution in a tissue Vd T the former will be described by an equation that takes into account all the tissues that act in different ways, that is: This represents

4050-444: The equation can be solved to give C = C initial × e − k el × t {\displaystyle C=C_{\text{initial}}\times e^{-k_{\text{el}}\times t}} . Not all body tissues have the same blood supply , so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (such as

4125-453: The extravascular formulation to the AUC for the intravascular formulation. AUC is used because AUC is proportional to the dose that has entered the systemic circulation. Bioavailability of a drug is an average value ; to take population variability into account, deviation range is shown as ± . To ensure that the drug taker who has poor absorption is dosed appropriately, the bottom value of

4200-483: The highest profiles for providing in-depth training include the Universities of Buffalo , Florida , Gothenburg , Leiden , Otago , San Francisco , Beijing , Tokyo, Uppsala , Washington , Manchester , Monash University, and University of Sheffield . Elimination (pharmacology) In pharmacology , the elimination or excretion of a drug is understood to be any one of a number of processes by which

4275-513: The intake of nutrients and non-drug dietary ingredients, the concept of bioavailability lacks the well-defined standards associated with the pharmaceutical industry. The pharmacological definition cannot apply to these substances because utilization and absorption is a function of the nutritional status and physiological state of the subject, resulting in even greater differences from individual to individual (inter-individual variation). Therefore, bioavailability for dietary supplements can be defined as

4350-444: The interaction between an organism and a chemical substance. Pharmacokinetic modelling may be performed either by noncompartmental or compartmental methods. Multi-compartment models provide the best approximations to reality; however, the complexity involved in adding parameters with that modelling approach means that monocompartmental models and above all two compartmental models are the most-frequently used. The model outputs for

4425-404: The intravenous dose to be administered with a minimum of toxicology and formulation. The technique was first applied using stable-isotopes such as C and mass-spectrometry to distinguish the isotopes by mass difference. More recently, C labelled drugs are administered intravenously and accelerator mass spectrometry (AMS) used to measure the isotopically labelled drug along with mass spectrometry for

4500-474: The kidney are usually greater in patients with kidney failure than they are in patients with normal kidney function receiving the same drug dosage. Population pharmacokinetics seeks to identify the measurable pathophysiologic factors and explain sources of variability that cause changes in the dose-concentration relationship and the extent of these changes so that, if such changes are associated with clinically relevant and significant shifts in exposures that impact

4575-468: The number of functioning hepatocytes , this is the reason that liver failure has such clinical importance. The steady state or stable concentration is reached when the drug's supply to the blood plasma is the same as the rate of elimination from the plasma. It is necessary to calculate this concentration in order to decide the period between doses and the amount of drug supplied with each dose in prolonged treatments. Other parameters of interest include

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4650-455: The organic acids) are actively secreted. In the proximal and distal convoluted tubules , non-ionised acids and weak bases are reabsorbed both actively and passively. Weak acids are excreted when the tubular fluid becomes too alkaline and this reduces passive reabsorption. The opposite occurs with weak bases. Poisoning treatments use this effect to increase elimination, by alkalizing the urine causing forced diuresis which promotes excretion of

4725-784: The production of crops (due to solubility limitation or absorption of plant nutrients to soil colloids) and in the removal of toxic substances from the food chain by microorganisms (due to sorption to or partitioning of otherwise degradable substances into inaccessible phases in the environment). A noteworthy example for agriculture is plant phosphorus deficiency induced by precipitation with iron and aluminum phosphates at low soil pH and precipitation with calcium phosphates at high soil pH. Toxic materials in soil, such as lead from paint may be rendered unavailable to animals ingesting contaminated soil by supplying phosphorus fertilizers in excess. Organic pollutants such as solvents or pesticides may be rendered unavailable to microorganisms and thus persist in

4800-416: The proportion of the administered substance capable of being absorbed and available for use or storage. In both pharmacology and nutrition sciences, bioavailability is measured by calculating the area under curve (AUC) of the drug concentration time profile. Bioavailability is the measure by which various substances in the environment may enter into living organisms. It is commonly a limiting factor in

4875-407: The ratio of the mean responses (usually of AUC and the maximum concentration, C max ) of its product to that of the "brand name drug" is within the limits of 80% to 125%. Where AUC refers to the concentration of the drug in the blood over time t = 0 to t = ∞, C max refers to the maximum concentration of the drug in the blood. When T max is given, it refers to the time it takes for

4950-472: The response of most mass spectrometers is not linear across large concentration ranges. There is currently considerable interest in the use of very high sensitivity mass spectrometry for microdosing studies, which are seen as a promising alternative to animal experimentation . Recent studies show that Secondary electrospray ionization (SESI-MS) can be used in drug monitoring, presenting the advantage of avoiding animal sacrifice. Population pharmacokinetics

5025-413: The route of administration is nearly always oral, bioavailability generally designates simply the quantity or fraction of the ingested dose that is absorbed. Bioavailability is a term used to describe the percentage of an administered dose of a xenobiotic that reaches the systemic circulation. It is denoted by the letter f (or, if expressed in percent, by F ). In nutritional science , which covers

5100-429: The same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as absolute bioavailability (see above ). Relative bioavailability is one of the measures used to assess bioequivalence ( BE ) between two drug products. For FDA approval, a generic manufacturer must demonstrate that the 90% confidence interval for

5175-417: The situation where the overall intake of a drug is fairly in dynamic equilibrium with its elimination. In practice, it is generally considered that once regular dosing of a drug is started, steady state is reached after 3 to 5 times its half-life. In steady state and in linear pharmacokinetics, AUC τ =AUC ∞ . Models have been developed to simplify conceptualization of the many processes that take place in

5250-402: The systemic drug concentrations achieved from the non-labelled oral dose). The intravenous and oral concentrations can then be deconvoluted by virtue of their different isotopic constitution, and can thus be used to determine the oral and intravenous pharmacokinetics from the same dose administration. This technique eliminates pharmacokinetic issues with non-equivalent clearance as well as enabling

5325-417: The therapeutic index, dosage can be appropriately modified. An advantage of population pharmacokinetic modelling is its ability to analyse sparse data sets (sometimes only one concentration measurement per patient is available). medication medication medication medication medication medication (HIV) medication Clinical pharmacokinetics (arising from the clinical use of population pharmacokinetics)

5400-407: The trapezoidal rule, the area estimation is highly dependent on the blood/plasma sampling schedule. That is, the closer time points are, the closer the trapezoids reflect the actual shape of the concentration-time curve. The number of time points available in order to perform a successful NCA analysis should be enough to cover the absorption, distribution and elimination phase to accurately characterize

5475-413: The true extent of systemic absorption (referred to as absolute bioavailability) is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires an intravenous reference ; that is, a route of administration that guarantees all of the administered drug reaches systemic circulation. Such studies come at considerable cost, not least of which

5550-504: The unlabelled drug. There is no regulatory requirement to define the intravenous pharmacokinetics or absolute bioavailability however regulatory authorities do sometimes ask for absolute bioavailability information of the extravascular route in cases in which the bioavailability is apparently low or variable and there is a proven relationship between the pharmacodynamics and the pharmacokinetics at therapeutic doses. In all such cases, to conduct an absolute bioavailability study requires that

5625-451: Was found to cause nephrotoxicity in a number of patients. However, it was then realized that it was possible to individualize a patient's dose of ciclosporin by analysing the patients plasmatic concentrations (pharmacokinetic monitoring). This practice has allowed this drug to be used again and has facilitated a great number of organ transplants. Clinical monitoring is usually carried out by determination of plasma concentrations as this data

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