Assessment of the clinical significance of pharmacokinetic parameters. Pharmacokinetic parameters
Bisoprolol
| Information from TKFS | |
| Bioavailability, % | 70% |
| Effect of food on absorption | Does not affect adsorption |
| In 2-4 hours | |
| 26-33% | |
| Volume of distribution, l/kg | 3.5 l/kg |
| _ | |
| Active metabolites | - |
| 9-12 hours | |
| Excretory organs | Kidneys |
| Clearance, ml/min | 15 l/h |
| 50% - kidneys 2% - bile | |
| Excreted in breast milk | |
| Penetrates to a small extent | |
Cardiomagnyl
| Pharmacokinetic parameter | Information from TKFS |
| Bioavailability, % | 80-100% |
| Effect of food on absorption | Slows down |
| Time of onset of maximum concentration (Tmax), h | 3h |
| Connection with blood plasma proteins, % | 90% |
| Volume of distribution, l/kg | 170 ml/kg |
| Cytochrome P-450 isoenzymes involved in metabolism | |
| First pass effect (hepatic clearance) | |
| Active metabolites | |
| Half-life, T 1/2, h | About 15 min |
| Excretory organs | Kidneys, intestines |
| Clearance, ml/min | |
| % of drug excreted unchanged | |
| Passage into breast milk | Penetrates quite well |
| Penetration through histohematic barriers | Penetrates |
Meldonium
| Pharmacokinetic parameter | Information from TKFS |
| Bioavailability, % | 78% |
| Effect of food on absorption | Inhibits adsorption |
| Time of onset of maximum concentration (Tmax), h | 1-2 hours |
| Connection with blood plasma proteins, % | |
| Volume of distribution, l/kg | |
| Cytochrome P-450 isoenzymes involved in metabolism | |
| First pass effect (hepatic clearance) | |
| Active metabolites | |
| Half-life, T 1/2, h | 4 hours |
| Excretory organs | Kidneys |
| Clearance, ml/min | |
| % of drug excreted unchanged | |
| Passage into breast milk | Partial |
| Penetration through histohematic barriers | Partial |
Valsartan
| Pharmacokinetic parameter | Information from TKFS |
| Bioavailability, % | 25% |
| Effect of food on absorption | Reduces by 40-50% |
| Time of onset of maximum concentration (Tmax), h | 1-2 hours |
| Connection with blood plasma proteins, % | 95% |
| Volume of distribution, l/kg | 16-17 |
| Cytochrome P-450 isoenzymes involved in metabolism | No |
| First pass effect (hepatic clearance) | |
| Active metabolites | - |
| Half-life, T 1/2, h | 6-7 hours |
| Excretory organs | Intestines, kidneys |
| Clearance, ml/min | |
| % of drug excreted unchanged | 70% intestines, 30% kidneys |
| Passage into breast milk | Missing data |
| Penetration through histohematic barriers | - |
For each drug, justify the choice of dosage form, route of administration, and dosage regimen. Indicate whether food intake should be taken into account during pharmacotherapy with these drugs. Justify the necessary adjustments in the dosage regimen or the patient’s diet for the pharmacotherapy you prescribe.
Dosage regimens:
Bisoprolol- 10 mg/day, tablets should be taken orally without chewing, with a small amount of liquid. It is recommended to take bisoprolol in the morning on an empty stomach or during breakfast.
Varsarta n-80 mg 1 time per day. The tablets should be taken orally, regardless of meals.
Cardiomagnyl- 75 mg 1 time per day. The tablets are swallowed whole with plenty of water.
Meldonium- IV (5-10 ml of solution for injection with a concentration of 0.5 g/5 ml), frequency of use 1-2 times/day.
11. Determine the duration of pharmacotherapy for each of the medications you have prescribed. Justify your choice (including an assessment of the level of evidence based on national and international recommendations and guidelines).
Duration of pharmacotherapy
Bisoprolol-The course of treatment is long.
Valsartan- the course of treatment is long.
Cardiomagnyl–Used for a long time, between courses of treatment (2 months), a break (1 month), then take a course of treatment again. The duration of treatment is determined by the doctor individually depending on the clinic, indications and severity of the disease.
Meldonium- The course of treatment is 1-1.5 months.
12 . Develop a program for assessing the effectiveness of prescribed medications in a patient (Table 3). If this is necessary to assess effectiveness, justify the need for therapeutic drug monitoring, indicate the therapeutic range of drug concentrations. It should be taken into account that the same drug can be prescribed to a patient for several indications. Below, after filling out Table 3, indicate the possible reasons for the ineffectiveness of the prescribed pharmacotherapy, and suggest ways to overcome it.
PharmacokineticsPHARMACOKINETICS
Pharmacokinetics (from ancient Greek φάρμακον - medicine
and κίνησις - movement) - a branch of pharmacology that studies
kinetic patterns of chemical and biological
processes occurring with the drug in
body of a mammal.
Pharmacokinetics should not be confused with pharmacodynamics;
They say that pharmacokinetics is the science of chemical
transformations of drugs in the body, while
pharmacodynamics is the science of the mechanism of action
medicines on the body.
absorption and distribution of drugs
substances.
Suction
Spreading
Elimination
Excretion
Distribution
Metabolism Routes of drug distribution
Injection site
Receptors
blood
Deposit
in tissues
Squirrels
plasma
Excretion
Biological response
metabolism Why do you need to know pharmacokinetic parameters?
and dosage regimen?
Pharmacokinetic parameters and
The dosage regimen is determined by:
The level of the drug in the body is
at any time
How long does it take to achieve
constant level of drug substance in
body with repeated administrations
How long does it take to complete
removal of the drug from
body
Main clinically significant pharmacokinetic parameters
MAIN CLINICALLY SIGNIFICANTPHARMACOKINETIC PARAMETERS
The most important pharmacokinetic parameters
when choosing a dosage regimen
clearance (a measure of an organism's ability
eliminate drugs)
volume of distribution (measure of apparent space in
body capable of containing drugs). Volume of distribution Vd (l, l/kg) - hypothetical volume of liquid
body, necessary for the uniform distribution of everything
quantity of drugs (administered dose) in a concentration similar to
concentrations in blood plasma.
where C0 is the initial concentration of the drug in the blood.
For intravenous administration: High volume values
distributions indicate that the drug is actively
penetrates into biological fluids and tissues. If the drug
actively binds, for example, to adipose tissue, its concentration in
blood can almost instantly become very
low, and the distribution volume will reach several hundred liters,
exceeding the actual volume of body fluids. In this regard, his
also called “apparent volume of distribution”. The volume of distribution is used when selecting a regime
dosing to calculate the ND (loading dose) required for
achieving the required concentration of the drug in the blood:
where C is the effective concentration of the drug in the blood. Total Cl clearance (ml/min, l/h) - plasma volume or
blood, which is completely cleared of the drug within
unit of time. Within the linear model:
Due to the fact that the main routes of excretion are the kidneys and
liver, total clearance is the amount
renal and hepatic clearance. Under the hepatic
clearance refers to metabolic clearance in
liver and excretion of the drug in bile Elimination rate constant kel (h-1) - percentage reduction
concentration of a substance per unit time (reflects the proportion
drug excreted from the body per unit of time).
Total clearance, volume of distribution and elimination constant
are related by the equation:
Tl/2 half-life (h) - time required for reduction
plasma concentrations by 50%:
Almost in one half-life it is eliminated from the body.
50% LS, for two periods - 75%, for three periods - about 87%, etc. Dependence between period
half-elimination and rate constant
elimination is important for choosing the interval
between doses, as well as to determine
the period of time required for
achieving equilibrium concentration
(usually 5-7 Tl/2) with repeated administration
PM.
If drugs are administered in a constant dose through
fixed time intervals,
less than the drug elimination time,
then its concentration in the blood increases, and
then comes a period when in each
interval between taking subsequent doses
Drug quantity of absorbed drug
equal to the amount eliminated. This state is called “stationary”, or Steady state, and
the concentration achieved in this case is “stationary” (less often “equilibrium”), - Css. As a result, drug concentrations fluctuate
within the average value with certain
maximum (Cssmax) and minimum
values (Cssmin) of drug concentration. In practice, the equilibrium concentration of a drug can be
calculate from the concentration of a given drug after
single administration:
where τ is the time interval between doses.
When calculating the dose required to maintain the desired
concentration of drugs in the blood, the so-called maintenance dose,
use the clearance value:
When extravascular administration of the drug for natural reasons does not
its entire amount reaches the systemic bloodstream. Bioavailability F (%) - the portion of the drug dose that reaches the systemic level
blood flow after its extravascular administration.
Bioavailability can be absolute or relative, and is determined
it as a ratio of the “area under the curve” (AUC) values. When
data on extravascular administration of the drug are compared with data
the same drug when administered intravenously, then you get
absolute bioavailability:
When two extravascular routes of administration are compared, they speak of
relative bioavailability (for more details, see the “Research” section
bioequivalence"). Using the above formulas, we get:
Thus, a tablet (capsule) containing a dose
approximately 350 mg, may be prescribed
after 12 hours. If an eight-hour interval is used, then the dose
should be about 233 mg, and at a 24-hour interval - 700
Many pharmacogenetic patterns are explained from the standpoint of pharmacokinetics - an important area of pharmacological research that describes the processes of absorption, distribution, metabolism and elimination (excretion) introduced into the body. The main pharmacokinetic parameters used to develop drugs and rationalize their use are outlined below.
Patients with chronic diseases such as diabetes and epilepsy must take medications every day throughout their lives. However, some people only need one dose to relieve their headaches.
The method a person uses to take a medicine is called a regimen. Both the duration of drug therapy and the dosage regimen depend on the goals of therapy (treatment, alleviation of the disease, prevention of the disease, and in the practice of sports training - general and special sports, acceleration of processes after heavy physical and psycho-emotional stress). Since almost all drugs have side effects, rationalization of pharmacotherapy is achieved by choosing the optimal ratio of therapeutic and side effects of the drug.
However, first of all, it is necessary to choose the right medicine. The decision is made on the basis of an accurate diagnosis of the disease, knowledge of the patient’s clinical condition and a deep understanding of both the pathogenetic mechanisms and the mechanisms of action of the drug. Next, you should determine the dose and duration of administration. The therapeutic latitude, or the difference between the effective and toxic dose, must be taken into account. The frequency of administration is determined by the time during which a significant decrease in the effect occurs after a single dose of the drug. The duration of treatment is determined by the time it takes to achieve a therapeutic effect without significant side effects; in some cases, pharmacoeconomic problems arise. For each patient, these issues should be considered in combination.
Relationship between pharmacokinetic and pharmacodynamic phases of drug action
In the recent past, the basis for their decision was the trial and error method, in which the dose, dosage schedule and route of administration were chosen empirically based on changes in the patient's condition. However, in a number of cases, the chosen regimens led to toxic effects or were ineffective. It was unclear, for example, why tetracycline should be prescribed every 6-8 hours, and digoxin - once a day; why morphine is more effective when administered intramuscularly than when administered orally, etc.
To overcome the limitations of the empirical approach and answer the questions that arise, it is necessary to understand the events that follow after taking the drug. In vitro and in vivo studies indicate that efficacy and toxicity are a function of the concentration of the drug in the biofluid at the site of action. It follows that the goal of pharmacotherapy can be achieved by maintaining adequate drug concentrations at the site of action throughout the treatment period. However, it is extremely rare that the drug immediately appears in the target area. For example, drugs that act on the brain, heart, neuromuscular junction, etc. are prescribed for oral administration, which requires their transport to the site of action. In this case, the drug is distributed in all other tissues, including those organs, especially the liver and kidneys, that remove it from the body.
The figure shows the phenomena that occur after taking the drug orally. Initially, the rate of its entry into the body exceeds the rate of elimination, and concentrations in the blood and other tissues increase, often exceeding the level necessary for the manifestation of a therapeutic effect, and sometimes causing toxic effects. Then the rate of elimination of the drug becomes higher than the rate of absorption, so the concentration of the drug in both the blood and tissues decreases, and the manifestations of its action decrease. Thus, to rationalize the use of the drug, it is necessary to have an understanding of the kinetics of the processes of absorption, distribution and elimination, i.e. pharmacokinetics. The application of pharmacokinetic parameters to the management of pharmacotherapeutic processes is the subject of clinical pharmacokinetics.
The patient’s condition after taking the drug can be divided into two phases: pharmacokinetic, in which dose, dosage form, dosage frequency, and route of administration are related to the drug concentration-time relationship, and pharmacodynamic phase, where the concentration of the drug at the site of action is related to the amplitude of the effect caused.
Isolation of these two phases facilitates the development of a dosage regimen. First, a distinction can be made between pharmacokinetic and pharmacodynamic causes of an unusual drug reaction. Second, basic pharmacokinetic parameters are used for all drugs; information obtained on the pharmacokinetics of one drug can be predictive of the pharmacokinetics of another, which has a similar biotransformation pathway. Thirdly, understanding the pharmacokinetics of a drug allows you to choose the method of its use and work out an individual dosage regimen with predictable consequences.
Thus, a basic principle of clinical pharmacokinetics is that the magnitudes of both the desired and toxic effects are functions of the concentration of the drug at the site(s) of its action. According to this, therapeutic failure occurs when the concentration of a drug is either too low to produce an effect or too high to cause toxic complications. Between these concentration limits lies the region that determines the success of therapy. This area can be considered a "therapeutic window". It is very rarely possible to directly measure the concentration of a drug at the site of its action; usually the content of the administered substance and/or its metabolites is measured in available biosubstrates - in plasma, blood serum. The optimal dosing regimen may be one that ensures the concentration of the drug in the blood plasma within the “therapeutic window”. Therefore, most often medications are prescribed at discrete intervals to maintain balance with the elimination process.
Curve of changes in the concentration of a drug in the blood plasma after a single oral dose
Development of pharmacokinetic research in the second half of the 20th century. was of great importance for the pharmaceutical industry. For example, if it is found that an active drug is not sufficiently absorbed even though it is intended for oral administration, then a compound with less activity but better penetration into the body can be selected. Such a decision can be made at the stage of preclinical studies, since the basic processes of pharmacokinetics for mammals are similar and can be extrapolated from animals to humans. The same conclusion can be made with respect to pharmacokinetic experiments on animals aimed at selecting recommended doses of the drug for humans.
Pharmacokinetics of two drugs containing the same drug substance in one dose: MTC - minimum toxic concentration; MEC - minimum effective concentration
Pharmacokinetic studies during phase 1 clinical trials, usually conducted in healthy volunteers, provide an opportunity to evaluate different dosage forms and dosage regimens. Pharmacokinetic control in the second phase of clinical trials provides an objective assessment of effectiveness and safety in a small sample of patients, and makes it possible to give recommendations for the rational use of the drug in the third phase of clinical trials. Where necessary, pharmacokinetic studies are continued after the approval of medical use in order to improve the pharmacotherapeutic profile. The sequence of activities for drug development and evaluation is presented in the diagram.
Pharmacokinetic studies are also necessary to solve the fundamental problem of pharmacotherapy - individual sensitivity. The reasons for differences in the effects of drugs include the age, gender, body weight of the patient, the type and severity of the disease, additional drugs taken by the patient, bad habits and other environmental factors that influence pharmacokinetic mechanisms, which in turn are controlled by an individual set of genes.
As a result, in some patients the standard dosage regimen will be optimal, in others it will be ineffective, and in others it will be toxic.
Prescribing several medications to a patient at the same time can also lead to problems, since their interaction in the body can cause changes in the pharmacokinetics of individual drugs.
Thus, the need to use pharmacokinetic parameters in the development and use of drugs is beyond doubt.
To describe the pharmacokinetic profile of a drug, a number of parameters are used to select a dosage regimen.
When considering the physiological processes (sections 6.6; 7.2.5; Chapter 9) that determine pharmacokinetic parameters, we gave their characteristics. In order to better understand the material, we repeat some of the above parameters, and some are considered for the first time.
Elimination rate constant (designation - Ke1, dimension - h-1, min-1) is a parameter characterizing the rate of elimination of the drug from the body through excretion and biotransformation. In multipart models, the Ke1 value usually characterizes the elimination of the drug from the central chamber, which includes blood and tissues that quickly exchange the drug with the blood. Elimination of the drug from the body in this case is characterized by the apparent elimination constant - a complex parameter (designation P, dimension - h-1, min-1), associated with other constants of the model (Kір, see below).
Absorption (absorption) rate constant (designation K01, dimension - h-1) is a parameter characterizing the rate of entry of the drug from the injection site into the systemic circulation during the extravascular route of administration.
The rate constant of the transition of the drug between parts (chambers) in multi-part (multi-chamber) models (designation Kf dimension - h-1, min-1) is a parameter characterizing the rate of release of the drug from the i-th chamber to the i-th chamber. For example, in a two-part model there are two transition rate constants - one characterizes the rate of transition from the central (first chamber) to the peripheral (second) and is denoted /C,2; the other characterizes the reverse process and is denoted K2X. The ratio of these constants determines the equilibrium distribution of the drug. In total, the kinetics of the distribution process between the two chambers is characterized by a complex parameter, which depends on the rate constant of all processes taken into account by the model.Within the framework of a two-part model, this parameter is denoted a, its dimension is h-1, min-1.
Excretion rate constant (designation Ke or Keh, dimension - h-1, min-1) is a parameter characterizing the rate of excretion of the drug with any excretion: urine, feces, saliva, milk, etc. Within the framework of the linear model, this constant must coincide in magnitude with the elimination rate constant if the drug is excreted from the body only unchanged in one way, for example, with urine. In other cases, the value of Kex is equal to the fraction of Ke1-
The semi-elimination period of the drug (designation Tx/2, dimension - h, min) is the time of elimination from the body of half of the administered and received dose of the drug. Corresponds to the time of halving the concentration of the drug in the blood plasma (serum) at the site of a monoexpotential decrease in the plasma (serum) level of the drug, i.e. in the P-phase.
The value of T|/2 is determined by the total excretion and biotransformation of the drug, i.e., its elimination. The half-life period uniquely depends on the elimination rate constant: for a single-part model - T1/2 = 0.693/Keh for a multi-part model - T1/2 - 0.693/r.
The period of half-absorption (half-absorption) of the drug (designation Tx/2a, dimension - h, min) is the time required for absorption (absorption) from the injection site into the systemic circulation of half of the administered dose. The parameter is used to describe the kinetics of the drug in the case of its extravascular administration and clearly depends on the rate constant of drug absorption.
The half-life of the drug (designation Tx/2a, dimension - h, min) is a conditional parameter that characterizes, within the framework of a two-part model, the distribution between the central chamber, including blood plasma, and the peripheral chamber (organs, tissues). The Tx/2a value corresponds to the time it takes to reach drug levels equal to 50% of the equilibrium concentrations that are observed when equilibrium is reached between the blood and other tissues.
The apparent initial concentration of the drug (designation C0 or C°, dimension - mmol/l, μg/l, ng/ml, etc.) is a conditional parameter equal to the concentration that would be obtained in the blood plasma if the drug was introduced into the blood and instantaneously its distribution among organs and tissues (when analyzing a one-part model) or in the volume of the central chamber (when analyzing two- and multi-part models). The value of C with linear kinetics of the drug in the body is directly proportional to the dose of the drug.
The stationary concentration of the drug in the blood plasma (designation Css, dimension - mmol/l, μg/l, ng/ml) is the concentration that is established in the blood plasma (serum) when the drug enters the body at a constant rate.
In the case of intermittent administration (administration) of a drug at equal intervals of time in equal doses, the concepts of maximum steady-state concentration (C™x) and minimum steady-state concentration (C™p) are used.
The volume of distribution of the drug (designation Vd or V, dimension - l, ml) is a conditional parameter characterizing the degree of drug uptake by tissues from blood plasma (serum). The value of Vd within the framework of a one-part model is equal to the conditional volume of liquid in which the entire dose of the drug entering the body is distributed so that a concentration equal to the apparent initial concentration (C0) is obtained. Often the volume of distribution is referred to a unit of body weight of the patient (G, kg) and the specific volume of distribution is obtained (designation Ad, dimension - l/kg, ml/g). In multi-part models, the concept of volume of distribution in the i-th chamber is introduced (designation Vh dimension - l, ml). For example, when analyzing a two-part model, the volume of the first, central chamber (1/), which includes blood plasma, is calculated. The total or kinetic volume of distribution in such models (designation V$, dimension - l, ml) characterizes the distribution of the drug after reaching a state of quasi-stationary equilibrium between the concentration of the drug in the blood (central chamber) and other tissues (peripheral chambers). For a two-part model, the expression Kp = (kei/$)/Vu is valid. For this model, it is also proposed to use the parameter stationary volume of distribution (designation Vss, dimension - l, ml), which is proportional to the value of the volume of distribution in the first chamber.
Often the volume of distribution is called “apparent”, which only makes the terminology more complicated, but does not provide additional clarification, since the convention of this parameter follows from its definition.
General clearance of the drug (synonyms: body clearance, plasma (serum) clearance, plasma (serum) clearance; designation C1, or C1T, dimension - ml/min, l/hour) - a parameter corresponding to the volume of test tissue released from the drug in unit of time. In the simplest case, drug clearance is the ratio of the rate of elimination by all possible routes to the concentration of the drug in biological tissues.
Renal (renal) clearance of the drug (designation C/renal, Clr, ClR, dimension - l/h, ml/min) is a parameter that determines the rate of elimination of the drug from the body through its excretion by the kidneys. The C1G value corresponds (conditionally) to that part of the volume of distribution from which the drug is eliminated in the urine per unit time.
Extrarenal (extrarenal) clearance of the drug (designation C1en S/v/ren, C1t, dimension - l/h, ml/min) is a parameter characterizing the rate of elimination of the drug from the body by other routes besides excretion in the urine, mainly due to biotransformation (metabolism ) of the drug and its excretion with bile. The value of C1er corresponds (conditionally) to that part of the volume of distribution from which the drug is eliminated per unit time by a total of all elimination routes, except excretion by the kidneys.
Area under the concentration-time curve (synonym - area under the pharmacokinetic curve; designation AUC or S, dimension - mmol-h-l-1, mmol-min-l-1, µg-h-ml-1, µg-min -ml_1, ng-h-ml-1, ng min-ml-1, etc.) - on the graph in coordinates the concentration of the drug in the blood plasma (serum), Cp - time after administration of the drug, G, area of the figure limited by the pharmacokinetic curve and coordinate axes. AUC is related to another pharmacokinetic parameter, the volume of distribution; AUC is inversely proportional to total drug clearance. If the kinetics of the drug in the body is linear, the AUC value is proportional to the total amount (dose) of the drug entering the body. Often they use not the area under the entire pharmacokinetic curve (from zero to infinity in time), but the area under part of this curve (from zero to some time t)\ this parameter is denoted by AUC.
Time to reach maximum concentration (designation £max or /max, unit - h, min) - time to reach the concentration of the drug in the blood.
