Tiêu đề 8. INDIVIDUALIZATION OF DRUG DOSAGE REGIMEN.pdf ✅

PHARMD GURU Page 1 INTRODUCTION:  It is the most accurate approach and is based on the pharmacokinetics of drug in the individual patient.  The approach is suitable for hospitalized patients but is quite expensive.  Same dose of drug may produce large differences in pharmacologic response in different individuals; this is called as Inter-subject variability.  In other words it means that the dose required to produce a certain response varies from individual to individual.  The main objective of individualization is aimed at optimizing the dosage regimen.  An inadequate therapeutic response calls for a higher dosage whereas drug related toxicity calls for a reduction in dosage.  Thus in order to aid individualization, a drug must be made available in dosage forms of different dose strengths. The number of dose strengths in which a drug should be made available depends upon two major factors: 1) The therapeutic index of the drug, and 2) The degree of inter subject variability.  Smaller the therapeutic index and greater the variability, more the number of dose strengths required. ADVANTAGES OF INDIVIDUALIZATION:  Individualization of dosage regimen help in development of dosage regimen which is specific for the patient.  Leads to decrease in Toxicity and side effects and increase in pharmacological drug efficacy.  Leads to decrease in allergic reactions of the patient for the chug if any.  Patient compliance increases. SOURCES OF VARIABILITY: 1) Pharmacokinetic Variability:  Due to difference in drug concentration at the site of action (as reflected from plasma drug concentration) because of individual differences in Drug absorption, Distribution, Metabolism and Excretion. INDIVIDUALIZATION OF DRUG DOSAGE REGIMEN
PHARMD GURU Page 2  Major causes are genetics, disease, age, body weight & Drug-Drug interactions. 2) Pharmacodynamics Variability:  Which is attributed to differences in effect produced by a given drug concentration. VARIABILITIES: 1. AGE:  The factors that affect drug absorption, including gastric pH, gastric emptying, intestinal motility, and blood flow change with age.  Thus, in the neonate a condition of achlorhydria persists for the first week of life, and only after 3 years of age gastric acid secretion approaches the adult value.  Gastric emptying is also prolonged and peristalsis is irregular during the early months of life.  Skeletal muscle mass is also much reduced, and muscle contractions, which tend to promote both blood flow and spreading of an intramuscularly administered drug, are relatively feeble.  An elevated gastric pH, a delay in gastric emptying, and both diminished intestinal motility and blood flow are also seen in the elderly.  Differences in drug absorption among adults, the very young and the elderly, are therefore expected.  Generally, changes in rate rather than in extent of absorption are found.  These changes tend to be less apparent in the elderly than in the very young.  Children often appear to absorb drugs as completely and, if anything, more rapidly than adults.  Accordingly, in subsequent calculations of dosage, extent of absorption is assumed not to vary with age.  A major exception is for some first-pass drugs given to the elderly, where oral bioavailability increase with age.  Generally, plasma binding is lower in neonates than adults.  During adulthood the value of fu (fraction of unbound drug in plasma) remains unchanged or tends to raise for those drugs bound to albumin, the concentration of which falls slightly with advancing years.  The change in binding is generally too small, to warrant any consideration of dose adjustment.
PHARMD GURU Page 3  Clearance, if normalized for body weight, is depressed in the neonate, but increases rapidly to reach a maximum value at 6 months, when it is almost twice that in the adult.  Therefore, weight –normalized clearance falls but still remains, throughout childhood, considerably above the adult value.  The half life is shortest around 1 year of age; it is longest in both newborn and elderly patients.  In premature newborns, the urinary excretion is even more depressed per kilogram of body weight than in full-term neonates.  Metabolic activity may take months to mature, the time required for full maturation varies with the enzyme system.  A decrease in unbound metabolic clearance in the elderly patient has been demonstrated for an increasing number of drugs, especially, those principally by oxidation.  These changes may be associated in part, with the decrease in the size of the liver, as a proportion of body weight, from 2.5 % in the young adult to 1.6 % at 90 years of age. 2. BODY WEIGHT:  One aspect of aging is body weight.  Weight, 3.5 kg at birth, increases rapidly in childhood and adolescence and then declines slowly in the elderly.  As body water spaces, muscle mass, organ blood flow, and organ function are related to body weight, the volume of distribution, clearance and hence dosage regimens of drugs also depend on body weight.  However, a weight adjustment is generally thought necessary only if the weight of an individual differs by more than 30% from the average adult weight (70 kg).  In practice, then, adjustments for weight are made only for the child and for the adult who is small, thin, big, or obese.  A dose correction must be considered for thin and obese patients.  The difference in loading dose may not be as great as anticipated from body weight alone.  Because, distribution get age-related changes and much depends on the physicochemical properties of the drug.
PHARMD GURU Page 4  For example, digoxin and other polar drugs (water soluble) show better correlation between unbound volume of distribution (Vu) with lean body mass, which is similar in obese and average persons of the same height and frame, than with total body weight.  In contrast, total body weight may be more relevant for a drug that is highly lipid soluble.  Though renal and hepatic functions are related to body size, obesity may not produce a corresponding increase in hepatic function.  Consequently, the use of total body weight to determine a drug dosage regimen could result in toxic effects if the patient is grossly obese.  Thus, though many drug doses are based on the body weight of the patient (expressed as mg/kg), the influence of obesity or malnourishments is not always considered. 3. GENDER:  Genetic and physiological differences between men and women can influence both PK and PD.  For example, many genes on the Y chromosome, which are expressed only in males, have no counterpart on the X chromosome.  The Y chromosome has genes involved in basic cellular function and some genes on the X chromosome are expressed at higher levels in females.  Gene expression and regulation are likely to be influenced by hormonal differences between males and females.  Genomic imprinting, body size, organ size, body fat, ADME can also affect pharmacological outcome.  Other factors such as gastrointestinal transit time, liver enzyme function and urinary creatinine clearance are influenced by both age and sex.  Across the path of a woman’s life it is necessary to consider the stages of ovarian function to appreciate the potential for drug, sex, and age interactions as they influence rational drug therapy.  Use of oral contraceptives and hormonal changes which occur throughout the menstrual cycle influence pharmacological results.  Necessary considerations during pregnancy are alterations in body composition, cardiac output, pulmonary and renal function as well as changes in immune and gastrointestinal systems.