Pharmacokinetic Variability PDF

    To understand why when individuals are given identical doses of a drug, large differences in pharmacologic response are seen. To identify the sources of variability. To study about intersubject and intrasubject variability. To understand the effect of body weight, size and obesity on vari...

    To understand why when individuals are given identical doses of a drug, large differences in pharmacologic response are seen. To identify the sources of variability. To study about intersubject and intrasubject variability. To understand the effect of body weight, size and obesity on variability in individuals. 1 #  Individuals given identical doses of a drug,  large differences in pharmacologic response Sleeping times of 72 rats after intraperitoneal administration of pentobarbital sodium (30 mg/kg) ranged from about 30 to 190 min.  Duration of paralysis in 96 rats after intraperitoneal administration of zoxazolamine (110 mg/kg): varied from 100 to 850 min.  3 2 Two sources of variability Differences in drug levels at site of action (as inferred by drug concentration in the plasma),  Differences in effect produced by a given drug concentration.  ~ 4  Both sources contribute to variability in response  Principal variation :  Drug concentration resulting from given dose.  Called pharmacokinetic variability.  Both pharmacokinetic and pharmacodynamic, Wide range of blood levels also seen in same subject taking drug on different occasions.  Intersubject variability much greater than Intrasubject variability.  midazolam, (intravenous benzodiazepine) 5 6  Contributing factor to intrasubject variability  Factors contributing to variability  Physical activity  Bioavailability of drug from the dosage form,  Renal clearance of digoxin significantly  Those that may affect the completeness of absorption. higher during a period of normal physical  Those that affect drug disposition. activity than during a period of immobilization. 7 8  ADME subject to individual variation  Age-related phenomena,  Genetic and environmental factors,  Consequences of disease, and  BODY WEIGHT AND SIZE  Apparent volume of distribution determined by  Anatomic space into which it distributes  Relative degree of vascular and extravascular binding. Volume of both total body water (TBW) and extracellular fluid (ECF) in adults with normal lean-to-fat ratios directly proportional to body weight,   Concomitant administration of other drugs.  Important source of variability  Patients fail to follow directions about taking medicine. Relationship particularly evident for drugs poorly bound in body.  10 9 Organ size, function, and blood flow also related to body weight  Initial blood levels following single dose or loading dose of a drug that is rapidly absorbed largely dependent on apparent volume of distribution;    Relationship between drug clearance and body weight not clear.  Larger volume of distribution : lower is blood level. Correlation between drug clearance and body weight in normal young adults is poor;  If peak blood levels are of concern Infants, children, and the elderly confounded by age effects on drug clearance.  Body weight should be considered in determining the appropriate dose.  No general guidelines to relate maintenance doses of drugs to body weight.  11 12  When are weight adjustments thought necessary ? Weight of an individual differs by more than 50% from the average adult weight (70 kg).   Obesity  Condition when patient’s total body weight is more than 25% above desirable weight    In practice, adjustments for weight made only for children and for  Ideal body weight (IBW) is usually defined as follows:  IBW (men) = 50 kg ± 1 kg/2.5 cm above or below 150 cm in height unusually small, or obese adult patients  IBW (women) = 45 kg ± 1 kg/2.5 cm above or below 150 cm in height 13 14 Drug distribution changes due to changes in body composition in the obese patient. To learn how to calculate IBW in men and women. Percentage of fat and lean body mass in an individual estimated by measuring  To understand calculations for Percent fat and Lean body mass  Height (in inches),  Weight (in kilograms), and  Girth (in inches, using the umbilical level at  exhalation), 15 16  Data used in equations  Percent fat  = 90 — 2 (Height — Girth) Lean body mass (LBM), sometimes conflated with fat-free mass, is a component of body composition. Fat free mass (FFM) is calculated by subtracting body fat weight from total body weight: total body weight is lean plus fat. In equations: LBM = BW − BF Lean body mass equals body weight minus body fat LBM + BF = BW Lean body mass plus body fat equals body weight.  Lean body mass  = (100 — Percent fat) x Weight – it would typically be 60–90%. Instead, the body fat percentage, which is the complement, is computed, and is typically 10–40%. The lean body mass (LBM) has been described as an index superior to total body weight for prescribing proper levels of medications and for assessing metabolic disorders, as body fat is less relevant for metabolism. 17     The Boer formula for calculating LBM is: For men: LBM = (0.407 × W) + (0.267 × H) − 19.2 For women: LBM = (0.252 × W) + (0.473 × H) − 48.3 where W is body weight in kilograms and H is body height in centimeters. 19 18  What could lead to changes in drug partitioning into various body compartments?  To learn about dosing guidelines in Neonates, Infants, and Children  To understand behaviour of drugs in Elderly Patients, pregnant females and twins 20  What could lead to changes in drug partitioning into various body compartments?  ●Smaller ratio of body water and muscle mass to total body weight,  ● Greater proportion of body fat in obese  Drug binding, metabolism, and excretion affected by obesity. Selection of appropriate dosing regimens for severely obese patient : formidable challenge Changes in dosing regimen for obese patients anticipated Fat contains less extracellular fluid than other tissues.  If drug largely excreted unchanged or eliminated through formation of sulfate or glucuronide conjugates.  Distribution space for polar drugs, like antibiotics, is relatively less in obese  21  Creatinine clearance increased in obese patients Renal clearance may be increased to a similar or greater extent.   22  Neonates, Infants, and Children Dosing guidelines for children more complicated than Renal excretion greater in obese patients those for adults. Changes in renal blood flow and glomerular filtration rate secondary to increased blood volume and cardiac output.   Children require and tolerate larger mg/kg doses of many drugs than do adults. Metabolic clearance reflecting conjugation with sulfate or glucuronic acid also increases as function of body weight  23 24  Example,  Usual doses of digoxin :  15 to 20 µg/kg per day for children 4 weeks to 2 These doses result in average digoxin concentrations in plasma of about 1 to 1.5 ng/ml when given to patients of appropriate age.  How do you estimate dose required for infants and children ?  years of age,  10 to 15 µg/kg per day for children 2 to 12 years On basis of surface area of young patient relative to surface area of an adult.  of age  4 to 5 µg/kg per day for adults. Body surface area (SA) calculated using the following height-weight formula  25  SA = (height X weight)1/2/60  Water- soluble drugs  Age-related changes in drug distribution 26  Decreased volume of distribution in adults compared with neonates.   Lipid soluble drugs  Lower volume of distribution in neonates     To understand the Pharmacokinetics in the Elderly Patients To understand the difference in Apparent volume of distribution in the elderly population. To learn about the changes with age Why? Age-related differences in adipose tissue 27 28 Percentage of total body weight composed of adipose • tissue  Elderly Patients Age-related changes in body composition at other end of life also affects drug distribution.   Lean body mass decreases and Body fat increases in relation to total body weight in aging individual.  • 36% in elderly men • 48% in elderly women, • Much higher than young adults • Young adults, • 18% in men and • 33% in women. • 30 29  • Apparent volume of distribution • Water-soluble drug such as antipyrine may  Drug binding, metabolism, and excretion change with age. remain the same or decrease slightly with age,  • AGE Lipid-soluble drugs such as diazepam may be Drug elimination impaired in newborns, particularly premature newborns; much larger in elderly patients than in younger  ones. Improves with age and tends to be more efficient in older infants and children.  31 Thereafter, drug elimination declines with age. 32  Drug Metabolism in Newborns  Most of the enzymatic microsomal systems Their titers usually lower than adult levels.  Drugs subject to biotransformation are eliminated Plasma Protein Binding in Newborns  Binding to plasma proteins less in the newborns than in the adults.  required for drug metabolism present at birth,   An increase in apparent volume of distribution in the newborn.  Diazepam, despite the fact that the fraction unbound to plasma proteins is 4 times larger in neonates than in more slowly in newborns than in adults adults. 33  Renal Excretion in Newborns  Ratio of kidney weight to total body weight in the Immature renal function affects elimination of :  Aminoglycosides,  Indomethacin,  Digoxin,  Penicillins,  Sulfonamides,  and many other drugs.  newborn is twice that in the adult,  Organ is anatomically and functionally immature;  All aspects of renal function are reduced.  Risk of adverse drug effects in newborns is high 34 35 36  Drug Metabolism in Children Drug metabolism impaired in neonates compared to adults,  To study Drug Metabolism in Children  To learn about drugs showing faster elimination in children than in adults  To learn how to calculate doses using body surface area equation  To know about drug elimination changes based on age, gender pregnancy as well as in twins.  Older infants and children actually metabolize certain drugs more rapidly than adults.  Rates of drug metabolism for many drugs reach a maximum somewhere between 6 months and 12 years of age and   Declines with age. Accordingly, children often require higher mg/kg doses than do adults.  37  38 Drugs showing faster elimination in children than in adults  Body surface area better correlate dosing  antipyrine, clindamycin,  diazoxide,  Child’s maintenance dose :  phenobarbital,  SA of child (m2)  requirements in children than body weight. Child’s dose = _______________ x Adult dose (mg/day) carbamazepine, valproic acid, 1.73 m2  ethosuximide, and theophylline  39 40  Drug Elimination in the Aged  Probability of experiencing adverse effects increase with age.    To understand the Pharmacokinetics in the Elderly Patients To understand the difference in Apparent volume of distribution in the elderly population. To learn about the changes with age  Decline in organ function with advancing age.  Cardiac output decreases by 30 to 40% between ages of 25 and 65 years.  Glomerular filtration rate (GFR) declines progressively with age after age of 20 yr. 41 Differences in the pharmacokinetics of certain drugs between young and old adults  42  Reason: Diminished urinary excretion of digoxin in the elderly.  Same amount (0.5 mg) of digoxin administered intravenously to elderly men (73 to 81 years) and young men (20 to 33 years)  Increasing age associated with reduced renal function,  Decreasing renal function might contribute to alteration in drug –disposition.  Higher blood concentrations and longer half-lives in the elderly.  43 44 Clearance of drugs with liver blood flowdependent elimination may decrease in the elderly.   Changes in drug metabolism with age are not as predictable as changes in renal excretion of drug. Important age-related changes reported for drugs showing marked first-pass metabolism   Hepatic blood flow declines with age, Why?  Partly because of reduced cardiac output.  46 45   ‘Increased sensitivity’ of the elderly to thiopental. Gender Kinetics of large number of benzodiazepines studied with respect to sex-related difference.   Smaller central compartment,  Elderly develop high serum levels of thiopental quickly  Require less drug to show an effect Dose of thiopental required to reach a surgical level of anesthesia significantly decreased with increasing age  47 Clearance or apparent clearance of temazepam, oxazepam and lorazepam significantly less in human female subjects than in males.  48 } Studies in human subjects with acetaminophen } Clearance 40% greater in males than in females. } Increased activity of glucuronidation pathway in ▲Salicylic acid clearance 60% higher in male than in female subjects, males; } } Why? Formation clearance of acetaminophen glucuronide 252 mI/min in males and 173 mI/min Enhanced activity of glycine conjugation pathway in males. } in females 50 49 Volume available for drug distribution increases during pregnancy, } } Pregnancy } Delayed gastric emptying and } Decreased motility of gastrointestinal tract. } } Why? } Growth of uterus, placenta, and fetus. Maternal plasma volume and ECF volume also increase. } Changes may reduce rate of drug absorption. Concentration of plasma proteins tend to fall gradually during pregnancy, } } 51 Drug binding may be reduced. 52 } GENETIC FACTORS Protein binding of many (but not all) drugs decreased during pregnancy, particularly during last trimester. } } Glomerular filtration increases } For drugs largely eliminated by renal excretion, } May result in unusually rapid elimination } Undermedication in pregnant patients Major cause of intersubject variability in drug metabolism. } Individuals who metabolize a drug much more slowly or much more rapidly than average person. } 53 Genetic factors contribute substantially to large differences among people in metabolic clearance of drugs. 54 Studies in Twins Genetic component can be estimated by comparing pharmacokinetics of a drug in identical and fraternal twins. } } Variability in rates of drug metabolism will be much smaller in monozygotic (identical) twin pairs than in dizygotic (fraternal) twin pairs } The study of these differences is called pharmacogenetics } 55 56 } } } 57 At the end of the chapter the students will be able to: Understand the reasons for variability in responses based on age, weight, genetic factors etc. Calculate and modify the doses based on the above factors. 58