Individualization of drug therapy Shariff Atiqulla

Design of drug therapy based on the need of an individual patient and clinical situation Variations in response to same dose of a drug between different patients and some time in same patient on different occasions

Need for individualization Individuals respond differently to a given drug Given drug may have no effect on one individual while it may work wonders in others For patients who needs less dose, instead of using wide therapeutic range, the dosage can be selected based on each patients individual need with a low incidence of ADRs

On contrast, if need is greater & if patient has not achieved any clinical benefit/response with previous dosage, one can select the higher dose To achieve individualized target total body concentration Ex. Patients with AF often require more digoxin than those with sinus rhythm One must always look at the patient not the serum level to evaluate widely varying sensitivities to SDC & to adjust the dose up or down

Why variations ? Genetic Age Weight Disease Interacting drugs

Age - children New borns have low GFR & tubular transport is not matured Similarly, hepatic drug metabolizing system is inadequate in new borns BBB is more permeable, hence drugs attain higher concentration in CNS Drug absorption may also be altered in infants because of lower gastric acidity & slower intestinal transit

As skin is thin, transdermal absorption of drugs is faster & is more permeable At one year, drug metabolism is faster than in adults Ex. Theophylline, Phenytoin, CBZ hence higher dose may be required

In general, The dose of a drug for children is often calculated from adult dose Young’s formula child dose = age/age+12 X AD Dilling’s formula child dose=age/20 X AD

Age - elderly As the age progresses, the renal functions are progressively declines Decline in liver blood flow & reduction in hepatic microsomal enzymes results in drug accumulation Slow absorption due to reduced intestinal motility & decreased blood flow, decreased plasma protein binding due to low plasma albumin Increased chances of drug interactions as a result of polypharmacy

Disease status GI disease: Alter absorption of orally administered drugs Decreased absorption of amoxycillin in coeliac disease Decreased absorption in achlorhydria

Liver disease Bioavailability of drugs which have high first pass metabolism is increased Decreased serum albumin decreased protein binding of acidic drugs increased free form of drugs Decreased metabolism & elimination hence reduce the dose

Prefer alternate drugs that do not depend on hepatic metabolism for elimination or those have short half-life Ex. Consider oxazepam or lorazepam instead of diazepam Avoid prodrugs as they need hepatic metabolism for activation

Kidney disease Affects PK of many drugs Clearence of drugs such as aminoglycosides, digoxin, phenobarbitone decreases Altered structure of plasma protein (albumin) in renal failure results in decreased binding of acidic drugs

Increased permeability of certain drugs (opiates, benzodiazepines, barbiturates, phenothiazines) to BBB in renal failure resulting in producing more CNS depression Target organ sensitivity may also be increased antihypertensives produce more postural hypotension

CHF Alters drug kinetics Decreased drug absorption from GIT due to mucosal edema Altered VOD – may increase for some drugs due to expansion of ECF or may decrease due to decreased tissue perfusion hence loading dose of some drugs should be lowered

Decreased drug elimination due to decreased perfusion & congestion of liver, decreased GFR & increased tubular reabsorption hence reduce dosing rate Ex. Theophylline Decompensated heart is more sensitive to digitalis

Thyroid disorder Hypothyroid patients are more sensitive to digoxin, morphine & CNS depressants Hyperthyroid patients are relatively resistant to inotropic action but more prone to arrhythmic action of digoxin

Body size Influences the concentration of drug at the site of action An adult dose refers to an individual of medium built Hence for obese or lean individuals & for children the dose must be calculated based on body weight Individual dose= BW x Avg.adult dose/70

BSA provides accurate basis for dose calculations because total body water, ECF volume & metabolic activity are better paralleled by BSA Individual dose = BSA X Avg. Adult dose / 1.7

Interacting drugs Drugs may modify the response to each other by PK/PD interactions between them Hence knowledge of drugs & patients at particular risk &

Genetics Genetic differences determine the disposition of a given drug in an individual Drug disposition is determined by rate kinetics of ADME, hence genetic differences determining various physiological processes affect the plasma levels of drugs eventually determining the differences in drug response by an individual

Cyt P 450 major enz system involved with metabolism of all xenobiotics The metabolic capacity of this enz system is not equal in all members of a population Hence we observe a wide inter individual variations in the rates of metabolism of some drugs

Pantoprazole/omeprazole metabolises in liver via cyt CYP2C19 & CYP3A48 Antidepressants paroxetine & fluoxatine extensively metabolised via cyt CYP2D6 Glimipride via cyt CYP2C9 Cyt p typically show large inter individual differences in activity that lead to differences in drug response

Hence metabolism & excretion of drugs vary between individuals 3% of caucasians & 15% asians are poor metabolizers 12% of north indians are poor metabolizers (pantoprazole) Collectively several hundred genes & their alleles & protein products determine the overall drug disposition in an individual

In pharmacogenomics, attempts are made to determine & quantify these genetic variations & use them in predicting drug disposition by an individual Genotyping techniques for cyt p 450 enz can be used to predict one’s disposition to a given class of drugs without doing any evaluation of PK parameters Which can be used for deciding choice of drug & its dose

Based on genotyping methods individuals may be classified as poor , intermediate, extensive & ultra rapid metabolizers for a group of given drugs Poor metabolizers will develop higher SDC in comparison with extensive metabolizers, hence they are at increased risk of developing concentration dependent ADRs Ultra rapid metabolizers will not reach therapeutic SDC upon treatment with standard doses, hence fail to respond to treatment

If the parent compound is a prodrug, which requires bio activation by the enz to a active form, the effect of polymorphism can be quite complex in poor metabolizers and ultra rapid metabolizers Hence these individuals differences in drug disposition could be compensated by dosage adjustment according to metabolic capacity, determination of drug metabolism genotypes

Poor metabolizers and ultra rapid metabolizers can be identified & dosage could be tailored to the individual patient in order to reach therapeutic levels of drug in plasma, which may help to avoid ADRs or therapeutic failures

Atypical pseudocholinesterase – prolonged succinylcholine apneoa G6PD deficiency- hemolysis with primaquine, sulfonamides, dapsone, quinine, chloroquine etc Acetylator polymorphism-INH neuropathy, procainamide & hydralazine induced lupus in slow acetylators Acute intermittent porphyria- precipitated by barbiturates due to genetic defects in repression of porphyrin synthesis

CYP2D6 abnormality causes poor metoprolol metabolizer status Malignant hyperthermia due to halothane Inability to hydroxylate phenytoin- toxicity at usual doses