Individualization of dosage regimen

Individuals respond differently to the given drugs, some drugs may have no effect on one individual while it may work effectively in others.

1. INDIVIDUALIZATION OF DRUG DOSAGE REGIMENS D r . S P Srinivas Nayak , PharmD , RPh , MSc., (PGDND) ( P h D) Assistant Professor, Dept. of Pharmacy Practice, PU. Dr S P NAYAK MED EASY

2. INTRODUCTION THERAPEUTIC DRUG MONITORING(TDM): TDM is a process of measuring drug concentration in plasma to optimise the therapy for the drugs having relationship between the plasma drug concentration and the desired clinical effect or between the plasma drug concentration and an adverse effect i.e drugs with a narrow therapeutic window (also known as critical-dose drugs and narrow therapeutic index (NTI ) drugs), such as digoxin , aminoglycosides , antiarrhythmics , anticoagulants , anticonvulsants , and some antiasthmatics , such as theophylline .

3. Critical-dose drugs are defined as those drugs where comparatively small differences in dose or concentration lead to dose- and concentration-dependent, serious therapeutic failures and/or serious adverse drug reactions

4. For those drugs in which plasma drug concentration and clinical effect are not directly related, other pharmacodynamic parameters may be monitored. For example, clotting time may be measured directly in patients on warfarin anticoagulant therapy. Glucose concentrations are often monitored in diabetic patients using insulin products. Asthmatic patients may use the bronchodilator, albuterol taken by inhalation via a metered-dose inhaler. For these patients, FEV1 (forced expiratory volume) may be used as a measure of drug efficacy. In cancer chemotherapy, dose adjustment for individual patients may depend more on the severity of side effects and the patient’s ability to tolerate the drug.

5. Example, therapeutic range for theophylline is 10–20 μ g/ mL. patients may exhibits various effects at various drug plasma levels: Mild symptoms of toxicity included nausea, vomiting , headache, and insomnia . A potentially serious effect was sinus tachycardia . severe toxicity shows life-threatening cardiac arrhythmias and seizures .

6. Many drugs like NSAIDs - ibuprofen, CCBs - nifedipine , have a wide therapeutic range and do not need therapeutic drug monitoring OTC drugs such as various cough and cold remedies, analgesics, and other products are also generally safe when used as directed.

7. INDIVIDUALIZATION OF DRUG DOSAGE REGIMENS Individuals respond differently to the given drugs, some drugs may have no effect on one individual while it may work effectively 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

8. VARIABILITY Because of interpatient variability in drug absorption, distribution, and elimination as well as changing pathophysiologic conditions in the patient, therapeutic drug monitoring (TDM) or clinical pharmacokinetic (laboratory) services (CPKS) have been established in many hospitals to evaluate the response of the patient to the recommended dosage regimen.

9. AGE (CHILDREN) New born have low GFR & tubular transport is not matured. Similarly , hepatic drug metabolizing system is inadequate in new born . 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.

10. 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 Clerk’s rule: wt in pounds/150 X AD Fried’s rule: age in months/150 X AD

11. AGE 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

12. DISEASE 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

13. Kidney disease: 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 Throid disease: 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

14. Body weight: 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

15. Drug interactions: Pharmacokinetic Absorbtion Distribution Metabolism Excretion pharmacodynamic

16. ABSORBTION DRUG INTERACTIONS INHIBITION OF DRUG ABSORPTION Various drugs and dietary supplements can decrease the absorption of drugs from the GIT. Antacids containing magnesium and aluminum hydroxide often interfere with absorption of many drugs. Coadministration of magnesium and aluminum hydroxide caused a decrease of plasma levels of PERFLOXACIN, TETRACYCLINS, DIGOXIN, THYROXIN etc. These drugs should be given at least 2 hours before the antacid to ensure sufficient therapeutic efficacy Sucralfate used for ulcer, is an aluminum glycopyranoside complex that is not absorbed but retards the oral absorption of ciprofloxacin .. Cholestyramine is an anion-exchange resin that binds bile acid and many drugs in the gastrointestinal tract. Cholestyramine can bind digitoxin in the GI tract and shorten the elimination half-life of digitoxin by approximately 30%–40%. Absorption of thyroxine may be reduced by 50% when it is administered closely with cholestyramine .

17. Nonhepatic enzymes can be involved in drug interactions. For example, drug interactions have been reported for patients taking linezolid ( Zyvox ) who are concurrently taking certain psychiatric medications. Linezolid is a reversible monoamine oxidase inhibitor (MAOI). Serotonergic psychiatric antidepressant drugs such as citalopram, paroxetine, fluoxetine, sertraline , and other drugs that affect the serotonergic pathway in the brain. MAOIs, such as phenelzine and isocarboxazid , are also contraindicated ., linezolid inhibits the action of monoamine oxidase A responsible for breaking down serotonin in the brain. It is believed that when linezolid is given to patients taking serotonergic psychiatric medications, high levels of serotonin can build up in the brain, causing toxicity. This is referred to as serotonin syndrome . Its signs and symptoms include mental changes (confusion, hyperactivity, memory problems), muscle twitching,

18. Grapefruit–Drug Interactions grapefruit juice, can significantly inhibit the metabolism by gut-wall cytochrome P-450 3A4 (CYP3A4) For example, grapefruit juice increases average felodipine levels about threefold, increases cyclosporine levels, and increases the levels of terfenadine , a common antihistamine. In the case of terfenadine , Spence (1997) reported the death of a 29-year-old man who had been taking terfenadine and drinking grapefruit juice 2–3 times per week. Death was attributed to terfenadine toxicity. Grapefruit juice can also affect P- gp -mediated efflux of some drugs.

19. ALTERED RENAL REABSORPTION DUE TO CHANGING URINARY pH The normal adult urinary pH ranges from 4.8 to 7.5 but can increase due to chronic antacid use. This change in urinary pH affects the ionization and reabsorption of weak electrolyte drugs . An increased ionization of salicylate due to an increase in urine pH reduces salicylate reabsorption in the renal tubule, resulting in increased renal excretion. Basic drugs tend to have longer half-lives when urinary pH is increased .

20. 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

21. CytP 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

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