1. CLINICAL PHARMACOKINETICS Department of Pharmaceutics 1

2. 2 Contents:- Definition Therapeutic drug monitoring Dosing of drugs in (a) infants (b) elders (c)obese patients Dosage adjustment in (a) renal failure (b) hepatic failure (c) cardiac failure

3. Clinical Pharmacokinetics : pharmacokinetics means rate at which ADME takes place. Clinical pharmacokinetics means the application of pharmacokinetic principles to the safe and effective therapeutic management of individual patient. This involves initial selection of drug, dosage regimen, including dose, dosing interval, route of administration and dosage form as well as readjustment of the dosage regimen based on therapeutic drug monitoring. 3

4. Therapeutic drug monitoring:  Administration of potent drugs to patients, the physician must maintain the plasma drug level with in a narrow range of therapeutic concentrations.  Various pharmacokinetic methods are used to calculate the initial dose or dosage regimen.  The initial dosage regimen is calculated only after knowing of pharmacokinetics of the drug, pathophysiological conditions of the patient and patient drug history.  Due to the inter-patient variability in drug absorption, distribution and elimination as well as changing pathophysiological conditions in the patient, therapeutic drug monitoring services have been established in many hospitals to evaluate the response of the patient to the recommended dosage regimen. 4

5. Functions of therapeutic drug monitoring: 1) Selection of drug 2) Designing of dosage regimen 3) Evaluation of patients response 4) Determining the need for measuring serum drug concentrations 5) Assay of drug 6) Performing pharmacokinetic evaluation of drug levels 7) Readjustment of dosage regimen 8) Monitoring serum drug concentration 9) Recommending special requirements 5

6. 1) Selection of drug: The selection of the drug and drug therapy depends on the physician. The choice of drug therapy is usually made on the basis of physical diagnosis of the patient, presence of any pathophysiological problems in the patient, previous medical history of the patient, concurrent drug therapy, known allergies (or) drug sensitivities and pharmacodynamic actions of the drug. 6

7. 2) Dosage regimen design: After the selection of drug to the patient, there are no. of factors that must be considered in the designing of dosage regimen.  The pharmacokinetics of drug (ADME)  physiology of patient such as age, weight, gender and nutrition status.  Any pathological conditions such as renal dysfunctions, hepatic disease and congestive heart failure are considered.  Exposure of the patient to other medication (or) environmental factors (like smoking) that also might alter the pharmacokinetics of drug. 7

8. 3) Evaluation of patients response: After a drug product is chosen and the patient is receiving the initial dosage regimen, the practitioner should clinically evaluate the patient response.  If the patient is not responding as expected, then the drug and dosage regimen should be reviewed for adequacy, accuracy and patient compliance to the drug therapy.  In many situations the clinical judgment is done based on the measurement of serum drug concentration. 8

9. 4) Measurement of serum drug concentration :  Before the blood samples are taken from the patient, the practitioner should establish if there is need to measure the serum drug concentration  In some cases, the patients response may not be related to the serum drug concentration (for e.g. allergy and mild nausea are may not be dose related).  The serum drug concentrations relates to the therapeutic or toxic effects of the drug.  The knowledge of the serum drug concentrations may clarify why the patient is not responding to the drug therapy (or) why the patient is having an adverse effect.  For the measurement of serum drug concentration, a single serum drug concentration may not yield useful information other factors are considered. 9

10.  For e.g. the dosage of the drug including size of dose and dosage, internal route of drug administration and time of sampling.  In many cases, a singular blood sample is insufficient and several blood samples are needed to clarify the adequacy of the dosage regimen.  In addition, there may be limitations in terms of the no. of blood samples which may be taken, the total volume of blood needed for the assay, and the time to perform the drug analysis.  For the measurement of serum concentration, the practitioner should also consider the cost of the assays, the risks and discomfort of the patient. 10

11. 5) Assay of drug:  Variety of analytical techniques available for drug measurement including HPLC, GC, spectroscopy, fluorimetry, immunoassay and radio isotopic method.  The method used by the analytical laboratories may depend on many factors such as physicochemical characteristics of drug, the amount and nature of the biological specimen, the available instrumentation, cost for each assay and analytical skills of laboratory personnel.  The laboratory should have a standard operating procedure for each drug analysis technique and follow good laboratory practices. 11

12. 6) Pharmacokinetic evaluation: After the serum drug concentrations are measured the pharmacokineticist must properly evaluate the data.  Most laboratories report the total drug concentrations (free and bound drug) in the serum.  The pharmacokineticist should be aware of the usual therapeutic range of serum concentration from the literature.  The assay results from the laboratory might shows that the patients serum drug levels are higher, lower (or) equivalent to the expected serum levels.  The pharmacokineticist should carefully evaluate these results while considering the patient and patients pathophysiological conditions. 12

13. 7) Readjustment of dosage regimen: From the serum drug concentration data and patient observations, the Pharmacokineticist might recommended an adjustment in the dosage regimen. The new dosage regimen should be calculated using the pharmacokinetic parameters derived from patients serum drug concentration. 13

14. 8) Monitoring serum drug concentration: In many cases, the patients pathophysiology might be unstable, either increasing or further deteriorating. For e.g. proper therapy for congestive heart failure will improve cardiac output and renal perfusion, there by increasing renal drug clearance. Therefore continuous monitoring of serum drug concentrations are necessary to ensure proper drug therapy for the patient. 14

15. 9) Special recommendations: At times the patient might not be responding to drug therapy due to other factors, for e.g. the patient is not following the instructions for taking the drug after a meal instead of before, the patient is not adhering to a special diet (e.g. low salt, therefore the patient might need special Instructions which are simple and easy to follow. 15

16. Dosing of drugs in infants: Dosing of drugs in infants is fully different with that of the adult Patients with regards to their pharmacokinetics and pharmacology of the drug.  The variation in body composition and maturity of liver and kidney functions are potential sources of pharmacokinetics with respect to age.  Infants are defined as children (0-2) years of age.infants less than 4 weeks old special consideration is necessary because their ability to handle drugs differ from more mature infants.  Until the third week of life, hepatic function is not attained. Oxidative process are fairly well developed in infants, but there is a deficiency of conjugate enzymes. 16

17.  In infants many drugs exhibit reduced binding to plasma albumin. New borns show only 30-50% of the renal activity of adults on an activity per unit of body weight bases drugs that are heavily dependent on renal excretion will have a sharply increased elimination half life.  The dosage of drugs given to infants based on pharmacokinetic consideration. Number of rules are available for calculation of the dosages of drugs for infants. Clarke’s rule based on weight of the patient child dose = weight (lb) * adult dose 150 Young’s rule based on age of the patient child dose = age 1/r * adult dose age (1/r) +12 17

18. Dosage of drugs in elderly: Special consideration is required in administration of drugs to the elder patient because various physiological changes occurs due to ageing.  The body composition of elderly patient is modified in many ways. Fatty tissues are increased and metabolic processes are slowed down.  Fat soluble drugs may have an altered volume of distribution due to increased amount of fatty tissues.  Free drug concentration in the body may be increased because of reduced drug plasma-protein binding. The cardiac output of the elderly patient is slightly modified. 18

19.  The perfusion of the blood to the intestinal region is greatly reduced, affecting the absorption of drugs from gastro-intestinal tract.  The glomerular filtration rate in elderly patients is significantly reduced, creating longer elimination half- lives for renally excreted drugs and potential drug accumulation in the body.  The correction of the dose in the elderly for drugs excreted by glomerular filtration is calculated from creatinine clearance in the elderly is quantified to calculate a reduced dose. If other pharmacokinetic parameters are available for elderly patients, the dose can be modified accordingly. 19

20. Dosing of drugs in obese patients:  The obese patients has a greater accumulation of fat tissue than necessary for normal body functions. The patient is considered obese if The actual body weight exceeds the desirable body weight by 10%.  Adipose (fat) tissue has a smaller proportion of water compared to muscle tissue. Thus the obese patient has a smaller proportion of total body water to total body weight compared to the patient with ideal body weight, which could affect the apparent volume of distribution of drug. 20

21.  The differences in total body water per kilogram body weight in the obese patient, the greatest portion of the body fat in the patient could lead to the distributional changes in the drugs pharmacokinetics due to partitioning of the drug between lipid and aqueous environment.  Drugs such as digoxin and gentamycin are very polar and tend to distribute into water rather than into fat tissue.  Other pharmacokinetic parameters may be altered in the obese patient due to possible physiologic alterations such as fatty infiltration of the liver affecting biotransformation and cardiovascular changes which might affect renal blood flow and renal excretion. 21

22. Dosage adjustment in renal failure: There are several methods for estimating the appropriate dosage regimen for a patient with renal impairment. Most of these methods assumes that the required therapeutic plasma drug concentration in impaired renal patients is similar to that required in patients with normal renal function. The design of dosage regimens for the patients with renal impaired function is based on the pharmacokinetic changes. Generally drugs in patients with kidney impairment have prolonged elimination half-lives and a change in the apparent volume of distribution. Consequently, the methods for dose adjustment are based on accurate estimation of the drug clearance in these patients. 22

23. Measurement of glomerular filtration rate (GFR): several drugs are endogenous substances have been used as markers to measure GFR. These markers are carried to the kidney by the blood via the renal artery and are filtered at the glomerulus. several criteria are necessary for using a drug to measure GFR: i) The drug must be freely filtered at the glomerulus. ii) The drug must not be reabsorbed nor actively secreted by the renal tubules. iii) The drug should not be metabolized. iv) The drug should not bind significantly to plasma proteins. v) The drug should not have an effect on the filtration rate nor alter renal function. vi) The drug should be nontoxic. vii) The drug may be infused in a sufficient dose which permits simple and accurate quantitation in plasma and urine. 23

24.  Therefore the rate at which these markers are filtered from the blood into the urine per unit of time reflects the filtration rate of the kidney. Changes in GFR reflect changes in kidney function.  Inulin, a fructose polysaccharide, fulfills most of the criteria listed above and is therefore used as a standard reference for the measurement of GFR. In practice, however the use of inulin involves a time consuming procedure in which inulin given by intravenous infusion until a constant steady –state plasma level is obtained.  Clearance of inulin may be then be measured by the rate of intravenous infusion divided by the steady – state plasma inulin concentration. While this procedure gives an accurate value for GFR, inulin clearance is not used frequently in clinical practice. 24

25.  The clearance of creatinine is used most extensively as a measurement of GFR. Creatinine is an endogenous substance formed during muscle metabolism from creatine phosphate.  Creatine production varies with age, weight and sex of the individual. In humans creatinine is mainly filtered at the glomerulus with no reabsorption.  However, a small amount may be actively secreted by the renal tubules and the values for GFR obtained by the creatinine clearance tend to be higher than GFR measured by inulin clearance. 25

26. Creatinine clearance:  Under normal circumstances creatinine production is roughly equal to creatinine excretion, so that the serum creatinine level remains constant.  In a patient with reduced glomerular filtration, serum creatinine will accumulate in accordance with the degree of loss of glomerular filtration in the kidney.  The serum creatinine concentration is frequently used to determine creatinine clearance, which is a rapid and convenient way of monitoring kidney function.  Pharmacokinetically, creatinine clearance may be defined as the rate of urinary excretion of creatinine/serum creatinine. 26

27.  Creatinine clearance can be calculated directly by determining the patient’s serum creatinine concentration and the rate of urinary excretion of creatinine.  The approach is similar to that used in the determination of drug clearance. In practice, the rate of urinary excretion of creatinine is measured by the entire day to obtain a reliable excretion rate.  The serum creatinine concentration is determined at the midpoint of the urinary collection period. creatinine clearance is clinically expressed in ml/min and serum creatinine concentration in mg%. The following equation used to calculate creatinine clearance in ml/ min when the serum creatinine concentration is known: Cl cr = rate of urinary excretion of creatinine serum concentration of creatinine Where Cl cr = Creatinine clearance 27

28. Cl cr = C u V 100 C cr 1440 where, C Cr = creatinine concentration (mg%) of the serum taken at the 12 th hour or at the midpoint of the urine collection period. V = Volume of urine excreted (ml) in 24hr C u = concentration of creatinine in urine (mg/ml) Cl cr = creatinine clearance in ml/min creatinine clearance has been normalized both to body surface area using 1.73 m 2 as the average and to body weight for a 70kg adult Male. Creatinine distributes into total body water and when clearance is normalized to a standard Vd, similar half-lives in adults and children correspond with identical clearance. 28

29. The normal creatinine clearance values range from 120-130 ml/min. Creatinine clearance values of 20-50ml signify moderate renal failure whereas values < 10 ml/min indicates severe renal failure Dosage adjustment in hepatic impairment:  Hepatic metabolism is an important route of drug elimination. Dysfunction of the liver would lead to changes in the pharmacokinetic of the drug.  The clinical significance of the changes in drug metabolism and elimination depends on the type and severity of the disease and on the pharmacokinetics of the drug.  No, differences were reported for drugs such as chlorpromazine, warfarin, dicumarol, phenytoin or salicylate. 29

30.  The elimination of many potent drugs is impaired in patients with chronic liver disease. The lack of predictability relates to the multiple effects that liver disease produces, effects on drug metabolizing enzymes, on drug binding and on hepatic blood flow.  Antipyrine has been used as a model drug to investigate the effects of liver disease on drug metabolism in man because it is negligibly bound to plasma protein and tissues, and because it is eliminated almost exclusively by hepatic metabolism with a low hepatic extraction ratio.  The t 1/2 and clearance are considered sensitive indicators of liver function with respect to oxidative metabolism process compared to healthy subjects who had an average t 1/2 of 12 hours, patients with cirrhosis and chronic active hepatitis had average antipyrine t ½ of 34 hours and 26 hours respectively. 30

31.  The average antipyrine clearance in control subjects was about 51ml/min. patient with cirrhosis but no signs of encephalopathy showed on average antipyrine clearance of 17ml/min. Dosage adjustment in cardiovascular disease:  The influence of heart disease on drug pharmacokinetics have been much profound.  Cardiovascular disease can alter the variables like intrinsic clearance of the elimination organ, blood flow to that organ and even plasma protein binding.  Decreased hepatic perfusion is usually found in patients with congestive heart failure because of reduced cardiac output. These changes reduce the clearance of Propranolol, Pentazocine, Lidocaine and related drugs highly extracted by the liver. 31

32.  Changes in cardiac function may alter the concentrations of drug binding proteins like AAG, alter blood or fluid PH or result in the production of endogenous binding inhibits.  Congestive heart failure (CHF) also affect drug metabolism. Aminopyrine clearance was 30 min/min in patients with CHF and 125 ml/min in control patients.  Recovery of labeled CO2, a byproduct of aminopyrine metabolism in the breath was markedly decreased in CHF patients.  Oral Quinidine has been used for many years in the treatment of cardiac arrhythmias. The pharmacokinetics of Quinidine were determined after intravenous administration to cardiac patients with and without CHF. 32

33. The half-life of Quinidine was about same in each group (6-7 hrs), but renal clearance was about 50% smaller and total clearance about 35% smaller in CHF patients than in control cardiac patients, suggesting the need for a smaller maintenance dose of Quinidine in patients with CHF.  Volume of distribution may be as much as 50% smaller in patients with CHF and IV loading doses should be decreased proportionately.  Decreased blood flow to the liver and kidney, decreased hepatic drug metabolizing enzyme activity may seriously compromise the elimination of an antiarrhythmic drug. 33

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