Clinical Pharmacokinetics

Introduction:
Pharmacokinetics: is the mechanisms of drug absorption, distribution, and elimination and the kinetics of these processes, Clinical pharmacokinetics: The application of pharmacokinetic principles to the therapeutic management of patients

Therapeutic Window:
It is the range between the minimum effective concentration and the minimum toxic concentration of the drug (region of therapeutic success) The optimal dosage regimen: defined as one that maintains the plasma concentration of a drug within the therapeutic window.

1) INDIVIDUALIZATION OF DRUG DOSAGE REGIMEN

There is an individual variation in pharmacokinetics pharmacodynamics Not all drugs need rigid individualization of the dosage regimen. Drugs with no need for individualization: Drugs that are relatively safe and have a broad safety dose range, such as the penicillins, cephalosporins, and tetracycline. Drugs that need individualization: 1- For drugs with a narrow therapeutic window, such as digoxin aminoglycosides, antiarrhythmics, anticonvulsants, and some antiasthmatics, such as theophylline. 2- For drugs with non-linear PK as phenytoin 3- For drugs that show large inter and intrasubject variation

Rates & orders of reactions:

The rate of a process is the velocity with which it occurs e.g. rate of elimination of drug (A) from the body is expressed as - dA / dt It is measured experimentally by measuring the drug level at given time intervals.

Zero order Reactions

The amount of drug is decreased at Constant rate i.e. independent on the initial conc. Zero order rate canst. dA / dt = - ko (mass / time) By integration A = Ao ko t Ao Amount Ao : amount of drug at t = o (Initial amount.) slope = - K

time

First order Reactions: -

The rate depends on the amount of drug remaining dA/dt = - KA K = 1 st order rate constant (unit = time -1) Ln A = -Kt + Ln Ao (A = Ao e kt ) In the log from log A = log Ao kt 2.303 log Ao Log A

Ao

Slope =

Amount A

-k 2.303

time

time not straight line.

* * Plot of A versus time

* * Plot of log A versus time

straight line.
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Half life (t 1/2 )

Is the time required for the amount (or cocentration) of the drug to decrease by one Half (e.g. from 10 5) First order t 1/2 T 1/2 = 0.693

K
1 st order t 1/2 is constant in spite of the conc.. Zero order t 1/2 It is not constant but proportional to the initial cancion. T 1/2 = Ao

2 Ko

VOLUME OF DISTRIBUTION (Vd)

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 It is a parameter relating the concentration of the drug in the plasma to the total amount of the drug in the body. It does not necessarily refer to any physiologic compartment in the body. It is simply the size of a compartment necessary to account for the total amount of drug in the body if it were present throughout the body in the same concentration found in the plasma. The plasma volume of adult 3 litres. If Vd > 3 the drug is present in tissues

Vd = Total amount of drug in the body (A) / Plasma conc. (Cp)

The apparent volume of distribution is a function of the lipid versus water solubility and of the plasma and tissue protein binding properties of the drug. Factors that tend to keep the drug in the plasma or increase C reduce the Vd. & factors which decrease C increase Vd .

Loading Dose:
Vd is important variable in estimating the loading dose necessary to rapidly achieve a desired plasma concentration.

LD = Vd x Cp / S x F

CLEARANCE (CL)
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 Clearance is the intrinsic ability of the body or its organs of elimination to remove drug from the blood or plasma. It is expressed as a volume per unit of time OR volume / time / Kg. It is not an indicator of how much drug is being removed. The amount of drug removed depends on the plasma concentration of drug and the clearance. It represents the theoretical volume of blood completely cleared of drug per unit time.

At steady state:

RA = R E

Clearance (Cl) can best be thought of as the proportionality constant that makes the average steady-state plasma drug level equal to the rate of drug administration (R A): RA = Cl x Css ave RA = (S x F x Dose) /

S x F x Dose / Cl = Css ave

Maintenance dose = (Cl x Css ave x )/ S x F

TBC = renal clearance + Hepatic clearance + lung Cl. + .. etc )

TWO-COMPRTMENT OPEN MODEL

The plasma level-time curve will be biexponential, as the sum of two first order processes: distribution and elimination. The drug distributes into two compartments: the central comp. And the peripheral comp. The curve is divided into two parts: 1- Distribution phase 2- Elimination phase Distribution phase After I.V. dose the drug decline rapidly due to both distribution and elimination. Elimination phase Cp = A.e-at + B.e-bt a & b are rate constants for distribution and elimination phases respectively. A & B are the intercepts on the y axis for each exponential segment of the curve. These values can be obtained by the method of residuals. The initial distribution rate is more rabid than the elimination rate (a>b). therefore at later time the term A.e-at will approach zero while B.e-bt will still have a value . the equation will be reduced to : Cp = B.e-bt Log Cp = log B bt/ 2.303. So the terminal part of the curve will be straight line ( first-order elimination) with a slope = -b/2.3 The t1/2 of the elimination phase ( half life ) t1/2 b = 0.693/ b A & B is determined by extrapolation. Values from the extrapolated line is subtracted from the original data points and a straight line is obtained representing the a phase

Effects of a Two-Compartment Model on the L D and (Cp):

Because some time is required for a drug to distribute into Vt, a rapidly administered loading dose calculated on the basis of V (Vi + Vt) would result is an initial C that is higher than predicted
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because the initial volume of distribution (Vi) is always smaller than V. The consequences of such an inaccurate prediction depend on whether the target organ behaves as though it were located in Vi or Vt. Drugs such as lidocaine, Phenobarbital, and Procainamide, exert therapeutic and toxic effects on target organs that behave as though they are located in Vi. In these instances, the concentration of drug delivered could be much higher than expected and produce toxicity if the loading dose is not administered appropriately. This problem can be circumvented by 1. First calculating the loading dose based on the total volume of distribution (V), then administering the loading dose at a rate slow enough to allow for drug distribution into Vt. 2. A second approach is to administer the loading dose in sufficiently small individual bolus doses such that the C in Vi does not exceed some predetermined critical concentration. Potassium is a good example of a drug that follows this principle of two compartment modelling with the end-organ being located in Vi. Potassium is primarily an intracellular electrolyte but its cardiac effects parallel the plasma concentration. In addition, there is a slow equilibrium between plasma and tissue potassium concentrations. When potassium is given IV the rate of administration should be carefully controlled as serious cardiac toxicity and death will occur if the patient experiences excessive plasma (Vi) concentrations.

When the drug's target organ is in the second or tissue compartment, Vt (e.g. digoxin), the rather high C, which may be observed before distribution occurs, is not dangerous.

Pharmacokinetics of oral absorption

After oral dose is given:

1- At time = o : all drug in the GIT, no drug in the body 2- Then the drug starts to be absorbed the amount in the GIT decreases and amount in the body increases

The rate of drug change in the body = rate of abs. rate of elimination dDB/ dt = dDGI /dt dDe / dt
In this period the drug is absorbed and also eliminated but the amount abs is > amount eliminated (absorption phase) dDGI / dt < dDe /dt 3- At the time of peak rate of abs = rate of elimination amount in body be come const dDGI / dt = dDe /dt 4- Then the rate of eliminate exceeds the rate of absorption amount of drug decreases in the body. dDGI /dt > dDe /dt. 5- When the drug at GIT is depleted the rate of absorption zero dDB/ dt = dDe / dt = - KDB ( elimination phase)

First-order Absorption model: First-order Absorption & First-order elimination.

This model applies to solution & immediate release DF dDGI / dt = -Ka DGI F ( F = fraction absorbed)

By integration

DGI = Do e-kat

dDB/ dt = dDGI /dt dDe / dt = FKaDGI KDB But DGI = Do e-kat By inegration: FDoKa Cp = VD( Ka K )

( e-kt e-kat)

tmax = Ln Ka Ln K / Ka - K So tmax is independent on the dose but only depends on Ka & K

Determination of Ka By method of residuals:

Assuming Ka << K , at later time the abs. is completed e =0 So the terminal portion of the line will represent drug elimination only so FDoKa Cp = VD( Ka K )
-kat

. e-kt

RENAL ELIMINATION
Many drugs have low metabolic clearance relative to their renal clearance, renal drug clearance cannot be greater than the renal blood flow

Renal clearance =filtration + secretion - reabsorption Glomerular filtration (GFR):

Blood flow through the glomerulus =1200 ml/minute About 10 % is filtered GFR = 120 ml / min. Unbound drug is filtered while drug bound to plasma proteins is not filtered. Thus, the renal clearance by glomerular filtration (CLGF)is:

CLGF=fu * GFR.
Creatinine and inuline are not bound to plasma proteins (fraction unbound is 1), are not secreted and, are not reabsorbed. This allows their renal clearances to be used as measures of GFR.

Active tubular secretion:

This component of renal clearance is designated as CLs. With some drugs the secretion mechanisms are so active that even bound drug can be stripped off plasma proteins in one pass of the blood through the kidney.
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 However, most secreted drugs have low intrinsic clearance by secretion and only unbound drug secreted. fu*CLs There are two major active transport systems; one for weakly acidic drugs (negatively charged) and one for weakly basic drugs (positively charged). ( acid pump & basic pump) Para-aminohippuric acid (PAH) is so actively secreted by the acid secretion system that almost all the PAH is removed from the renal blood in one pass through the kidneys. As PAH is not reabsorbed in the renal tubule, its clearance is a measure of renal blood flow Active secretion is characterized by: 1) Competitive: Penicillin and Probenecid are both substrate for the acid pump, so Probenecid is used to compete with Penicillin to reduce its renal clearance and intensify and prolong its action. Cimetidine and Procainamide are basic drugs, which compete with each other for the base secretion mechanism renal clearance and steady state drug concentration of both 2) Saturable: The active processes are saturable so that renal clearance can become nonlinear at high doses.

Passive tubular reabsorption:

Most of the 120mL/minuteof plasma water filtered at the glomerulus is reabsorbed. Only about 1-2mL/min. appears as urine. The drug filtered in the plasma water is reabsorbed from the tubular fluid back into the blood due to concentration gradient between drug in the tubular fluid and unbound drug in the blood (if the drug is able to pass through the membranes of the tubular cells). If the urine is diluted (urine flow is high, less of the 'filtered water is being reabsorbed), the concentration gradient is less, and less drug is reabsorbed.

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Factors affecting reabsorption: 1. Urine flow rate. 2. Ability of the drug to move through the membranes of the tubule cells. ( depends on K, Pka and PH) For drugs which are lipid soluble enough to be reabsorbed, and can ionize renal clearance varies with urine pH.

Renal clearance:

Where (1- FR) is the fraction that escapes reabsorption. If actual renal drug clearance is greater than (fu*GFR), the drug must be secreted -it may also be reabsorbed, but to a lesser extent than it is secreted. If actual renal clearance is less than (fu*GFR), it must be reabsorbed - it may also be secreted, but to a lesser extent than it is reabsorbed. To check for secretion or reabsorption, the following can be done. 1. If the drug is a weak acid or weak base, a known competitor, for example, Probenecid (acid) or Cimetidine (base), can be given. 2. The effect of changing the urine flow rate and/or pH can be investigated for reabsorption

Dose adjustment in renal dysfunction:

The renal clearance of drugs is reduced in proportion with the reduction in creatinine clearance (the intact tubule hypothesis). Therefore, creatinine provides a simple guide to the reduction of dose rate in renal dysfunction. As serum creatinine is determined by both its rate of production from Guidelines for the adjustment of dose in renal failure: 1. Adjustment is usually only necessary when a drug is more than 50% cleared by renal elimination (fe> 0.5) and renal function is reduced to half of normal or less. 2. Dose rate is reduced proportionally to the reduction in creatinine clearance (either by reduction in the size of each dose, or by lengthening the dosage interval, or both.

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CREATENINE CLEARANCE (Clcr)

Creatinine clearance is considered by many clinicians to be the most accurate test for renal function.

Creatinine Pharmacokinetics:
Creatinine is metabolic byproduct of muscle, and its rate of formation (RA) is primarily determined by an individual's muscle mass or lean body weight. It varies, therefore, with age (lower in the elderly) and gender (lower in female). RA = Clcr x Cssave
Where RA = rate of Creatinine production

The rate of Creatinine production remains constant even when renal clearance diminishes Any decrease in the GFR rise in the serum creatinine level.

There are a number of equations that consider age, gender, body size, and serum creatinine when calculating or estimating creatinine clearance for adults.

The two most critical factors to consider when using the above equations are the assumption that 1. The serum creatinine is the steady state and 2. The weight, age and gender of the individual reflect normal muscle mass.

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When estimating a creatinine clearance for an obese patient, the nonobese or ideal body weight should be used.

As a clinical guideline, make an adjustment for IBW if :

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HEPATIC CLEARANCE
Drugs with low hepatic extraction (20 %) tend to be more available to the systemic circulation and have a low systemic clearance. Drugs with hepatic extraction (> 80 %) tend to be less available to the systemic circulation and have a high systemic clearance. Drugs with extraction ratios between 20 and 80 are termed intermediate-extraction drugs. The factors that determine the extraction ratio and its relationship to overall hepatic clearance can be shown mathematically as:
E = extraction ratio CLint = Intrinsic clearance QH = hepatic blood flow

CLH = QH x E
clearance of drug by the liver will depend on the rate of delivery of drug to the liver (the hepatic blood flow) and on the efficiency of removal of the drug, which is presented to it (the extraction ratio) For example, consider the case of Propranolol where 80 % of the drug in the blood entering the liver is extracted in each pass (the extraction ration 0.8) and liver blood flow is 90 L/hour. Then 0.8 of 90 L of blood is cleared of Propranolol each hour, that is, the hepatic clearance is 72 L/hour.

Unbound fraction (fu): In some, but not all case, it is only free (unbound) drug, (which is available for diffusion from the blood into the liver cell) is metabolized in the liver

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Intrinsic Clearance (Clin) This is intrinsic ability of the liver to remove (metabolize) drug if hepatic blood flow were unlimited and all the drug were unbound. It may have values many times higher than hepatic blood flow. But actual hepatic clearance cannot be higher than hepatic blood flow. It is really a measure of how active the liver drug metabolizing enzymes

Vmax is maximal velocity of the reaction at saturating substrate concentration (the maximal rate at which the enzyme can convert the drug to a metabolite.) Km is the Michaelis constant and express how tightly the enzyme binds the drug The lower the Km, the tighter the binding (it is dissociation constant). From the previous equations, the full expression describing hepatic drug clearance is:

This is complicated, can be "simplified by considering two limiting cases; A. The very low enzyme activity: When the intrinsic clearance (enzyme activity) is much, much less than liver blood flow, the Equation cancels out as follows

This is because when QH >> fu*Clint the same as QH, then:

QH+ fu*CLint is approximately

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 Thus we can say that clearance of such a drug by the liver is directly proportional to the degree of protein binding in the blood and does not depend on liver blood flow. Such drugs are called capacity-limited, low hepatic clearance or low hepatic extraction ratio drugs. (e.g. Diazepam). B. The very high enzyme activity case: When the intrinsic clearance is much, much higher than liver blood flow, the equation cancels out as follows:

This is because when fu*Clint is >> QH, then QH+ fu*Clint is approximately the same as fu*Clint. Then:

Hepatic clearance = Liver blood flow

These drugs are called flow-limited, high hepatic clearance or high hepatic extraction ration drugs. (e.g. Glyceryl trinitrate and verapamil)

Systemic Clearance and pre-systemic or first-pass extraction:

Pre-systemic or first-pass extraction refers to removal of drugs during the first pass through the liver during drug absorption. First pass effect is defined as the extent to which a drug is removed by the liver during its first passage in the portal blood through the liver to the systemic circulation.

F = fraction that reach the systemic circulation Fg = Fraction of the dose, which is absorbed from the gut FH = Fraction that escapes the first pass effect

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 If the entire dose of a drug is absorbed intact from the gut lumen into the portal circulation., then Fg =1

Low hepatic extraction ration drugs (e.g. theophylline) Even doubling or halving the minor proportion extracted by the liver does not make any significant difference to bioavailability. High hepatic extraction ratio drugs:(e.g. verapamil) Inducing or inhibiting the metabolizing enzymes has only a small effect on hepatic extraction ratio, and thus on systemic clearance, but has a major effect on the proportion escaping extraction which is (1 hepatic extraction ratio), and thus has a major effect on bioavailability. Changes in hepatic blood flow affect the first pass clearance and bioavailability of high hepatic extraction ratio drugs. However, changes in hepatic blood flow also alter the systemic clearance of these drugs. The two effects are in opposite directions, about equal in magnitude and therefore cancel each other out.

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