Pharmacokinetics & BA - Part-2.pdf

Applications of Pharmacokinetics & Bioavailability in
Clinical Situations
When drug is administered to a large population may lead to Some variation, this
variation is due to wide inter-patient variability, although drug is administered in similar
dose level and dosage regimen.
Inter-patient and intra-patient variability in the concentration
of drug in plasma caused by many factors:
1. Variation in absorption
2. Presence of other
3. Drug interactions
4. Genetic differences
5. Disease States
6. Physiologic differences

WHY DO WE REQUIRE INDIVIDUALIZATION OF
DOSAGE REGIMEN?
"The right medicine for the right person at the right
dosage regimen"
Inter-patient
Intra-patient

1.Variation in absorption:
The rate and extend of absorption of drug is seen different due to variation
in physicochemical and physiological factors like:
 GI motility
 pH of GIT
 Gastric emptying
 GI secretions
 Presence or absence of food in GIT
 Blood vessels of GI System
 Presence of bacteria in GIT

2. Drug interactions:
 DI is the phenomenon which occurs when effects of one drug is
modified by the presence of another drug.
 One drug alters the expected therapeutic of another drug that
has been response administered just prior to simultaneously, or
just after another drug.
 Self-medication is another reason Variability as Surveys done
have shown those drugs prescribed by physicians are entirely
different from self-medications taken for the same ailment.

• Changes in metabolism and elimination, results in
difference in metabolism and elimination of some
drugs, therefore causes differences in:
 Duration of action
 Biological half-life of drug
3. Genetic differences:
in different individuals

 Concomitant administration of certain drugs of presence of drugs
in GIT, influences the rate and extent of absorption and
elimination.
4. Presence of drugs:
Example: Concomitant use of drugs causing acidosis and alkalosis of
urine influence the elimination of weakly acidic and weak basic
drugs.

It refers to:-
 Age
 Gender
 Weight
 Nutritional Status
Example: Drugs with Strong affinity for lipids will have tendency
to bind to the lipids to greater. Extend in obese patients than in
lean individual with very little fatty tissue. Such binding may
necessitate administration of large dose of drug to an obese
person in order to achieve desired therapeutic level of free or
unbound drug in plasma.
5. Physiological differences:

 Disease State in patient affect ADME of administered
drug.
 Several disease states which affect stomach empting
time, these disease affect rate and extent of absorption and
also distribution of drug in various body fluids and tissues.
 Condition & cause hepatic and renal failure. may also
affect elimination of drugs.
6. Disease States:

Clinical Situations
Estimation of initial
dosage of drug
Evaluation of the
patient
Adjustment of the
dosage regimen
Dosage
Regimen
Activity-Toxicity Pharmacokinetics
Other factors
Clinical factors
Therapeutic window
 Side effects
Toxicity
 Conc. Response
ADME
• Patients
(Age,weight,pathological conditions)
• Management of others
 Route of administration
 Dosage form
 Tolerence dependence
 Drug interaction

 Dosage regimen is defined as the manner in which a drug is taken.
For some drugs like analgesics, hypnotics, anti-emetics, etc., a
single dose may provide effective treatment.
However, the duration of most illnesses is longer than the
therapeutic effect produced by a single dose.
In such cases, drugs are required to be taken on a repetitive basis
over a period of time depending upon the nature of illness.
Thus, for successful therapy, design of an optimal multiple dosage
regimen is necessary.

Approaches to Design of Dosage Regimen
The various approaches employed in designing a dosage regimen are –
1. Empirical Dosage Regimen
2. Individualized Dosage Regimen
3. Dosage Regimen on Population Averages
(a) Fixed model (b) Adaptive model
4. Dosage Regimen based on partial pharmacokinetic parameter

1. Empirical Dosage Regimen – is designed by the physician based on
empirical clinical data, personal experience and clinical observations. This
approach is, however, not very accurate.
2. Individualized Dosage Regimen – is the most accurate approach and is
based on the pharmacokinetics of drug in the individual patient. The
approach is suitable for hospitalized patients but is quite expensive.
Dosage regimen id decided on the basis of
Pharmacokinetic
parameters of the
drug in the individual
patient
Patient’s age
LBW (Low Birth Weight)
Creatinine
Clearance

3. Dosage Regimen based on Population Averages – This is the most often used
approach. The method is based on one of the two models
(a) Fixed model – here, population average pharmacokinetic parameters are
used directly to calculate the dosage regimen.
(b) Adaptive model – is based on both population average
pharmacokinetic parameters of the drug as well as patient variables such as
weight, age, sex, body surface area and known patient patho-physiology
such as renal disease.

4. Dosage regimen based on population averages —
Irrespective of the route of administration and complexity of pharmacokinetic
equations, the two major parameters that can be adjusted in developing a
dosage regimen are —
1. The dose size — the quantity of drug administered each time, and
2. The dosing frequency — the time interval between doses.
Both parameters govern the amount of drug in the body at any given time.
1. It is assumed that all pharmacokinetic parameters of the drug remain
constant during the course of therapy once a dosage regimen is established.
The same becomes invalid if any change is observed.
2. The calculations are based on open one-compartment model which can also be
applied to two compartment model if β is used instead of KE, and
Vd,ss instead of Vd while calculating the regimen.

Determination of Dose & Dose Size
 The magnitude of both therapeutic and toxic responses depends upon
dose size.
 Dose size calculation also requires the knowledge of amount of drug
absorbed after administration of each dose.
 Greater the dose size, greater the fluctuations between Css,max and
Css,min during each dosing interval and greater the chances of toxicity
(Below fig.).
Fig., Schematic representation of influence of dose size on plasma concentration-time profile after
oral administration of a drug at fixed intervals of time.

 For a drug that is given in multiple doses for an extended period of
Time, the dosage regimen is usually calculated so that the average
Steady-state blood level is within the therapeutic range.
 The dose can be calculated with equation:
C
Dо F
Vd
The average drug concentration at steady-state Css,av is a function of –
 The maintenance dose Xo,
 The fraction of dose absorbed F,
 The dosing interval τ and
 Clearance ClT (or Vd and KE or t½) of the drug.
 Bioavailability F
 Initial dose Do
 Half-life t1/2
 Dosing freequency T

Pharmacokinetic data for clindamycin were reported by DeHaan, et al
(1972) as
K= 0.247 hr follows:
t1/2 = 2.81 hr
Vd =43.9L/1.73 m²
What is the Steady - State concentration of the drug, after 150 mg of the
drug given orally every 6 hours for a week? (Assume the drug is 100%
absorbed)
Practice problem:
C
Dо F
Vd
Cav = 144 × 150000 ×2.81 × 1
43900 × 6
Cav = 2.3 mcg/mL

 The dose interval (inverse of dosing frequency) is calculated on the basis of half-life of the
drug.
 If the interval is increased and the dose is unchanged, Cmax, Cmin and Cav decrease
but the ratio Cmax/Cmin increases.
 Opposite is observed when dosing interval is reduced or dosing frequency increased.
It also results in greater drug accumulation in the body and toxicity.
Fig. Schematic representationof the influenceof dosingfrequency on plasma concentration-
timeprofile obtained afteroral administrationof fixed dosesof a drug.

Clinical Situations
 After the patient's dosing is controlled by intravenous infusion, it is often
desirable to continue to medicate the patient with the same drug using the oral
route of administration.
 When IV infusion is stopped, the serum drug concentration decreases according to
first-order elimination kinetics.
 For most risk drug product, the time to reach steady state depends on the first order
elimination rate constant for the drug.
 Therefore if the patient starts the dosage regimen with the oral drug product at the
same time as IV infusion is stopped, then the exponential decline of serum levels from the
IV infusion stopped, the exponential decline of serum levels from the IV infusion should
be matched by the exponential increase in serum drug levels from the oral drug product.

The conversion from IV infusion to a controlled-release oral medication
given once or twice daily has become more common with the availability of
more controlled-release drug products, such as theophylline and guanidine.
 Computer simulation for the conversion of IV theophylline therapy to oral
controlled-release theophylline demonstrated that oral therapy should be
started at the same time as IV infusion is stopped.
 With this method, minimal fluctuation are observed between the peak and
through serum theophylline levels.
 Moreover giving the first oral dose when iv infusion is stopped mo make it
easier for the nursing staff or patient to comply with the dosage regimen..
 Either of these methods may be used to calculate an appropriate oral
dosage regimen for a patient whose condition has been stabilizes by an Iv
drug infusion. Both methods assume that the patient's plasma drug
concentration at steady state.

METHOD-1
Method 1 assumes that the steady state plasma drug
concentration (Css), after IV infusion is identical to the desired
(Cav) after multiple oral doses of the drug. therefor, the
following equation maybe used:
Cav=
=
Where S is the salt form of the drug and
Do/T is the dosing rate.
SFDo
Kv DT
CavKvD
SF
Do
T

EXAMPLE: 1
An adult male asthmatic patient(age 55.78kg) has been maintained on an iv infusion
of aminophylline at a rate of 34mg/hr, the steady-state theophylline drug
concentration was 12 µg/mL and total body clearance was calculated as 3.0L/hr.
Calculate an appropriate oral dosage regimen of theophylline for this patient.
Aminophylline is a soluble salt of theophylline and contains 85% theophylline (S-0.85).
Theophylline is 100% bioavailable (F=1) after an oral dose.
Because total body clearance, CLT=KvD
Theophylline dose rate= [SFDo/T] = 0.85 ×1×34 / 1 = 28.9 mg/hr
The theophylline dose rate of 28.9 mg/hr must be converted to a reasonable schedule for the
patient with a consideration of the various commercially available theophylline drug products.
Therefore, the total daily dose is 28.9 mg/hrx24 hr (or)
693.6 mg/day.
Possible theophylline dosage schedules might be 700 mg/day, 350 mg every 12 hours, or 175
mg every 6 hours.
Each of these dosage regimens would achieve the Same Cav but different Cmax and Cmin
which should be calculated.
The dose of 350 mg every 12 hours could be given in sustaine-release form to
avoid any excessive high drug concentration in the body.

Method 2: Assumes that the rate of IV infusion (mg/hr) is the same
desired rate of oral dosage.
METHOD-2
An adult male asthmatic patient(age 55.78kg) has been maintained on an iv infusion
of aminophylline at a rate of 34mg/hr, the steady-state theophylline drug
concentration was 12 µg/mL and total body clearance was calculated as 3.0L/hr.
Calculate an appropriate oral dosage regimen of theophylline for this patient.
EXAMPLE: 2
The aminophylline is given by iv infusion at a rate of 34 mg/ hr.
The total daily dose of aminophylline is 34 mg/hrx24 hr=816mg.
The equivalent daily dose in terms of theophylline is 816x0.85=693.6 mg.
Thus the patient should receive approximately 700 mg of theophylline per day
or 350 mg controlled-release theophylline every 12 hours.

Clinical Situations
Dosing in elderly patient:-
The geriatric population is often arbitrarily defined as patients who are older
than 65 years, and many of these people live active and healthy lives.
In addition, there is an increasing number of people who are living more
than 85 years, who are often considered as the older elderly population.
The aging process is more often associated with physiological changes
during aging rather than purely chronological age.
 Chronologically, the elderly have been classified as:
1. Young old (ages 65-75 years)
2. The old (ages 75-85 years)
3. The old-old (age above 85 years)

 Performance capacity and the loss of homeostatic reserve decreases with
advanced age but occurs to a different degree in each organ and in each
Patient.
 Physiologic and cognitive functions tend to change with the aging
process and can affect compliance and the therapeutic Safety and efficacy
of a prescribed drug.
 The elderly also tend to be on multiple drug therapy due to concomitant
illness.
 Decreased cognitive function
 Complicated drug dosage schedules
 High cost of drug therapy

 Several vital physiologic functions related to age as measured by markers. Show that renal plasma flow,
glomerular filtration, cardiac out- put and breathing capacity can drop from 10%. to 30% in elderly
Subjects compared to those at age 30.
 The physiologic changes due to aging may necessitate Special considerations in administering drugs in
the elderly which is due to an age dependent increase in adverse drug reactions. or toxicity may be
observed.
 This apparent increased drug sensitivity in the elderly may be due to pharmacodynamic and
Pharmacokinetic changes.
 The pharmacodynamic hypothesis assumes that age causes alterations in the quantity and quality of
target drug receptors leading to enhanced drug response.
 Quantitatively, the number of drug receptors may decline with age, whereas qualitatively, a change in
the affinity for the drug may Occur.
 The pharmacokinetic hypothesis assumes that age dependent increase in adverse drug reactions are
due to physiologic changes in drug ADME.
 Age dependent alterations in drug absorption may include-
Decline in the splanchnic blood flow
 Altered gastrointestinal motility
 Increase in gastric pH
 Alteration in the gastrointestinal absorptive surface

Age dependent alterations in drug distribution may include:
 Decreased drug protein binding in the plasma as a result of decrease in the
albumin concentration.
 Change in the apparent volume of distribution due to decrease in muscle
mass and increase in body fat.
 Renal drug excretion also generally declines with age as a result of decrease
in GFR and active tubular secretion.
 The activity of enzymes responsible for drug biotransformation may
decrease with age, leading to a decline in hepatic drug clearance.
Patient dose = × Adult dose
(weight,Kg) 0.7 × (140-age,year)
1660

Dosing in obese Patient:
 Obesity is a major problem in the united states and is also becoming a
problem in other countries.
 Obesity has been associated with increased mortality resulting from
increases in the incidence of HTN, Atherosclerosis, coronary Artery
Disease, Diabetes and other conditions compared to non obese patients.
 A patient is considered obese if actual body weight exceeds ideal or
desirable body weight by 20%. according to Metropolitan Life Insurance
company data Ideal or desirable body weights are based on average
body weights and heights for males and for females considering age.
 Athletes who have a greater body weight due to greater muscle mass
are not considered obese.

 Obesity often defined by Body Mass Index (BMI) a value that normalizes body
weight based on height.
 BMI is expressed as body weight (kg) divided by the Square of the person's height
(meters) or Kg/m.
2
BMI = × 703
(Height in inches) × (Height in inches)
Weight in Pounds
BMI =
Weight in Kg
(Height in meters) × (Height in meters)
 The obese patient (BMI >30) has a greater accumulation of fat tissue than is
necessary for normal body functions.
 Adipose (fat) tissue has a smaller proportion of compared to muscle tissue. Thus,
the obese patient has a smaller proportion of total body water to total body weight
compared to the patient of ideal body weight, which can affect the apparent volume
of distribution of the drug.

 In addition to differences in total body water per kilogram body weight in the obese
patient, the greatest proportion of body fat in these Patients could lead to
distributional changes in the drug's pharmacokinetics due to partitioning of the drug
b/w lipid and aqueous environments.
 Drugs such as digoxin and gentamicin are very polar and tend to distribute into water
rather than into fat tissue, although lipophilic drugs are associated with larger volumes
of distribution in obese patients compared to hydrophilic drugs.
 Other pharmacokinetic parameters may be altered in the obese patient as a result of
physiologic alterations such as fatty in filteration of the liver affecting
biotransformation and cardiovascular changes that may affect renal blood flow and
renal excretion.
 Dosing by actual body weight may result in overdosing of drugs such as
aminoglycosides (Eg., gentamicin), which are very polar and are distributed in
extracellular fluids. Dosing of these drugs are based on ideal body weight.

 Lean Body Weight has been estimated by Several emperical equations
based on the patient's height and actual (total) body weight.
 The following equations have been used for estimating lean body weight,
particularly for adjustment of dosage in renally impaired patients.
LBW (male) = 50kg+2.3kg for each inch over 5ft
LBW (female) = 45.5kg+2.3kg for each inch over 5ft
Example
Calculate the lean body weight for an adult male patient who is 5ft 9 in
(175.3 cm) tall and weight 264 lb (120 kg).
Solution
LBW = 50+(2.3x9) =70·7 kg

Dosing in Pediatric patient:
 Dosing of drugs in this population requires a through Consideration of the
differences in the pharmacokinetics and pharmacology of a specific drug.
 Unfortunately, the pharmacokinetics and pharmacodynamics of most drugs
are not well known in children under 12 years of age.
 The variation in body composition and the maturity of liver and kidney
function are potential sources of differences in pharmacokinetics with
respect to age.
 Infants are defined as children 0-2 years age. However, within this group,
special consideration is necessary for infants less than 4 weeks (month) old,
because their ability to handle drugs often differs from that of more mature
infants.

 In addition to different dosing requirements of the pediatric population,
there is a need to consider the use of pediatric dosage forms that permit
more accurate dosing and patient compliance.
 For example, liquid pediatric drug products may come with calibrated
dropper or a premeasured teaspoon (5ml) for accurate dosing and have a
cherry flavor for pediatric patient compliance.
 Pediatric drug formulations may also contain different drug concentrations
compared to the adult drug formulation.
 In general, complete Hepatic function is not attained until the 3rd week of
life and oxidative process are fairly well developed in infants, but there is a
deficiency of conjugative enzymes.
 In addition, many drugs exhibit reduced binding to plasma albumin in
infants.

 Newborns show only 30%-50% of the renal activity of adults on the basis
activity per unit. of body weight and drugs that are heavily dependent on renal
excretion will have a Sharply decreased elimination hall-life.
For example, the penicillin's are excreted for the most part through the kidney
and elimination half-life of such drugs are much reduced in infants.

Different methods to calculate the dose of drugs for infants and children are:
 Based on the Age
 Based on the Body weight
 Based on the Body Surface area.
Depending upon whether the dose was calculated for an infants or a child,
the method use the age in year for the child and age in month for the infant,
these methods are:
1. Fried's rule (for infants and children up to 2 years
Dose = (Age in month) /(adult dose) × 150
2. Young's rule ( for children up to 1 to 12 years)
Dose= (Age in year / age +12) × Adult Dose

3. Cowling's rule:
Dose = [Age in birthday/ 24 ] × (Adult dose)
4. Clark's rule:
Dose = (Weight in lb / 150 ) × (Adult dose)
Another adjustment method is based on the body weight of the infants and
children by the use of methods such as:
5. Augus-Berger method:
CD = (AD) (1.5) X (Cw+10) / 100
6. Crawford-terry-rourke method:
Based on Body surface area of the infants and Children
BSA = (AD) (Body Surface area of child) / 1.73 m²

 Methods such as Young's rule or Clark's rule for dose
adjustment are at best crude approximations. in that they take
into account only body age and Size change attributable to
growth and to not consider the rate of drug elimination.
 Other method which is based on the body Surface area has
the advantage of avoiding bias due to obesity or unusual body
weight, because the height and weight of the patient are both
considered.
 The body surface area method gives only a rough estimation
of the proper dose, because the pharmacokinetic differences of
specific drugs are not considered.

Practice problem:-
The elimination half-life of penicillin G is 0.5 hour in adults and 3-2
hours in neonates (0-7 days old). Assuming the normal adult dose of
penicillin G is 4 mg/kg every 4 hours, Calculate the dose of penicillin G
for an 11 pound infant.
Solution: T1
T2
= (t1/2)1
(t1/2)2
(t1/2) = 0.5 hour T2 = 4 X 3-2
0.5
= 25.6 hr
Therefore, this infant may be given the following dose:
Dose = 4mg/kg = 11 lb = 20mg every 24hrs 2.2 lb/kg
Alternatively, 10mg every 12hrs would achieve the same (Cav).

Pharmacokinetics & BA - Part-2.pdf

Pharmacokinetics & BA - Part-2.pdf

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Pharmacokinetics & BA - Part-2.pdf