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- Pharmaceutical Biotechnology Fundamentals and Applications - Lecture Notes, Study Materials and Important questions answers
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calculation, necessary to decide whether

successive doses of drug will have any effects

on the previous dose

compare successive dosage in repetitive dose

between IV Infusion and oral

Analyse bioavailability and bioequivalence in

a multiple oral dose regimen

• To maintain prolonged therapeutic activity, many drugs are given in

a multiple-dosage regimen.

maintained within the narrow limits of the therapeutic window (eg,

plasma drug concentrations above the MEC but below the minimum

toxic concentration or MTC) to achieve optimal clinical effectiveness.

3

To calculate a multiple-dose regimen for a

patient or patients, pharmacokinetic

parameters are first obtained from the

plasma level–time curve generated by single-

dose drug studies.

necessary to decide whether successive doses

of drug will have any effect on the previous

dose.

The principle of superposition allows one to project the

plasma drug concentration–time curve of a drug after

multiple consecutive doses based on the plasma drug

concentration–time curve obtained after a single dose.

The basic assumptions are that the drug is eliminated by

first-order kinetics and that the pharmacokinetics of the drug

after a single dose (first dose) are not altered after taking

multiple doses.

doses and accumulation of blood levels when equal doses are given at

equal time intervals

The dose given at similar time interval and same

dosage

In Table: dose given is 350µg/ml at every 4hrs

There are situations, however, in which the

superposition principle does not apply.

change after multiple dosing due to various

factors:

◦ changing pathophysiology in the patient,

◦ saturation of a drug carrier system,

◦ enzyme induction, and

◦ enzyme inhibition

◦ Drugs that follow nonlinear pharmacokinetics generally do

not have predictable plasma drug concentrations after

multiple doses using the superposition principle.

shorter than the time required to "completely"

eliminate the previous dose, drug accumulation

will occur in the body.

As repetitive equal doses are given at a constant frequency,

the plasma level–time curve plateaus and a steady state is

obtained.

At steady state, the plasma drug levels fluctuate between C ∞

max and C min. Once steady state is obtained, C

∞ ∞

max

and C ∞ min are constant and remain unchanged from dose to

dose.

The C ∞ max is important in determining drug safety. The C ∞

max should always remain below the minimum toxic

concentration. The C ∞ max is also a good indication of drug

accumulation.

If a drug produces the same C ∞ max at steady state, compared

with the (C n = 1)max after the first dose, then there is no drug

accumulation. If C ∞ max is much larger than (C n = 1)max, then

there is significant accumulation during the multiple-dose

regimen.

Accumulation is affected by the elimination half-life of the

drug and the dosing interval.

The index for measuring drug accumulation

R is

Equation 11.1

Substituting for C max after the first dose and at steady state

yields

Equation 11.2

Equation 11.2 shows that drug accumulation measured

with the R index depends on the elimination constant

and the dosing interval and is independent of the

dose.

required to reach steady state is dependent on the

elimination half-life of the drug and is independent of

the size of the dose, the length of the dosing interval,

and the number of doses.

rate but as an infusion (eg, 25 mg/hr), the average

plasma drug concentrations (C ∞ av) will be the same

but the fluctuations between C ∞ max and C ∞ min will

vary.

An equation for the estimation of the time to reach one-half of the

steady-state plasma levels or the accumulation half-life has been

described by :

Equation 11.3

comparison to k a and can be omitted in the denominator of Equation

8.3. Thus, Equation 11.3 reduces to

Equation 11.4

administered intravenously is the elimination t 1/2 of the drug. From this

relationship, the time to reach 50% steady-state drug concentrations is

dependent on the elimination t 1/2 and not on the dose or dosage

interval.

As shown in Equation 11.4, the accumulation t 1/2 is directly proportional

to the elimination t 1/2. gives the accumulation t 1/2 of drugs with various

elimination half-lives

The maximum amount of drug in the body following a single rapid IV

injection is equal to the dose of the drug. For a one-compartment open

model, the drug will be eliminated according to first-order kinetics.

Equation 11.5

If זis equal to the dosage interval (ie, the time between the first dose

and the next dose), then the amount of drug remaining in the body after

several hours can be determined with

Equation 11.6

The fraction (f) of the dose remaining in the body is related to the

elimination constant (k) and the dosage interval ( )זas follows:

Equation 11.7

With any given dose, f depends on k and ז. If is large, f will be smaller

because D B (the amount of drug remaining in the body) is smaller.

A patient receives 1000 mg every 6 hours by

repetitive IV injection of an antibiotic with an

elimination half-life of 3 hours. Assume the drug is

distributed according to a one-compartment model

and the volume of distribution is 20 L.

drug in the body.

b.The average amount of drug in the body at

steady state, D ∞ av

c. Determine the maximum and minimum plasma

concentration of the drug.

a.

b.

c. To determine the concentration of drug in the body after multiple doses,

divide the amount of drug in the body by the volume in which it is dissolved.

For a one-compartment model, the maximum, minimum, and steady-state

concentrations of drug in the plasma are found by the following equations:

The patient in the previous example received 1000

mg of an antibiotic every 6 hours by repetitive IV

injection. The drug has an apparent volume of

distribution of 20 L and elimination half-life of 3

hours. Calculate

(a) the plasma drug concentration C p at 3 hours

after the second dose,

(b) the steady-state plasma drug concentration C ∞

p at 3 hours after the last dose,

(c)C ∞ max,

(d) C ∞ min, and

(e)C SS.

a &b

Generally, if the missing dose is recent, it will affect the

present drug level more. If the missing dose is several half-

lives later (>5t1/2), the missing dose may be omitted because

it will be very small.

Concentration contributed by the missing dose is

miss

scheduled dose was missed

If steady state is reached (ie, either n = large or after many doses), the equation

simplifies to

A cephalosporin (k = 0.2 hr– 1, V D = 10 L)

was administered by IV multiple dosing; 100

mg was injected every 6 hours for 6 doses.

What was the plasma drug concentration 4

hours after the 6th dose (ie, 40 hours later) if

(a) the 5th dose was omitted,

(b) the 6th dose was omitted,

(c) the 4th dose was omitted?

When one of the drug doses is taken earlier or later than

scheduled, the resulting plasma drug concentration can still

be calculated based on the principle of superposition. The

dose can be treated as missing, with the late or early dose

added back to take into account the actual time of dosing

scheduled, and t actual = time elapsed since the dose (late or

early) is actually taken.

Assume the same drug as above (ie, k = 0.2

hr– 1, V D = 10 L) was given by multiple IV

bolus injections and that at a dose of 100 mg

every 6 hours for 6 doses. What is the plasma

drug concentration 4 hours after the 6th

dose, if the 5th dose were given an hour late?

The plasma concentration at any time during an oral or

extravascular multiple-dose regimen, assuming a one-compartment

model and constant doses and dose interval, can be determined as

follows:

absorbed, and t = time after administration of n doses.

The mean plasma level at steady state, C ∞ av, is determined by a similar

method to that employed for repeat IV injections

dosing interval at steady state may be substituted to obtain C ∞ av

and the extent of drug absorbed. Furthermore, if the dosage interval ()ז

is shortened, then the value for C ∞ av will increase. The C ∞ av will be

predictably higher for drugs distributed in a small V D (eg, plasma water)

or that have long elimination half-lives than for drugs distributed in a

large V D (eg, total body water) or that have very short elimination half-

lives.

Because body clearance (Cl T) is equal to kV D, substitution

into Equation :

Thus, if Cl T decreases, C ∞

av will

increase.

by

The maximum and minimum drug concentrations (C ∞

max and C ∞

min)

can be obtained with the following equations:

occurs following a single oral dose is

particularly with drugs that have a narrow therapeutic index. The larger

the number of divided doses, the smaller the fluctuations in the plasma

drug concentrations. For example, a 500-mg dose of drug given every 6

hours will produce the same C ∞ av value as a 250-mg dose of the same

drug given every 3 hours, while the C ∞ max and C ∞ min fluctuations for

the latter dose will be decreased by one-half . With drugs that have a

narrow therapeutic index, the dosage interval should not be longer than

the elimination half-life.

An adult male patient (46 years old, 81 kg) was given orally 250 mg

of tetracycline hydrochloride every 8 hours for 2 weeks. From the

literature, tetracycline hydrochloride is about 75% bioavailable and

has an apparent volume of distribution of 1.5 L/kg. The elimination

half-life is about 10 hours. The absorption rate constant is 0.9 hr– 1.

From this information, calculate

(a) C max after the first dose,

(b) C min after the first dose,

(c) plasma drug concentration C p at 4 hours after the 7th dose,

(d) maximum plasma drug concentration at steady-state C ∞ max,

(e) minimum plasma drug concentration at steady-state C ∞ min, and

(f) average plasma drug concentration at steady-state C ∞ av.

Bioavailability may be determined during a multiple-dose regimen

only after a steady-state plasma drug level has been reached. As

discussed, the time needed to reach the steady-state plasma level is

related to the elimination half-life, t 1/2, of the drug.

from a multiple-dose regimen are similar to those obtained with a

single-dose regimen. In the former case, the first plasma samples

are taken just before the second dose of the drug. Thereafter,

plasma samples are taken periodically after the dose is

administered, in order to describe the entire plasma level–time curve

adequately. Parameters including AUC, time for peak drug

concentration, and peak drug concentration are then used to

describe the bioavailability of the drug.

The extent of bioavailability, measured by assuming the

[AUC]∞ 0, is dependent on clearance:

changes that are normally not detected in a single-dose

study. For example, nonlinear pharmacokinetics may occur

after multiple drug doses, due to the higher plasma drug

concentrations saturating an enzyme system involved in

absorption or elimination of the drug. With some drugs, a

drug-induced malabsorption syndrome can also alter the

percentage of drug absorbed. In this case, drug bioavailability

may decrease after repeated doses if the fraction of the dose

absorbed (F) decreases or if the total body clearance (kV D)

increases.

A bioequivalence study may be performed using a multiple-dose

study design. Multiple doses of the same drug are given

consecutively to reach steady-state plasma drug levels. The

multiple-dose study is designed as a steady-state, randomized,

two-treatment, two-way, crossover study comparing equal doses of

the test and reference products in adult, healthy subjects. Each

subject receives either the test or reference product separated by a

"washout" period, which is the time needed for the drug to be

completely eliminated from the body.

trough concentrations (C min) are determined. The last morning dose

is given to the subject after an overnight fast, with continual fasting

for at least 2 hours following dose administration. Blood sampling is

then performed similar to the single-dose study

Pharmacokinetic analysis includes calculation for each subject of

the steady-state area under the curve (AUC0–t), t max, C min, C max, and

the percent fluctuation [100(C max – C min)/C min]. The data are

analyzed statistically using analysis of variance (ANOVA) on the log-

transformed AUC and C max. To establish bioequivalence, the AUC

and C max parameters for the test (generic) product should be within

80–125% of the reference product using a 90% confidence interval.

For some situations, such as hormone replacement therapy, a

bioequivalence study may be performed in patients already

maintained on the drug. In this case, a washout period would place

the patient at substantial risk by being without drug therapy.

Therefore, the patient continues on his or her own medication, and

blood sampling is performed during a dosage interval (, drug

product A). Once this is accomplished, the patient begins to take

equal oral doses of an alternate drug product. Again, time must be

allowed for the theoretical attainment of C ∞ av with the second drug

product. When steady state is reached, the plasma level–time curve

for a dosage interval with the second drug product is described (,

drug product B). Using the same plasma parameters as before, the

bioequivalence or lack of bioequivalence may be determined.

Multiple-dose bioequivalency study comparing the bioavailability of drug

product B to the bioavailability of drug product A. Blood levels for such

studies must be taken after C ∞ av is reached. The arrow represents the start

of therapy with drug product B.

The advantages:

(1) the patient acts as his or her own control;

(2) the patient maintains a minimum plasma drug

concentration; and

(3) the plasma samples after multiple doses contain

more drug that can be assayed more accurately.

The disadvantages:

(1) the study takes more time to perform, because

steady-state conditions must be reached; and

(2) sometimes more plasma samples must be

obtained from the patient to ascertain that steady

state has been reached and to describe the plasma

level–time curve accurately.

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