Designing of Dosage Regimen and Multiple Dosage Regimens

1. Dosage Regimen
Dosage regimen is defined as the manner in which a drug is taken. It is the schedule of doses of a medicine including, the dosage form, the time between doses, the duration of treatment and the amount to be taken each time.
2. Designing of Dosage Regimen
For some drugs like analgesics, hypnotics or anti emetics, a single dose may provide effective treatment. However, the duration of most of the 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. So for a successful drug therapy, designing of an optimal multiple dosage regimen is required.
3. Objective
The primary objective in dosage regimen design is to obtain a safe plasma drug concentration which neither exceeds the maximum safe concentration nor falls below the minimum effective concentration.
4. Criteria For Optimum Dosage Regimen
The plasma levels of drug given must be maintained within the therapeutic window. For example, the therapeutic range of theophylline is 10-20μg/L. So, the best is to maintain the CP around 15μg/L. Therapeutic window is a range of doses that produces therapeutic response without causing any significant adverse effect in patients. Generally therapeutic window is a ratio between minimum effective concentrations (MEC) to the minimum toxic concentration (MTC).
5. Factors to be Considered In Dosage Regimen Design
Numerous factors must be considered in designing a dosage regimen.
1. Pharmacokinetic Factors
These include absorption, distribution, metabolism and excretion characteristics of a drug.
2. Physiological Factors
Age, Weight, Gender and Nutritional status of a patient under treatment must be considered.
3. Pathophysiologic Factors
Existence of diseases like Renal failure, Hepatic diseases, Congestive heart failure, Myocardial infraction etc., must be considered in the patient being treated. This is because co-existence of these diseases will prolong the elimination of drugs. Therefore, the dose in such patients must be carefully adjusted.
4. Personal Lifestyle Habits
Lifestyle habits like cigarette smoking, alcohol abuse, voracious eating etc, must also be taken into consideration.
5. Exposure of patient to Long Term Medication
Chronic intake of medicines can alert the drug pharmacokinetics.
6. Other Factors
These include-
▪ Desired concentration of drug at site of action
▪ Alteration in the sensitivity of the receptors to the drug
▪ Drug dosage form
▪ Drug interactions
▪ Tolerance-dependence
▪ Pharmacogenitics – idiosyncracy
Multiple-Dosage Regimens
Why Multiple-Dosage Regimens is necessary?
 After single-dose drug administration, the plasma drug level rises above and then falls below the minimum effective concentration (MEC), resulting in a decline in therapeutic effect.

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1. Dosage Regimen
Dosage regimen is defined as the manner in which a drug is taken. It is the schedule of doses of a
medicine including, the dosage form, the time between doses, the duration of treatment and the amount
to be taken each time.
2. Designing of Dosage Regimen
For some drugs like analgesics, hypnotics or anti emetics, a single dose may provide effective
treatment. However, the duration of most of the 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. So for a successful drug therapy, designing of an optimal
multiple dosage regimen is required.
3. Objective
The primary objective in dosage regimen design is to obtain a safe plasma drug concentration which
neither exceeds the maximum safe concentration nor falls below the minimum effective concentration.
4. Criteria For Optimum Dosage Regimen
The plasma levels of drug given must be maintained within the therapeutic window. For example, the
therapeutic range of theophylline is 10-20μg/L. So, the best is to maintain the CP around 15μg/L.
Therapeutic window is a range of doses that produces therapeutic response without causing any
significant adverse effect in patients. Generally therapeutic window is a ratio between minimum
effective concentrations (MEC) to the minimum toxic concentration (MTC).

Figure: Plasma concentration-Time curve, Therapeutic window
5. Factors to be Considered In Dosage Regimen Design
Numerous factors must be considered in designing a dosage regimen.
1. Pharmacokinetic Factors
These include absorption, distribution, metabolism and excretion characteristics of a drug.
2. Physiological Factors
Age, Weight, Gender and Nutritional status of a patient under treatment must be considered.
3. Pathophysiologic Factors
Chapter 03
Multiple-Dosage Regimens

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Existence of diseases like Renal failure, Hepatic diseases, Congestive heart failure, Myocardial
infraction etc., must be considered in the patient being treated. This is because co-existence of these
diseases will prolong the elimination of drugs. Therefore, the dose in such patients must be carefully
adjusted.
4. Personal Lifestyle Habits
Lifestyle habits like cigarette smoking, alcohol abuse, voracious eating etc, must also be taken into
consideration.
5. Exposure of patient to Long Term Medication
Chronic intake of medicines can alert the drug pharmacokinetics.
6. Other Factors
These include-
▪ Desired concentration of drug at site of action
▪ Alteration in the sensitivity of the receptors to the drug
▪ Drug dosage form
▪ Drug interactions
▪ Tolerance-dependence
▪ Pharmacogenitics – idiosyncracy

Multiple-Dosage Regimens
Why Multiple-Dosage Regimens is necessary?
 After single-dose drug administration, the plasma drug level rises above and then falls below the
minimum effective concentration (MEC), resulting in a decline in therapeutic effect. To maintain
prolonged therapeutic activity, many drugs are given in a multiple-dosage regimen.
 The plasma levels of drugs given in multiple doses must be maintained within the narrow limits
of the therapeutic window (e.g., plasma drug concentrations above the MEC but below the
minimum toxic concentration or MTC) to achieve optimal clinical effectiveness.
 Among these drugs are antibacterials, cardiotonics, anticonvulsants, and hormones. Ideally, a
dosage regimen is established for each drug to provide the correct plasma level without excessive
fluctuation and drug accumulation outside the therapeutic window.
 For certain drugs, such as antibiotics, a desirable MEC can be determined. Some drugs that have a
narrow therapeutic range (e.g., digoxin and phenytoin) require definition of the therapeutic
minimum and maximum nontoxic plasma concentrations (MEC and MTC, respectively).
 In calculating a multiple-dose regimen, the desired or target plasma drug concentration must be
related to a therapeutic response, and the multiple-dose regimen must be designed to produce
plasma concentrations within the therapeutic window.
 There are two main parameters that can be adjusted in developing a dosage regimen:
(1) the size of the drug dose and
(2) the frequency of drug administration (i.e., the time interval between doses).

Important Definitions In Multiple Dosing
• Dosage regimen. The systematized dosage schedule for a drug therapy, or the optimized dose (D0)
and dosing interval (τ, tau) for a specific drug.
• Drug accumulation (R). The build-up of drug in the blood/body through sequential dosing.

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➢ Drug superposition: early doses of drug do not affect the pharmacokinetics of subsequent doses.
Blood levels after the second, third, or nth dose will overlay or superimpose the blood level attained
after the previous dose.
Steady-state condition. Steady state is achieved at a time when, under a given dosage regimen, the
mass (amount) of drug administered (for intravenous) or absorbed (for extravascular route), is equal
to the mass (amount) of drug eliminated over a dosing interval.
• Loading dose (DL). A single dose administered in order to reach steady state condition instantly.
• Maintenance dose (Dm). The dose administered every dosing interval to maintain the steady-state
condition.

Superposition Principle
Superposition principle applies to the linear pharmacokinetic parameters, which means when the
ADME is linear. Hence the drug concentration after each dose can be added to calculate the
concentration of drug after multiple doses.

Basic Assumptions for Superposition
Principle
These are the two major basic assumptions for superposition principle
• Drug elimination must follow the linear kinetics
• PK of the drug does not change after multiple doses.

Drug Accumulation (R)
 If the drug is administered at a fixed dose and a fixed dosage interval, as is the case with multiple-
dose regimens, the amount of drug in the body will increase and then plateau to a mean plasma level
higher than the peak Cp obtained from the initial dose.
 When the second dose is given after a time interval shorter than the time required to "completely"
eliminate the previous dose, drug accumulation will occur in the body. In other words, the plasma
concentrations following the second dose will be higher than corresponding plasma concentrations
immediately following the first dose.
 However, if the second dose is given after a time interval longer than the time required to eliminate
the previous dose, drug will not accumulate.

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 Accumulation is affected by the
1-elimination half-life of the drug and
2-the dosing interval.

The index for measuring drug accumulation R is

The value of R simply indicates how high the plasma concentration will be at steady state compared
with the first dose of the drug at a comparable time within the dosage regimen.
Equation shows that drug accumulation measured with the R index depends on the elimination constant
and the dosing interval and is independent of the dose. For a drug given in repetitive oral doses, the
time 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.

Fluctuation
Fluctuation is defined as the ratio Cmax/ Cmin. Greater the ratio, greater is the fluctuation.
Like accumulation, it depends upon;
▪ Dosing frequency
▪ Half-life of the drug
▪ Rate of absorption.
The greatest fluctuation is observed when the drug is given as i.v. bolus. Fluctuations are small when
the drug is given extravascularly because of continuous absorption.

Calculation of loading and maintenance doses
The steady state plasma concentration is usually attained after 6.6 t1/2 (if the drug is administered at
time interval τ = t1/2). This is a long time before the desired ‘‘average’’ steady-state drug concentration
is attained. Therefore, an intravenous bolus loading dose (DL) may be administered to obtain an instant
steady-state condition.
Maintenance dose (DM): is the dose required to maintain plasma concentration level at steady state.

If the calculated dose ration equals to 2, the loading dose will be equal to double the initial drug dose.

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Determination of Bioavailability and Bioequivalence from MDR
Absolute Bioavailability
Absolute bioavailability is the ratio of drug concentration obtained after oral administration of drug to
drug concentration obtained after intravenous administration. Intravenous formulations exhibit 100%
bioavailability.

Relative Bioavailability
Relative bioavailability is the ratio of drug concentration obtained after oral administration of test drug
to that of standard of same drug both administered orally.

Objectives of Bioavailability Studies
Bioavailability play key role in
1. Dose development of new drug and determination of its therapeutic utility
2. New formulation development of an already known drug
3. Determination of alteration in absorption due to drug interactions, excipient used, or patient related
factors.
4. Control of the quality of drug and determining factors influencing absorption such as stability,
storage conditions and processing related factors.
5. Evaluation of a dosage form with other dosage form or with same dosage form from different
manufacturer.

Need For Bioavailability Study
1. Bioavailability and bioequivalence studies are imposed by FDA for all drugs before getting approval
for marketing.
2. Important pharmacokinetic parameters need to be estimated for a new drug by single and multiple
dose administration as this is important for establishing dosage regimen and for supporting drug
labeling.
3. Bioavailability study for a new formulation of a drug which is NDA approved should be done and
the pharmacokinetic parameter of new formulation, dosage form, should be determined.
4. Safety and efficacy of a drug is also determined by bioavailability study.

Single Vs. Multiple- Dose Study Design
Single- Dose Studies: In this method only one dose of the drug is given to the patient and after that
determination of bioavailability is done. This method is used for dosage forms that are to be evaluated
only for bioequivalence purpose. It requires overnight fasting for at least 10 hour and subsequent
fasting for 4 hours. Dosage forms meant for a single dose administration for a therapeutic benefit such
as analgesic for relief of headache.

Multiple Dose Studies: In this more than one dose is administered to the patient and then the
bioavailability is determined. This method is used for dosage forms that are designed to achieve special

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release profiles. It requires fasting for 2 hour before and after dose administration. E.g. time-release
and enteric-coated preparations.

Measurement of Bioavailability
There are various methods which are used for estimation of bioavailability and are classified into two
categories: direct methods and indirect methods.
I. Pharmacokinetic methods:
This method is used widely for estimation of bioavailability and is known as the indirect method as
this method assumes that the therapeutic effectiveness is reflected from pharmacokinetic profile of a
drug. The two pharmacokinetic methods are:
1. Plasma level-time studies
2. Urinary excretion studies.

II. Pharmacodynamic methods:
It is complementary to pharmacokinetic approach and is a direct measurement of effectiveness of drug
as a function of time. Determination of bioavailability by pharmacodynamic method involves two
methods:
1. Acute pharmacological response
2. Therapeutic response
Plasma level- Time studies
It is considered to be the most reliable method unless it is difficult to determine plasma drug
concentration. This method is preferred over urine data method. This method assumes that two
dosage forms that having plasma level-time profiles that super-imposable or overlaps shows similar
therapeutic activity. Upon administration of drug (via any route), blood samples are collected till two
to three biological half-lives of drug and then the samples are analyzed for drug content and a plasma
concentration versus time graph is plotted. In i.v. dose 1st sample is taken within 5 minutes and then
at 15-minute intervals, at least three samples in case of one compartment kinetic and; five to six sample
for drugs that follows two-compartment model kinetic. In case of oral administration, at least 3 samples
for ascending part of curve and for descending part in a manner similar to i.v. dose.

Figure: Plasma level- Time studies
Data determined from plasma level time studies for determining bioavailability are:
1. Cmax- It is the maximum possible concentration of the drug in plasma that is available for its
therapeutic activity. It depends on rate and extends of absorption of drug. Cmax is directly proportional
to dose and absorption rate.

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2. Tmax- It is the maximum time taken by the drug to reach peak plasma concentration and is an
indication of the rate of absorption. It is inversely proportion to rate of absorption.
3. AUC- The area under the curve that gives an idea about amount of drug that is absorbed and extent
of absorption. AUC is directly proportional to the dose but this is not true in every case. When AUC
is not proportional to the dose of drug, then determination of bioavailability is difficult.
Bioequivalence Study
Earlier the pharmaceutical drug products which were considered equivalent did not showed
comparative results, hence bioequivalence came into existence. One of the incidents which occurred
in 1968 in case of phenytoin was, when calcium sulphate which was used as an excipient in the
formulation was substituted with lactose causing faster dissolution and lead to phenytoin toxicity.
Bioavailability is an absolute term as it measures the true rate and extent of drug absorption whereas
bioequivalence is a relative term which determines the rate and extent of a drug in comparison with a
different branded drug.

There are different type of equivalence:
1. Pharmaceutical equivalence
Two formulations are said to be pharmaceutical equivalents if they have identical amount of same
active pharmaceutical ingredient but non active ingredient are not same.
2. Chemical equivalence
When two or more formulation of a particular drug claims same amount of drug as specified in
pharmacopoeia and the claims is found to be true by chemical assay of the product then the two
products are said to be chemically equivalent.
3. Clinical equivalence
Two branded formulations of a particular drug are said to be clinically equivalent if they show identical
in vivo pharmacological response.
4. Therapeutic equivalence
When one drug shows a same therapeutic/pharmacological effect in treatment of same disease as
shown by other drug which is structurally different then they are called therapeutically equivalent.

References
Applied-Biopharmaceutics-Pharmacokinetics-by-Leon-Shargel-Andrew-B.C.-Yu-Seventh-Edition