The document provides a comprehensive overview of therapeutic regimens, including definitions, dose-response curves, drug toxicity, and methods for designing dosage regimens tailored to individuals, especially focusing on infants, children, and the elderly. It discusses the principles of drug dosage, factors influencing drug metabolism, and the importance of clinical trials in evaluating drug safety and efficacy. Additionally, it addresses the complexities of effective dosing strategies and the impact of patient-specific factors on pharmacotherapy.

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Presented by
MISS HARSHITA SINGHAI
DEPARTMENT OF PHARMACEUTICAL SCIENCES
DR. HARISINGH GOUR VISHWAVIDYALAYA SAGAR (M.P.)
( A CENTRAL UNIVERSITY )
THERAPEUTIC REGIMENS

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CONTENTS
1. Introduction
2. Therapeutic Regimen
3. Dose-response Curve
4. Drug Toxicity
5. Symptoms, Diagnosis & Treatment Of Drug Toxicity
6. Dosage Regimen
7. Factors To Consider In Design Of Drug Dosage
Regimens
8. Methods To Design A Dosage Regimen
9. Dosing Of Drugs In Infants And Children
10. Dosing Of Drugs In The Elderly
11. Clinical Trial

3. THERAPEUTIC REGIMEN
• A therapeutic regimen is a systematic plan (as of diet, therapy, or
medication) especially when designed to improve and maintain the
health of a patient.
• A therapeutic response is a result of a medical treatment of any
kind, leading to a desirable and beneficial effect.
For example, an individual taking aspirin for their heart would
consider the therapeutic effect to be the prevention of heart attacks.
When aspirin is taken for a headache, the desired result will be
reduction in pain.

4. DOSE-RESPONSE CURVE
Dose-response data are typically
graphed with the dose or dose function
(Eg: log10 dose) on the x-axis and the
measured effect (response) on the y-
axis.
Measured effects are frequently
recorded as maximal at time of peak
effect or under steady-state conditions.
(Eg: During continuous IV infusion).
Drug effects may be quantified at the
level of molecule, cell, tissue, organ,
organ system, or organism.
FIG: A hypothetical dose-response curve

5. Dose-response curve determines
the required dose and frequency
as well as the therapeutic index
for a drug in a population.
Increasing the dose of a drug
with a narrow therapeutic index
increases the probability of
toxicity or ineffectiveness of
the drug. However, they differ
by population and patient-
related factors, such
as pregnancy, age, and organ
function (Eg: estimated GFR).
DOSE-RESPONSE CURVE

6. • COMPARISON OF DOSE-RESPONSE CURVES
Drug X has greater biologic activity per dosing equivalent and is thus more potent than
drug Y or Z. Drugs X and Z have equal efficacy, indicated by their maximal attainable
response (ceiling effect). Drug Y is more potent than drug Z, but its maximal efficacy is
lower.

7. DRUG TOXICITY
“Drug toxicity is formally defined as the level of damage that a
compound can cause to an organism”.
The threshold between an effective dose and a toxic dose is very
narrow. A therapeutic dose for one person might be toxic to another
person. Plus, drugs with a longer half-life can build up in a person's
bloodstream and increase over time, resulting in drug toxicity.
CAUSES OF DRUG TOXICITY ARE-
• Drug toxicity can occur as a result of the over-ingestion of medication,
causing too much of the drug to be in a person's system at once.
• Drug toxicity can also occur as an adverse drug reaction. In this case,
the normal therapeutic dose of the drug can cause unintentional,
harmful, and unwanted side effects.

8. SYMPTOMS OF DRUG TOXICITY
Drug toxicity symptoms can differ depending on the medication you
are taking and is determined by chemical structure, concentration of
drug the body can absorb and the body's ability to detoxify and
eliminate the substance.
In the case of lithium, for instance, mild symptoms of acute lithium
toxicity (which is drug toxicity after taking the drug one time) can
include:
1. Diarrhea
2. Dizziness
3. Nausea
4. Stomach pains
5. Vomiting
6. Weakness

9. DIAGNOSIS OF DRUG TOXICITY
• Acute drug toxicity is more easily diagnosed as the symptoms
follow the taking of the medication just one time.
• Blood tests can also screen for levels of the medication in the
bloodstream, showing whether these levels are too high.
• Chronic drug toxicity, or drug toxicity that occurs due to long-
term build-up, is harder to identify. Stopping the medication,
then "re-challenging" it later is one method of testing whether
the symptoms are caused by the medicine. This method can be
problematic, however, if the medication is essential and doesn't
have an equivalent substitute.

10. TREATMENT OF DRUG TOXICITY
There are several ways drug toxicity may be treated-
1. A person may undergo stomach pumping to remove drugs that
have not yet been absorbed in case acute overdose of drug.
2. Activated charcoal can be used to bind the drug, preventing it
from being absorbed into the blood and eliminating it from
the body through stool.
3. Other medications may also be given as an antidote for drug
toxicity.
4. If you believe that you or someone else has symptoms of drug
toxicity or overdose, contact medical services immediately.
Quick treatment can result in fewer complications.

11. DOSAGE REGIMEN
• Dosage regimen design is the selection of drug dosage form, route of
administration and frequency of administration in an informed
manner to achieve therapeutic objectives.
• An “optimal multiple dosage regimen” is the one in which the drug is
administered in suitable doses, by suitable route, with sufficient
frequency that ensures maintenance of plasma concentration within the
therapeutic window without excessive fluctuation and drug
accumulation for the entire duration of therapy.
• The initial dosage regimen is calculated based on body weight or body
surface after a careful consideration of the known pharmacokinetics of
the drug, the pathophysiologic condition of the patient, and the
patient's drug history.
• The overall objective of dosage regimen design is to achieve a target
drug concentration at the receptor site.

12. • For certain analgesics, hypnotics, anti-emetics etc. a single dose
may provide an effective treatment. But the duration of most
illness 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.
• Planning of drug therapy is necessary because the administration of
drugs usually involves risk of unwanted effects.
• Specific drugs have different risks associated with their use and
a dosage regimen should be selected which will maximize safety.
• At the same time, the variability among patients in
pharmacodynamic response demands individualized dosing to
assure maximum efficacy.

13. Two major parameters that can be adjusted in
developing a dosage regimen are:
1. DOSE SIZE :- It is the quantity of the drug administered each time. The
magnitude of therapeutic & toxic responses depend upon dose size.
• Amount of drug absorbed after administration of each dose is
considered while calculating the dose size.
• Greater the dose size greater the fluctuation between Css,max &
Css,min (max. and min. steady state concentration) during each dosing
interval & greater chances of toxicity.
2. DOSE FREQUENCY :- It is the time interval between doses. Dose
interval is inverse of dosing frequency.
• Dose interval is calculated on the basis of half life of the drug.
• When dose interval is increased with no change in the dose size, Cmin,
Cmax & Cav decrease, but when dose interval is reduced, it results in
greater drug accumulation in the body and toxicity.

14. CERTAIN CONCEPTS
A)Drug accumulation during multiple dosing: Following the 1st
dose, if the 2nd dose is given before the 1st dose is eliminated then
the drug will start accumulating and we will get higher
concentration with the 2nd and 3rd dose. Upon repeating the dose, it
is seen that the drug accumulation continue until a limit is reached.
The reason being that as the plasma conc. increases the rate of
elimination will also increase following 1st order elimination.
B)Time to reach steady state during multiple dosing: The time
required to reach steady state depends primarily upon the half life of
the drug. Provided Ka>>Ke, plateau is reached in approximately 5
half lives. The time taken to reach steady state is independent of
dose size, dose interval & no. of doses. It is determined only by Ke.

15. MULTIPLE DOSING WITH RESPECT TO I.V
On repeated drug administration, the plasma conc. will be added
upon for each dose interval giving a plateau or steady state with the
plasma conc. fluctuating between a minimum and maximum.

16. MULTIPLE DOSING WITH RESPECT TO ORAL
ROUTE
In this plasma conc. will increase, reach a maximum and begin to
decline. A 2nd dose will be administered before the absorbed drug
from the 1st dose is completely eliminated. Consequently plasma
conc. resulting from 2nd dose will be higher than from 1st dose. This
increase in conc. with dose will continue to occur until a steady state
reaches at which rate of drug entry into the body is equal to rate of
exit.

17. LOADING DOSE
• A drug dose does not show therapeutic activity unless it
reaches the desired steady state.
• It takes about 4-5 half lives to attain it and therefore time
taken will be too long if the drug has a long half-life.
• Plateau can be reached immediately by administering a
dose that gives the desired steady state instantaneously
before the commencement of maintenance dose X0.
• Such an initial or first dose intended to be therapeutic is
called as priming dose or loading dose X0.

18. CALCULATION OF LOADING DOSE
For IV drugs given by infusion,
Dose rate (mg/hr) = dose (mg) divided by dosing interval (hrs)
Maintenance dose rate (mg/hr) = desired peak concentration
(mg/L) × clearance (L/hr)
Loading dose = desired peak concentration (mg/L) × volume of
distribution (L)
For drugs not given IV, these doses need to be divided by the
bioavailability.

19. CALCULATION OF LOADING DOSE
• If the loading dose is not optimum either too low or too high,
the steady state is attained within a 4-5 half lives in a manner
similar to when no loading dose is given.

20. I. Route of Administration
II. Dose
III. Dosage interval
IV. Complications
FACTORS TO CONSIDER IN DESIGN OF DRUG DOSAGE REGIMENS

21. I. ROUTE OF ADMINISTRATION:
1. Drug absorption characteristics
2. Presence of pre-systemic elimination or unusual first-pass
metabolism in some patients
3. Accumulation of drug at absorption site. E.g. Intramuscular
depots.
4. Need for immediate onset of action
5. Ease of administration
6. Half-life: infusion may be necessary for drugs with short t1/2
or sustained release formulation.
7. Patient acceptance of route and dosage form
FACTORS TO CONSIDER IN DESIGN OF DRUG
DOSAGE REGIMENS

22. II. DOSE:
1. Pharmacokinetics of the drug—including its absorption,
distribution, and elimination profile—are considered in the
patient.
2. Volume of distribution: to estimate peak plasma
concentration
3. Documented nonlinearity of pharmacokinetics
4. Cost of medication
5. Half-life: tapering of dose may not be necessary for some
drugs with long t1/2
6. Availability of treatment for overdose
7. Existence of a therapeutic or toxic concentration range
8. Therapeutic index

23. EXAMPLE OF EFFECT OF DOSE

24. III. DOSAGE INTERVAL:
1. Half-life: Dosage interval can generally be extended in
relation to half-life.
2. Therapeutic index: The higher the TI, the longer an interval
can be spaced with higher doses.
3. Body clearance to evaluate accumulation
4. Side effects which may require special administration times.
e.g. bed time to avoid sedation.

25. EXAMPLE OF DOSAGE INTERVAL

26. IV. COMPLICATIONS:
1. Analytical methodology and reliability in monitoring Cp
2. Active metabolites
3. Changing pathophysiology such as renal dysfunction, hepatic disease, or
congestive heart failure
4. Drug interactions
5. Auto or exogenous enzyme induction
6. Development of pharmacodynamic tolerance
7. Side effects which are not dose or concentration related
8. Physiology of the patient, age, weight, gender, and nutritional status will
affect the disposition of the drug

27. METHODS TO DESIGN A DOSAGE REGIMEN
1. Individualized dosage regimen
2. Dosage regimen based on population average
3. Dosage regimen based on partial pharmacokinetic
parameters
4. Empirical dosage regimen

28. 1. INDIVIDUALIZED DOSAGE REGIMEN
• It is a most accurate approach.
• Dose calculated based on the pharmacokinetics of the drug in the
individual patient derived from measurement of serum or plasma
drug levels.
• Not feasible for calculation of the initial dose, however,
readjustment of the dose is quite possible.
• Most dosing program record the patient’s age and weight and calculate
the individual dose based on creatinine clearance and lean body mass.

29. 2. DOSAGE REGIMENS BASED ON
POPULATION AVERAGES
• Dosage regimen is calculated based on average
pharmacokinetic parameters obtained from clinical studies published
in the drug literature.
• There are two approaches followed
1. Fixed model
2. Adaptive model
1. Fixed Model:
• Assumes that population average pharmacokinetic parameters may be
used directly to calculate a dosage regimen for the patient, without
any alteration.
• The practitioner may use the usual dosage suggested by the literature
and then make a small adjustment of the dosage based on the patient’s
weight and / or age.
• When a multiple dose regimen is designed, multiple dosage equations
based on the principle of superposition are used to evaluate the dose.

30. 2. Adaptive Model:
• This approach attempts to adapt or modify dosage
regimen according to the need of the patient.
• Uses patient variable such as weight, age, sex, body
surface area, and known patient’s pathophysiology such as,
renal disease, as well as known population average
pharmacokinetic parameters of the drug.
• This model generally assumes that pharmacokinetic
parameters such as drug clearance do not change from one
dose to the next. However, some adaptive models allow for
continuously adaptive change with time in order to simulate
more closely the changing process of drug disposition in
the patient, especially during a disease state.

31. 3. DOSAGE REGIMEN BASED ON PARTIAL PHARMACOKINETIC PARAMETERS:
• For many drugs, the entire pharmacokinetic profile for the drug is
unknown or unavailable. Therefore,some assumptions are made in
order to calculate the dosage regimen.
• These assumptions will depend on the safety, efficacy, and
therapeutic range of the drug.
• The use of population pharmacokinetics uses average patient
population characteristics and only a few serum or plasma
concentration from the patient.
• Population pharmacokinetic approaches to therapeutic drug
monitoring have increased with the increased availability of
computerized data bases and development of statistical tools for the
analysis of observational data.

32. 4. EMPIRICAL DOSAGE REGIMENS:
• In many cases, physician selects a dosage regimen of the
patient without using any pharmacokinetic variables.
• The physician makes the decision based on empirical
clinical data, personal experience and clinical observations.

33. DOSING OF DRUGS IN INFANTS AND
CHILDREN
• Infants and children have different dosing requirements than
adults.
• Variation in body composition and the maturity of liver and
kidney function are potential sources of differences in
pharmacokinetics with respect to age.
• In general, complete hepatic function is not attained until the
third week of life. Oxidative processes 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.

34. • Newborns show only 30–50% of the renal activity of adults on the
basis of activity per unit of body weight . Drugs that are heavily
dependent on renal excretion will have a sharply decreased elimination
half-life. For example, the penicillins are excreted for the most part
through the kidney. The elimination half-lives of such drugs are much
reduced in infants.
• Pediatric drug formulations may also contain different drug
concentrations compared to the adult drug formulation. Furthermore,
alternative drug delivery such as an intramuscular antibiotic drug
injection into the gluteus medius may be considered for a pediatric
patient, as opposed to the deltoid muscle for an adult patient.

36. DOSING OF DRUGS IN THE ELDERLY
• 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 and can affect compliance and the
therapeutic safety and efficacy of a prescribed drug.
• Elderly patients may have several different pathophysiologic
conditions that require multiple drug therapy that increases the
likelihood for a drug interaction.
• Example: Both penicillin and kanamycin show prolonged t 1/2 in
the aged patient, as a consequence of an age-related gradual
reduction in the kidney size and function.

37. CLINICAL TRIAL
• “Clinical trials are research studies that explore whether a medical
strategy, treatment, or device is safe and effective for humans.
These studies also may show which medical approaches work best
for certain illnesses or groups of people.”
• Clinical trial studies are often done with a limited number of
subjects, due to either cost or the availability of subjects who meet
the study requirements.
• The study subjects are selected according to exclusion and
inclusion criteria that are written into the protocol.
• .

39. All subjects must give informed consent to be in the study. Since
most studies are done over a period of time, it is important to ensure
that both the treatment and control groups are balanced and to avoid
any temporal influence.
CLINICAL TRIAL

40. ADVANTAGES
• Provides the strongest evidences in support of cause effect
relationships.
• Basis for clinical and public health policy.
• Toxicokinetic studies are performed in animals during
preclinical drug development and may continue after the drug
has been tested in clinical trials.
• Clinical studies are monitored for side effects and rare events
• Clinical trials in humans establish the safety and effectiveness
of drug products and may be used to determine bioavailability

41. FUNCTIONS
• The purpose of the clinical trial is assessment of efficacy,
safety, or risk benefit ratio. Goal may be superiority, non-
inferiority, or equivalence.
• The actual dosing regimen (dose, dosage form, dosing
interval) was carefully determined in clinical trials to provide
the correct drug concentrations at the site of action.

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REFERENCES
• SHARGEL L., PONG S.W., ANDREW B.C. ,“APPLIED BIOPHARMACEUTICS
AND PHARMACOKINETICS ”,ED-5,BY MC GRAW- HILL, MEDICAL PUB.,
NEW YORK, CH-13,14
• BRAHMANKAR D.M., JAISWAL S.B., “BIOPHARMACEUTICS AND
PHARMACOKINETICS”, ED-2, 2019, VALLABH PRAKASHAN, DELHI, 399-
401.
• https://pubrica.com/academy/statistical/on-biostatistics-and clinical-
trials/
• https://cead.cumc.columbia.edu/content/research-clinical-trials
REFERENCES

43. • https://www.editage.com/insights/a-young-researchers-guide-
to-a-clinical-trial
• https://www.researchgate.net/figure/Drug-dosing-tool-
development-process-Pharmacokinetic-PK-pharmacodynamic-
PD-studies_fig2_319050728
• https://www.sciencedirect.com/topics/biochemistry-genetics-
and-molecular-biology/drug-toxicity
• https://www.collinsdictionary.com/dictionary/english/
therapeutic-response
REFERENCES

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