plays the most important role in obtaining the desired therapeutic outcomes.
The focus perpetually is on the design of doses, their intervals and duration
to acquire the optimum response. Many factors like age, gender, weight, body
surface area, pathological state play a role in formulating these regimens and
each factor is given importance in deciding regimen that gives the optimum
response. The experiments gradually reveal the correct regimens after
repeatedly being worked upon. Different parameters such as Cmax, Tmax, are
calculated and estimated in order to decide by which dose and its interval the
therapeutic level is maintained in the blood. Therapeutic drug monitoring is
one of the most important aspects in dosage regimen where the narrow
therapeutic index drugs are given and designed in such a way as to get the
therapeutic response with minimized toxicity.
Dosage Regimen, Therapeutic
Drug Monitoring, Multiple Dosage Regimen
regimen is the timetable of portions of a medication, including the time
between dosages, the term of treatment and the add up to be taken each time.
Dose regimens additionally incorporate how a medication is to be taken, and in
what plan (Jelliffe,
Neely, & Bayard, 2020).
Choice of medication administration regarding
formulation, route of administration, drug portion, dosing span and treatment
For most of the
drugs, a preapproved dosage regimen proposed by manufacturer and approved by
registration bodies is used. The regimen must meet average patient’s
requirements. As an innovation and considered important, dosage regimen individualization
is considered fruitful, leading toe effective treatment of patients and limited
cases to apply selected dosing decision to improve the treatment of patient and
ultimately patients’ health. For example, the standard regimen should be adapted
to the individual characteristics on behalf of patients (e.g., weight and age)
and to the presence of comorbidity that affects the pharmacokinetics of the
drugs (e.g., renal failure, liver disease).
After the therapy is initiated, individualizationof the dosage regimen, considering the response, may be important
to better adapt the treatment to the condition of patients.
regimens makes us design the dose and frequency of particular drug for a
MTC can be determined by using dose regimens.
to establish of doses of narrow therapeutic index drugs.
drug monitoring analyzes the therapeutic effects of such drugs which require
proper monitoring to provide beneficial therapeutic effects.
to have prolonged therapeutic activity multiple dosing regimens are given.
multiple dosage regimens, we can keep the plasma concentration of the drug
within the narrow limits of the therapeutic index hence chronic diseases can be
treated for example, Drug concentration in the plasma above the MEC and below
dosage regimen is maintained in such a way so that exact plasma level of the
drug should be maintained without the accumulation or variation of drug outside
the therapeutic window.
achieve the required MEC for some specific medications like anti-microbials.
having a very narrow therapeutic index for example digoxin, needs MEC and MTC
to be defined properly.
optimizing a dosage regimen for multiple administration, main target plasma
concentration of the drug substance must be in between the therapeutic window
to produce the response that is desired.
Factors Affecting Dose Regimen
Babies (pediatric) are unusually delicate to specific
medications on account of the youthful condition of their hepatic and renal
capacity by which medications are inactivated and eliminated from the body.
Inability to detoxify and eliminate drugs brings about their amassing in the
tissues to a poisonous level. - The decrease in renal and hepatic capacity in
the older (geriatric) may slow drug clearance and expands the chance of
medication amassing in the body and ensuing toxicity.
The official doses for drugs are viewed as
appropriate for 70 kg (150 pounds) people. - The proportion between the measure
of medication administered and the size of the body impacts the medication
concentration at the site of activity. Thusly, drug dosage may require change
from the standard adult dose for strangely lean or fat patients.
Body Surface Area
A close relation exists between a large number of
physiological processes and body surface area (BSA).
Ladies are more defenseless
with the impacts of specific medications than are men. Pregnant ladies and
nursing moms should utilize drugs just with the advice and under the directions
by physicians. Instances of medications that are transported from the maternal
to the fetal circulation for example liquor, sedative gases, barbiturates,
anticoagulants, and so on. Due to the lacking medication detoxification and
discharge mechanisms present in the baby, concentrations of medications may
arrive at a more significant level in the embryo than in the maternal
The exchange of medications
from the mother to the nursing baby through human milk may happen with
different medications with the medication impacts
getting show in the newborn child.
The impacts of specific medications might be altered
by the pathological state of the patient and should be considered in deciding
the dose. Cautioning and precautionary measures are utilized in the medication
labelling to make the doctor aware of specific limitations in the utilization
of a specific medication.
Is utilized to inform the prescriber regarding some
potential issues specialist with the utilization of the medication. It is less
prohibitive than notice. for example The utilization of antibiotic medication
anti-toxin may bring about excess of growths of fungi. In such a case, the
doctor may recommend a substitute medication.
It is utilized when the potential for damage is more
noteworthy than in cases in which the safeguard is utilized. For example, On
the off chance that tetracycline is utilized within the sight of renal
disability, it might prompt amassing of the medication and conceivable liver
toxicity. So lower than common doses are indicated. On the off chance that
treatment is delayed, blood serum levels of the medication ought to be taken
and the patient checked at ordinary spans to guarantee the support of
non-harmful levels of the medication.
A term that used to indicate an absolute prohibition
to the use of a drug in the presence of certain stated conditions. It is the
most restrictive of the warnings which limits the use of drugs.
The capacity to persevere
through the impact of a medication, especially when obtained by a proceeded
with utilization of the substance. Tolerance happens ordinarily in such
medications e.g. anti-histaminic, opiate analgesics. Normal sensitivity might
be recovered by suspending the medication administration for a while. The
development of tolerance can be minimized by:
ØInitiating therapy with the
lowest effective dose.
The impacts of a medication might be adjusted by the
simultaneous administration of another medication. These medication drug
interactions are because of: A- chemical or physical interaction between drugs.
B- alteration of the absorption, distribution, metabolism or excretion patterns
of one of the medications.
Dosage Regimen and Superposition
designing a dosage regimen, all pharmacokinetic parameters of the drug remain
constant during therapy once the dosage regimen is established.The calculations are based on
one- compartment model which can also applied for two- compartment model (Sime, Roberts, & Roberts,
Dosage Regimen from Plasma Concentration
the event that the Vd and half-life of a medication is known, at that point the
dosage regimen can be planned to maintain the medication concentration in
therapeutic range. Maximum dosage interval which preferably relies on the
therapeutic index and the elimination half-life of the medication.
parameters that can be adjusted in developing a dosage regiment are as follows.
is characterized as, the measure of medication given to the patient at every
patient straight forwardly identified with the size of therapeutic and toxic
impacts. It manages Amount of medication retained after admission of each dose
is thought of while figuring the dose size. Dose size is proportional to
fluctuations among Cmax and Cmin in during each dosing interval. Subsequently,
with more dose, danger of medication toxicity is more. Expanded danger of
results for drugs with small therapeutic window.
fluctuations, greater risk of toxicity apart from therapeutic response.
fluctuations, poor therapeutic response.
is characterized as the time interval between the dose for example guarantee of
dosing frequency is dosing interval. Dosing interval is assessed from half -
life of the medication. At the point when dosage interval is expanded with no
adjustment in dose size then Cmin and Cmax diminished however when the dosing
span is decline, at that point the medication accumulation in the body and
cause toxicity. In the event that the increased and dose is unaltered, Cmax,
Cmin, Cav decline yet the proportion Cmax/Cmin increase.
frequency (< T1/2)
Øshows therapeutic response
Øbut greater risk of toxicity
dosing frequency (=T1/2)
ØGood therapeutic response
ØBut poor therapeutic response
legitimate equilibrium ought to be acquired between dose frequency and size to
accomplish steady state concentration. And with least fluctuations to guarantee
therapeutic efficacy and safety.
For drugs with wide therapeutic index, for example, Penicillin's
larger doses might be managed at larger intervals (the greater half-life of
medications) with no toxicity impacts. For drugs with limited therapeutic index
like Digoxin, little doses with frequent interval (not exactly half-life of
medication) are smarter to acquire a profile with least fluctuations which is
more modest to that saw with controlled drug release system.
Therapeutic Drug Monitoring
TDM includes the estimation of medication
concentrations in biological fluid and the understanding of those
concentrations. TDM is the
clinical evaluation of a medication's pharmacokinetic properties.
requires information on the pharmacokinetics,
sampling time, drug history and the patient's clinical condition.
Why We Perform Therapeutic
(assessment of MD)
when the manifestation of toxicity and disease state are similar (theophylline)
ØChanging patient’s clinical
ØMonitoring and detecting drug
ØNarrow therapeutic index (NTI)
ØA reasonable relationship
between plasma conc. and clinical effects
ØAvailability of cost-effective
Interpretation of TDM Through
In most cases when steady state is reached earlier if
toxicity is suspected. At the appropriate time in relation to the last dose
generally measured in the elimination phase gives a more reliable guide to drug
dosing like some antibiotics (aminoglycosides).
Interpretation Through Sample Concentration
Individualization of Dose
Following parameters should be
considered before making the dosage regimen
ØSample should be taken at the
time after the last dose was given
ØSteady or plateau state has
been achieved or not.
ØWhether the patient follows
the dosage regimen
ØThere is drug-drug interaction
ØWhether kidney or liver
dysfunction is there or not.
ØDrug is obeying the linear
kinetics or not assessed by the clinical pharmacokinetic principles.
Concentration after Multi Dose
administration of a fixed dose at a regular time interval, through a given
route” In repeated administration, accumulation happens when the medication is
administered before the past dose is totally wiped out. The measure of
medication in the body will at that point continuously rise. In the most
well-known instance of first-order kinetics, the pace of medication disposal
will increment relatively. At the point when the pace of medication end
remunerates the pace of medication administration, the normal medication
fixation arrives at steady state or plateau. At steady state, the measure of
medication lost in every interval rises to the sum acquired, that is the dose increased
by the bioavailability. Hence, the plasma concentration fluctuates between
dosages likewise starting with one dosing interval then onto the next.
Factors that affect the average steady state concentration are:
administration rate (unit dose divided by dosing interval), affecting the
steady state plasma concentration proportionally.
which manages rate of dose administration.
being inversely related to steady state concentration.
During the dosing interval, the factors affecting the fluctuation
of plasma concentration around the average concentration are:
of drug administration: For a similar dosing rate, relative frequency of
administration is inversely proportional to plasma fluctuation.
half-life: half-life and plasma fluctuation showing inverse proportionality.
of absorption: slower rate of absorption ultimately leading to a decline in
Drug's half-life determines the time required to reach steady
state, as is the time it takes to reach a new plateau after a change in
We can assess the plateau state concentration using the following
τ indicates the
dosing interval in hours, F indicates the Bioavailability of the drug and CL
indicates the clearance of the drug.
We can calculate the accumulation index by using the given
Where λ is equal to the elimination rate constant which is equal to the
clearance/Volume of distribution
Now the accumulation index can be used to assess the
steady or plateau state concentration:
Accumulation Rate to Steady State Concentration
concentration of the drug rises in the body upon the multiple dosing regimen
just like the constant IV infusion rate. In this way, the steady state
concentration of the drug will be dependent upon the elimination half-life of
the medication. Phenobarbital, an antiepileptic drug will be reenacted. This
drug's half-life for elimination is 100 hours i.e. 4 days and 100mg single dose
is given daily.
Some chronic diseases are treated using more
than one doses using multiple dosage regimen for example joint pain and high
blood pressure because single drug leads to the decline of the drug
concentration below the MEC after a certain interval of time. Therefore, the
multiple dosage regimen is useful to treat the persistent diseases that keeps
up the plasma concentration of the drug within the narrow range limits of
therapeutic index to achieve the required clinical outcomes. Cardiotonic,
anti-hypertensives and anti-convulsant are examples of such medications.
Setting up a dosage regimen which maintains the plasma concentration level
within the range without any fluctuation or accumulation is an ideal case. To
calculate the dosage regimen individualized to a patient the plasma
concentration vs time curve prepared by single dose study is used to attain the
PK boundaries. Using these PK parameters and the data on the dosing interval
and dose size of the drug, we can predict the Plasma concentration vs time
curve at any time after the dosage regimen is started.
get an estimation of the multiple dosage regimen we need to select such
subsequent dosage of the medicine in order to avoid or have an effect on the
previously given dose. Superposition rule predicts that the medication's early
doses will not have an impact on the pharmacokinetic parameters of the progressive
doses. Therefore, following the 2nd, 3rd, and nth dose of the drug the blood
concentration will superimpose the level of the drug that is attained after the
n-1 portion. Moreover, the area under the curve for the principally
administered dose must be equal to the plateau state area between the two
The understanding of such
concept is of utmost
importance as the main focus
has always been on the correct combination of dose, interval and its duration
which helps treat the condition efficiently. The maximum therapeutic response
with least toxicity is the main goal and deciding a regimen providing this is
an achievement. As it is obvious, many factors which vary from individual to
individual greatly effect these regimens and for such patients the regimens are
to be designed according to them. The individualization of dose has helped a
lot in effectively treating the condition avoiding unnecessary administration
of doses. So, in calculating the multiple dosage regimen desired plasma
concentration must be related to the therapeutic response that is the
concentration must remain in the therapeutic window. The strategy followed is
to focus the therapeutic goals and then assessing the pharmacokinetic
parameters along with quantitative effects and the clinical response. So
therapeutic drug monitoring helps in the dose adjustment and individualizing
the regimen based on various factors to gain maximum therapeutic response.
Jelliffe, R., Neely, M., % Bayard, D. (2020). Pharmacokinetic methods for TDM data analysis and optimal individualization of drug dosage regimens. In (pp. 135-168). Sime, F. B., Roberts, M. S., % Roberts, J. A. (2015). Optimization of dosing regimens and dosing in special populations. Clinical Microbiology and Infection, 21(10), 886-893. doi:10.1016/j.cmi.2015.05.002