Pharmacokinetics of IV infusion

Group #4

• Members
• Hafsa shahid 06331513005
• Saman shahjehan 06331513014
• Hafiz Hassan butt 06331513023
• Masooma Naqvi 06331513034
• Parniya akbar ali 06331513061
Contents

• Introduction
• Describe the concept of steady state and how it relates to
continuous dosing.
Calculate loading doses to be used with an intravenous
infusion
• purpose of a loading dose
• Pharmacokinetic models
• Bioavailability and bioaccesibility
• Subcutaneous vs intravenous rituximab administration
• Advancement in IV technology
Introduction
• Definition :
• "Drug administration through the intravenous route at a constant rate over a
determined time interval.“
• The two main methods of IV infusion use either gravity or a pump to send
medication into your catheter:
• Pump infusion: The pump is attached to your IV line and sends medication and a
solution, into your catheter in a slow, steady manner. Pumps may be used when
the medication dosage must be precise and controlled.
• Drip infusion: This method uses gravity to deliver a constant amount of
medication over a set period of time. With a drip, the medication and solution
drip from a bag through a tube and into your catheter.
Description
• When a drug is infused intravenously at a constant rate, a plateau
concentration will be reached progressively
• On starting the infusion, there is no drug in the body and therefore,
no elimination. The amount of drug in the body then rises, but as the
drug concentration increases, so does the rate of elimination. Thus,
the rate of elimination will keep rising until it matches the rate of
infusion. The amount of drug in the body is then constant and is said
to have reached a steady state or plateau.
• steady state
When the rate of drug input is equal to the rate of drug elimination
• Rate of drug input =rate of drug output
• (infusion rate) = (elimination rate)
• ONE-COMPARTMENT MODEL DRUGS
• The pharmacokinetics of a drug given by constant IV infusion follows
a zero-order input process in which the drug is directly infused into
the systemic blood circulation. elimination of drug from the plasma is
a first-order process. Therefore, in this one-compartment model,the
infused drug follows zero-order input and firstorder output.
• The change in the amount of drug in the body at any time (dDB/dt)
during the infusion is the rate of input minus the rate of output.
Steady-State Drug Concentration (Css) and
Time Needed to Reach Css
• Once the steady state is reached, the rate of drug leaving the body is equal to
the rate of drug entering the body (infusion rate). In other words, there is no
net change in the amount of drug in the body, DB, as a function of time during
steady state concentration.

Mathematically, the time to reach true steadystate drug concentrations, Css,

would take an infinite time. The time required to reach the steady-state drug
concentration in the plasma is dependent on the elimination rate constant of
the drug for a constant volume of distribution
Number of t1/2 to Reach a Fraction of Css

Percent of Css Reached a Number of Half-Lives

• 90 3.32
• 95 4.32
• 99 6.65
Rapid infusion rate
• An increase in the infusion rate will not shorten the time to reach the
steady-state drug concentration.If the drug is given at a more rapid
infusion rate, a higher steady-state drug level will be obtained, but
the time to reach steady state is the same
Loading Dose
• Loading dose is the minimum effective dose which is given initially at
a time to obtain the steady state plasma drug concentration as early
as possible
Pharmacokinetic models
MASOOMA NAQVI
(06331513034)
Pharmacokinetic models
• Pharmacokinetic modelling is performed by
noncompartmental or compartmental methods.
Noncompartmental methods estimate the exposure
to a drug by estimating the area under the curve of a
concentration-time graph. Compartmental methods
estimate the concentration-time graph using kinetic
models.
• Noncompartmental methods produce accurate results also acceptable for
bioequivalence studies.
• The final outcome of the transformations that a drug undergoes in an
organism and the rules that determine this fate depend on a number of
interrelated factors. A number of functional models have been developed in
order to simplify the study of pharmacokinetics.
• These models are based on a consideration of an organism as a number of
related compartments. The simplest idea is to think of an organism as only
one homogenous compartment.
• This monocompartimental model presupposes that blood plasma
concentrations of the drug are a true reflection of the drug’s concentration in
other fluids or tissues and that the elimination of the drug is directly
proportional to the drug’s concentration in the organism (first order kinetics).
Graph representing the monocompartmental action model.
• However, these models do not always truly reflect the real situation within
an organism. For example, not all body tissues have the same blood supply
so the distribution of the drug will be slower in these tissues than in others
with a better blood supply.
• In addition, there are some tissues (such as the brain tissue) that present a
real barrier to the distribution of drugs, they can be breached with greater or
lesser ease depending on the drug’s characteristics.
• If these relative conditions for the different tissue types are considered along
with the rate of elimination, the organism can be considered to be acting like
two compartments: one that we can call the central compartment that has a
more rapid distribution, comprising organs and systems with a welldeveloped
blood supply; and a peripheral compartment made up of organs with a
lower blood flow. Other tissues, such as the brain, can occupy a variable
position depending on a drug’s ability to cross the barrier that separates the
organ from the blood supply.
This two compartment model will vary depending on which compartment
elimination occurs in. The most common situation is that elimination occurs in the
central compartment as the liver and kidneys are organs with a good blood supply.
However, in some situations it may be that elimination occurs in the peripheral
compartment or even in both. This can mean that there are three possible variations
in the two compartment model, which still do not cover all possibilities.
This model may not be applicable in situations where some of the enzymes responsible for
metabolizing the drug become saturated, or where an active elimination mechanism is
present that is independent of the drug's plasma concentration. In the real world each
tissue will have its own distribution characteristics and none of them will be strictly linear. If
we label the drug’s volume of distribution within the organism VdF and its volume of
distribution in a tissue VdT the former will be described by an equation that takes into
account all the tissues that act in different ways, that is:
This represents the multi-compartment model with a number of curves that
express complicated equations in order to obtain an overall curve. A number
of computer programmes have been developed to plot these equations.
However complicated and precise this model may be it still does not truly
represent reality despite the effort involved in obtaining various distribution
values for a drug. This is because the concept of distribution volume is a
relative concept that is not a true reflection of reality. The choice of model
therefore comes down to deciding which one offers the lowest margin of
error for the type of drug involved.
Noncompartmental analysis

Noncompartmental PK analysis is highly dependent on estimation

of total drug exposure. Total drug exposure is most often
estimated by area under the curve (AUC) methods, with the
trapezoidal rule (numerical integration) the most common
method. Due to the dependence on the length of 'x' in the
trapezoidal rule, the area estimation is highly dependent on the
blood/plasma sampling schedule. That is, the closer time points
are, the closer the trapezoids reflect the actual shape of the
concentration-time curve.
Compartmental analysis

Compartmental PK analysis uses kinetic models to describe and predict the concentration-
time curve. PK compartmental models are often similar to kinetic models used in other
scientific disciplines such as chemical kinetics and thermodynamics. The advantage of
compartmental over some noncompartmental analyses is the ability to predict the
concentration at any time. The disadvantage is the difficulty in developing and validating the
proper model. Compartment-free modelling based on curve stripping does not suffer this
limitation. The simplest PK compartmental model is the one-compartmental PK model with
IV bolus administration and first-order elimination. The most complex PK models (called
PBPK models) rely on the use of physiological information to ease development and
validation.
Single-compartment model

Linear pharmacokinetics is so-called because the graph of the

relationship between the various factors involved (dose, blood plasma
concentrations, elimination, etc.) gives a straight line or an
approximation to one. For drugs to be effective they need to be able to
move rapidly from blood plasma to other body fluids and tissues.
The change in concentration over time can be expressed as ;

C=Cinitial*E^(-kelt)
Multi-compartmental models

Graphs for absorption and elimination for a non - linear

pharmacokinetic model.
The graph for the non-linear relationship between the various factors is
represented by a curve, the relationships between the factors can then be
found by calculating the dimensions of different areas under the curve.
The models used in 'non linear pharmacokinetics are largely based on
Michaelis-Menten kinetics. A reaction’s factors of non linearity include
the following:
Multiphasic absorption :

Drugs injected intravenously are removed from the plasma through two primary
mechanisms:
(1) Distribution to body tissues

(2) metabolism + excretion of the drugs. The resulting decrease of the drug's
plasma concentration follows a biphasic pattern
Plasma drug concentration vs time after an IV dose
• Alpha phase: An initial phase of rapid decrease in plasma concentration. The decrease
is primarily attributed to drug distribution from the central compartment (circulation)
into the peripheral compartments (body tissues). This phase ends when a pseudo-
equilibrium of drug concentration is established between the central and peripheral
compartments.
• Beta phase: A phase of gradual decrease in plasma concentration after the alpha
phase. The decrease is primarily attributed to drug metabolism and excretion.

• Additional phases (gamma, delta, etc.) are sometimes seen.

• Enzymatic saturation: When the dose of a drug whose elimination depends on

biotransformation is increased above a certain threshold the enzymes responsible for
its metabolism become saturated. The drug’s plasma concentration will then increase
disproportionately and its elimination will no longer be constant.

• Induction or enzymatic inhibition: Some drugs have the capacity to inhibit or stimulate
their own metabolism, in
• Negative or positive feedback reactions. As occurs with fluvoxamine,
fluoxetine and phenytoin. As larger doses of these pharmaceuticals are
administered the plasma concentrations of the unmetabolized drug
increases and the elimination half-life increases. It is therefore necessary to
adjust the dose or other treatment parameters when a high dosage is
required.

• The kidneys can also establish active elimination mechanisms for some
drugs, independent of plasma concentrations.

It can therefore be seen that non-linearity can occur because of reasons that
affect the whole of the pharmacokinetic sequence: absorption, distribution,
metabolism and elimination.
Bioavailability &
Bioaccessibility
Parniya Akbar Ali
06331513061
Bioavailability

At a practical level, a drug’s bioavailability can be defined as:

“The proportion of the drug that reaches its site of action.”
From this perspective the intravenous administration of a drug provides the
greatest possible bioavailability, and this method is considered to yield a
bioavailability of 1 (or 100%). Other delivery methods is compared with that of
intravenous injection («absolute bioavailability») or to a standard value related to
other delivery methods in a particular study («relative bioavailability»).
Bioavailability

Once a drug’s bioavailability has been established it is possible to calculate the

changes that need to be made to its dosage in order to reach the required blood
plasma levels. Bioavailability is therefore a mathematical factor for each individual
drug that influences the administered dose. It is possible to calculate the amount of
a drug in the blood plasma that has a real potential to bring about its effect using
the formula:

Where De is the effective dose, B bioavailability and Da is the administered dose.

Bioavailability

Therefore, if a drug has a bioavailability of 0.8 (or 80%) and it is administered in a

dose of 100 mg, the equation will demonstrate the following:
De = 0.8 x 100 mg = 80 mg
That is the 100 mg administered represents a blood plasma concentration of 80 mg
that has the capacity to have a pharmaceutical effect.

Different forms of tablets, which will have different pharmacokinetic behaviors after their administration.
Bioavailability

This concept depends on a series of factors inherent to each drug, such as:
• Pharmaceutical form
• Chemical form
• Route of administration
• Stability
• Metabolism
These concepts can be mathematically quantified and integrated to obtain an
overall mathematical equation:

Where Q is the drug’s purity.

Bioavailability

Where Va is the drug’s rate of administration and is the rate at which the
absorbed drug reaches the circulatory system.
Finally, using the Henderson-Hasselbalch equation, and knowing the drug’s
pKa (pH at which there is an equilibrium between its ionized and non ionized
molecules), it is possible to calculate the non ionized concentration of the
drug and therefore the concentration that will subject to absorption:
Bioaccessibility

It is a concept related to bioavailability in the context of biodegradation and

environmental pollution. A molecule (often a persistent organic pollutant) is said to
be bioaccessible when;

“[it] is available to cross an organism's cellular membrane from the environment, if

the organism has access to the chemical.”
Bioequivalents

When two drugs have the same bioavailability, they are said to be biological
equivalents or bioequivalents. This concept of bioequivalence is important
because it is currently used as a yardstick in the authorization of generic
drugs in many countries. A number of phases occur once the drug enters into
contact with the organism, these are described using the acronym Liberation
of the active substance from the delivery system,
• Absorption of the active substance by the organism,
• Distribution through the blood plasma and different body tissues,
• Metabolism that is, inactivation of the xenobiotic substance, and finally
• Excretion or elimination of the substance or the products of its
metabolism.
Subcutaneous vs intravenous
rituximab administration
Hafsa Shahid
(06331513005)
Subcutaneous vs intravenous rituximab in patients with non-
Hodgkin lymphoma : a time and motion study in the United
Kingdom.
Rituximab is part of standard therapy for many non-Hodgkin lymphoma (NHL)
patients, and is usually administered as an intravenous (IV) infusion. A
formulation for subcutaneous (SC) injection will be available from June 2014. A
time and motion study was conducted to investigate the staff time and costs
associated with administration of SC and IV rituximab.
RESEARCH DESIGN AND METHODS:
The time and motion study was conducted in three UK centers alongside a phase
III trial of SC rituximab in patients with NHL. Active healthcare professional (HCP)
time spent on the preparation and administration of IV and SC rituximab was
recorded and used to calculate the associated costs.
RESULTS:

• Total active HCP time associated with administration of IV rituximab was

223.3 min (95% CI = 218.0-228.7), vs 48.5 min (95% CI = 45.5-51.6) for SC
rituximab, a saving of 174.8 min (95% CI = 172.5-177.1) per session.

• Patient time in the treatment room was 263.8 min (95% CI = 236.6-294.3) for
IV rituximab and 70.0 min (95% CI = 57.1-87.2) for SC rituximab, per session.

• The SC formulation reduced total mean staff costs by £115.17 (95%

CI = 98.95-136.93) per session. Differing monitoring scenarios during infusion
consistently showed time and cost savings for SC rituximab.
LIMITATIONS:
Study limitations include the non-interventional design and lack of
statistical power, and the investigational nature of SC rituximab. The
data collected did not account for patient and center characteristics
and variability on active HCP time.

CONCLUSIONS:
SC rituximab was associated with reduced active HCP time and costs
vs IV rituximab, as well as reduced patient time in the treatment
room. Switching from IV to SC rituximab could increase treatment
room capacity and patient throughput, as well as improving the
patient experience.
Comparison of IV and Subcutaneous Formulations of Rituximab
Advancement in IV
technology
Hassan Butt
(06331513023)
• A little more than a decade ago the introduction of
“smart” pumps with dose error-reduction systems (DERS)
dramatically improved the safety of intravenous (IV)
infusion therapy. Wireless connectivity enhanced system
management and laid the foundation for integrating
smart pumps with other systems and devices
From “Dumb” to “Smart” Pumps

• The first programmable IV infusion pumps came into use more than
40 years ago. Being able to program a specific rate and volume made
modern infusion therapy possible; but these “dumb” pumps could
accept any infusion rate from 0.1 to 999 mL/hr or higher.
Programming 54 instead of 5.4, 800 instead of 8, or entering the
volume as the rate could each deliver a fatal dose. Compared to
medications delivered via other routes, IV medication errors are twice
as likely to cause patient harm (Proceedings, 2008). For the next three
decades, the potential for pump mis-programming and other errors
remained a critical issue.
smart pumps have:
• Fostered development of drug dose limits.
• Promoted standardization of concentration and dosing units.
• Allowed hospitals to configure pumps to match applications.
• Provided a “treasure trove” of infusion data.
• Documented many “good catches” of prevented programming errors.
• Uncovered high degree of variation in infusion practices.
• Identified human factors issues/opportunities for manufacturers.
• Promoted wireless connectivity/server applications.
Available pumps have limitations such as the following:
• Typically not assigned to specific patients.
• Not aware of intended therapy.
• Cannot prevent drug mix-ups, incorrect library selection.
• Do not record caregiver or reason for alert overrides.
• Do not populate infusion records.
• Do not maximize value of BCMA.
• Do not overcome poor compliance with DERS use or rapid overrides of alerts.
• Do not communicate alarms, alerts, or status of infusions in near-real time.