- The document discusses nonlinear pharmacokinetics where parameters like clearance and volume of distribution change with dose. This occurs when transporters or enzymes involved in absorption, distribution, metabolism and excretion get saturated at high drug concentrations.
- The Michaelis-Menten equation is used to describe saturation kinetics and estimate parameters Km and Vmax. Various methods like Lineweaver-Burk, direct linear and graphical plots are presented to determine these values using in vivo or in vitro concentration and rate data.
- Estimation of Km and Vmax is also described at steady-state concentrations achieved after constant rate infusion or multiple dosing, through plots of steady-state concentration versus dosing rate.
PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies.
The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are
Model approach, and
Model-independent approach (also called as non-compartmental analysis).
PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies.
The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are
Model approach, and
Model-independent approach (also called as non-compartmental analysis).
This presentation will give the students a basic knowledge about the pharmacokinetics of durgs. It will help them clear the basics before digging deep into the topic.
This presentation will give the students a basic knowledge about the pharmacokinetics of durgs. It will help them clear the basics before digging deep into the topic.
ABSTRACT
The parenteral administration route is the most effective and common form of delivery for active drug substances with poor bioavailability and the drugs with a narrow therapeutic index. Drug delivery technology that can reduce the total number of injection throughout the drug therapy period will be truly advantageous not only in terms of compliance, but also to improve the quality of the therapy and also may reduce the dosage frequency. Such reduction in frequency of drug dosing is achieved by the use of specific formulation technologies that guarantee the release of the active drug substance in a slow and predictable manner. The development of new injectable drug delivery system has received considerable attention over the past few years. A number of technological advances have been made in the area of parenteral drug delivery leading to the development of sophisticated systems that allow drug targeting and the sustained or controlled release of parenteral medicines.
“It is a process by which a drug leaves a drug product
& is subjected to ADME & eventually becoming
available for pharmacological action.”
It involves the study of drug release rate, dissolution
/diffusion/erosion studies and the study of factors
affecting release rate of the drug.
Novel Drug Delivery System is to provide a therapeutic amount of drug to the appropriate site in the body to accomplish promptly and then maintain the desired drug concentration
The study of absorption, distibution,metabolism,excretio of drug and their relationship to pharmacological response. In simple word ; what the body dose to the drug. Linear pharmacokinetics.In the pharmacokinetic parameter for drug would not change when difference dose or multiple dose of drug is given. Non linear pharmcokinetics-if any deviation cause linear pharmacokinetics called non linear, mixed, capacity – limited kinetics.
Nomograms and tabulations in design of dosage regimens pavithra vinayak
Nomograms and tabulations in the design of dosage regimens --- NOMOGRAM IN UREMIC PATIENTS: NOMOGRAM FOR RELATIONSHIP BETWEEN CREATININE CLEARANCE AND ELIMINATION RATE CONSTANT FOR FOUR DRUGS clinical pharmacokinetics and therapeutic drug monitoring ---fifth PharmD notes
Drug distribution typically refers to the process of getting pharmaceutical products from manufacturers or wholesalers to pharmacies, hospitals, clinics,
Palestine last event orientationfvgnh .pptxRaedMohamed3
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The Art Pastor's Guide to Sabbath | Steve ThomasonSteve Thomason
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How to Split Bills in the Odoo 17 POS ModuleCeline George
Bills have a main role in point of sale procedure. It will help to track sales, handling payments and giving receipts to customers. Bill splitting also has an important role in POS. For example, If some friends come together for dinner and if they want to divide the bill then it is possible by POS bill splitting. This slide will show how to split bills in odoo 17 POS.
Synthetic Fiber Construction in lab .pptxPavel ( NSTU)
Synthetic fiber production is a fascinating and complex field that blends chemistry, engineering, and environmental science. By understanding these aspects, students can gain a comprehensive view of synthetic fiber production, its impact on society and the environment, and the potential for future innovations. Synthetic fibers play a crucial role in modern society, impacting various aspects of daily life, industry, and the environment. ynthetic fibers are integral to modern life, offering a range of benefits from cost-effectiveness and versatility to innovative applications and performance characteristics. While they pose environmental challenges, ongoing research and development aim to create more sustainable and eco-friendly alternatives. Understanding the importance of synthetic fibers helps in appreciating their role in the economy, industry, and daily life, while also emphasizing the need for sustainable practices and innovation.
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The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
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This is a presentation by Dada Robert in a Your Skill Boost masterclass organised by the Excellence Foundation for South Sudan (EFSS) on Saturday, the 25th and Sunday, the 26th of May 2024.
He discussed the concept of quality improvement, emphasizing its applicability to various aspects of life, including personal, project, and program improvements. He defined quality as doing the right thing at the right time in the right way to achieve the best possible results and discussed the concept of the "gap" between what we know and what we do, and how this gap represents the areas we need to improve. He explained the scientific approach to quality improvement, which involves systematic performance analysis, testing and learning, and implementing change ideas. He also highlighted the importance of client focus and a team approach to quality improvement.
5. #
» Dose independent paharmacokinetic
Pharmacokinetic paraméters dont change with increse or
decrease in dose
» In such situation the rate processes are follw first order or
linear kinetics and all semilog plots of C Vs t for different
doses are superimposable.
LINEAR PHARMACOKINETICS
6. #
NONLINEAR PHARMACOKINETICS
» Dose dependent paharmacokinetic
Pharmacokinetic paraméters change with increse or decrease
in dose
Pharmacokinetic paraméters(ADME ) are depend upon carrier
or enzymes that are substrate specific, have definite
capacities and are susceptible to saturation at a high drug
concentration.
» In such cases, first-order kinetics transform into a mixture of
first-order and zero-order rate processes
»
7. #
Linear Pharmacokinetics Non Linear
Pharmacokinetics
Pharmacokinetic parameters
for a drug would not change
with change in dose
Pharmacokinetic
parameters for a drug can
change with change in dose.
Dose Independent Dose dependent
First Order kinetics Also called as Mixed order,
Saturated kinetics, capacity
limited
All semilog plots of C vs t for
diff. doses are
superimposable.
Not superimposable
8. #
CAUSES OF NON-LINEARITY
• Three causes:-
• I) Solubility / dissolution of drug is rate-limited;
Griseofulvin - at high concentration in intestine.
II) Carrier - mediated transport system; Ascorbic
acid - saturation of transport system.
III) Presystemic gut wall / hepatic metabolism
attains saturation; Propranolol.
Drug absorption
9. #
At high doses non-linearity due to
• Two causes:-
• I) Binding sites on plasma proteins get
saturated; Phenylbutazone.
• II) Tissue binding sites get saturated.
• In both cases there is increase in plasma drug
concentration.
.
Drug distribution
10. #
• Non-linearity occurs due to capacity limited metabolism, small
changes in dose administration - large variations in plasma
concentration at steady state.
• Two imp causes:-
• I) Capacity - limited metabolism - enzyme &/
cofactor saturation; Phenytoin, Alcohol.
• II) Enzyme induction - decrease in plasma
concentration; Carbamazepine.
Drug metabolism
11. #
Drug excretion
• Two active processes which are saturable,
I) Active tubular secretion - Penicillin G
II) Active tubular reabsorption - Water soluble
vitamins & Glucose.
• Saturation of carrier systems - decrease in renal clearance
& increase in Half life.
• Other reasons like forced diuresis, change in urine pH,
nephrotoxicity & saturation of binding sites.
• In case of biliary excretion non - linearity due to saturation -
Tetracycline & Indomethacin.
12. #
Drugs that demonstrate saturation kinetics
usually show the following characteristics:
1. Elimination of drug does not follow simple first-order kinetics—
that is, elimination kinetics are nonlinear.
2. The elimination half-life changes as dose is increased. Usually,
the elimination half-life increases with increased dose due to
saturation of an enzyme system.
13. #
3. The area under the curve (AUC) is not proportional to
the amount of bioavailable drug.
4. The saturation of capacity-limited processes may be
affected by other drugs that require the same
enzyme or carrier-mediated system
(ie,competition effects).
14. #
Saturable Enzymatic Elimination
Processes
• Michaelis–Menten kinetics:
dCp/dt = rate of decline of drug concentration with time.
Vmax = theoretical maximum rate of the process.
Km = Michaelis constant.
15. #
C p
>> K m
C p
= K m
C p
<< K m
• saturation of the
enzymes occurs.
•The value for K M
is negligible.
•The rate of
elimination
proceeds at a
constant rate
•Rate of process is
= one half of its
max. rate
• -dc/dt = Vmax/2
•rate of drug
elimination becomes
a first-order process
16. #
Drug Elimination by CapacityLimitedPharmacokinetics:
One-Compartment Model, IV Bolus Injection:
• If a single IV bolus injection of drug (D 0
) is
given at t = 0, the drug concentration (C p
) in
the plasma at any time t may be calculated by
an integrating equation,
17. #
• Amount of drug in the body after IV Bolus ,
• Where, D 0
is the amount of drug in the body at
t = 0.
• To calculate time for dose in the boy
• Rearranging equation:
19. #
ESTIMATION OF Vmax & Km
In enzymatic kinetic work, the classic Michaelis-Menten
equation:
Vmax . C ………..(1)
KM + C
where, V= reaction rate,
C= substrate conc. both are
used to determine Vmax
& Km.
The velocity of the reaction(V) at various concentration levels of
drug(C) are determined either by in-vitro experiments or in-vivo
experiments at constant enzyme levels.
V =
20. #
Method 1
By inverting equation (1), we get :
1 Km . 1 1 ……..(2)
V Vmax . C Vmax
When 1/V is plotted against 1/C, a straight line is
obtained with a slope of Km/Vmax and an Intercept of
1/Vmax.
= +
21. #
Figure 2
Plot of 1/V vs 1/C for determining Km & Vmax
-1/ Km
Km/Vmax
1/ Vmax
22. #
Multiplying eq. 2 by C, we get :
C Km C
= + ………..... (3)
V Vmax Vmax
A plot of C /V vs C gives a straight line with 1 / Vmax as the slope and
Km / Vmax as the intercept (shown in the fig. 3).
Method 2
24. #
The equation can also be written
as :
V = - Km V + Vmax …………(4)
C
A plot of V vs V / C gives a straight line with a slope of –Km & an Intercept
of Vmax. (shown in the fig. 4)
Method 3
26. #
CALCULATION OF KM & VMAX
STEADY- STATE CONCENTRATION
• If drug is administered for constant rate IV infusion/ in a multiple
dosage regimen, the steady-state conc. is given in terms of
dosing rate (DR):
DR = Css
• If the steady-state is reached, then the dosing rate = the rate of
decline in plasma drug conc. & if the decline occurs due to a
single capacity-limited process then eq. I become as:
• From a plot of Css vs. DR, a typical curve having a shape of
hocky-stick is obtained which is shown in fig. 5.
……………….. (1)
=
Vmax Css
KM+ Css
DR ……………….. (2)
27. #
Css
Km
Vmax / 2 Vmax
DR (in mg/hr or mg/day )
Curve for a drug following nonlinear kinetics
By plotting the steady-state concentration against dosing rates
Figure 5
29. #
• There are three methods which are used to define the KM
& Vmax at steady-state with appreciable accuracy:
1) Lineweaver-Burk Plot:- the reciprocal of eq. (2) we get
• If 1/DR is plotted against 1/Css a straight line is obtained
having slope KM/Vmax & y-intercept 1/Vmax.
2) Direct linear plot:-
• Plotting a pair of Css, i.e.Css1,&Css2 against corresponding
dosing rates DR1 & DR2 we get following fig. 6 which
gives values KM &Vmax
1
DR
=
KM
Vmax Css
1
Vmax
+ ……………….. (3)
30. #
Css
Css 1 Css 2
0 KM
KM
DR
DR1
DR2
Vmax
Direct linear plot for estimation of KM & Vmax
at steady-state conc. Of a drug, when it is
administered at different dosing rates
Figure 6
31. #
3) Graphical method:-
• In this method by rearranging eq. (2) we get
• In graph DR is plotted against DR/Css, a straight line is
obtained with slope –KM & y - intercept Vmax.
• KM & Vmax can be estimated by simultaneous eq. as
DR
DR
Css
KM
= Vmax
……………….. (4)
=DR1
=DR2
……………….. (6)
…………….…...(5)
-
Vmax
Vmax
-
-
KM
KM
DR1
DR2
Css1
Css2
32. #
• On solving above eq. 5 & 6 we get,
• By substituting values of DR1, DR2, Css1 & Css2 we get value of
KM & from KM we can found value of Vmax at steady-state
concentration.
• From experimental observations, it shows that KM is much
less variable than Vmax.
KM =
DR2- DR1
Css 1 Css 2
DR1 DR2
-
……………….. (7)
DR
3) Graphical method:-
