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APPLICATIONS OF PHARMACOKINETICS IN 
NEW DRUG DEVELOPMENT,DOSAGE FORM 
DESIGN & NDDS 
PRESENTATION BY 
ROJA THOGUTA 
ROLL NO: 256212886025 
1
CONTENTS 
 Introduction 
 New drug development Pharmacokinetic principles 
 Novel drug delivery system 
 Pharmacokinetic applications 
 Pharmacokinetic parameters 
 Pharmacokinetic characterization 
 Dosage form design 
 Conclusion 
 References 
2
INTRODUCTION 
 Drug research encompasses several diverse disciplines united by a 
common goal, namely the development of novel therapeutic agents. 
 The search for new drugs can be divided functionally into two 
stages: discovery and development. 
 The former consists of setting up a working hypothesis of the target 
enzyme or receptor for a particular disease, establishing suitable 
models (or surrogate markers) to test biological activities, and 
screening the new drug molecules for in vitro and/or in vivo 
biological activities. 
 In the development stage, efforts are focused on evaluation of the 
toxicity and efficacy of new drug candidates. 3
PHARMACOKINETICS 
 Study and characterization of the time course of drug absorption, 
distribution, metabolism and excretion, and relationship of these 
processes to the intensity and time course of therapeutic and 
toxicology effects of drug. 
 It describes the process where by a specific mode and by a specific 
dose is handled by the body, leading to the specific drug 
concentrations in different tissues/organs. 
 Part of drug will reach the site(s) of action and exerts its pharmaco 
dynamic action. 
 Another way it can be said as what body does to drug. 
Pharmacokinetics is used in the clinical setting to enhance safe and 
effective therapeutic management of the individual patient. This 
application is termed as Clinical pharmacokinetics. 
4
PRINCIPLES: 
 Design and development of new drugs for improving therapeutic 
effectiveness. 
 Design and development of an optimum formulation for better use of the 
drug. 
 Design and development of controlled/targeted release formulation. 
 Select the appropriate route for drug administration. 
 Select the right drug for a particular illness. 
5
 Predict and explain drug-food and drug-drug interactions. 
 Design an appropriate multiple dosage regimen. 
 Therapeutic drug monitoring in individual patients. 
 Dosage adjustments in situations of altered physiology and drug 
interactions. 
6
APPLICATIONS OF PHARMACOKINETICS 
 Drug Development 
 Formulation Development 
 Deciding Dosage Regimen 
 Designing Rational Dose, Frequency and Duration 
 Rational Drug Design (QSPKR) 
 Clinical Pharmacy 
 ADME study, Bioavailability and Bioequivalence studies 
 In Vitro –In Vivo correlation studies 
 Pharmacokinetics, Pharmacodynamics Relationship 
7
PHARMACOKINETIC PARAMETERS 
 Overall first order elimination rate constant(K) 
 Half life(t1/2) 
 Clearance (Total. Renal, Hepatic etc.(Cl) 
 Effective concentration range 
 Absorption rate constant(Ka) 
 Extent of bioavailability(F) 
α) 
 Fraction of dose excreted unchanged in urine (Xu 
 Blood -Plasma concentration ratio 
 Apparent volume of distribution (Vd) 
 Fraction of protein binding(Fb) 
 Peak concentration(Cp) 
 Time to reach peak concentration(tp) 
 Toxic concentrations 
8
APPROACHES FOR DESIGN OF SAFER DRUGS 
 From toxicological and pharmacological points of view, it is desirable to 
design a “safer” drug that undergoes no metabolism. 
 Hard drugs: The concept of nonmetabolisable drugs called hard drugs. 
Drugs are excreted primarily through either bile or kidney. 
Eg: Bisphosphonates, enalaprilat, lisinopril 
 Soft drugs: It is pharmacologically active, it undergoes a predictable and 
controllable metabolism to nontoxic and inactive metabolites. 
 The main concept is to avoid oxidative metabolism as much as possible 
and to use hydrolytic enzymes to achieve predictable and controllable 
drug metabolism. Eg: Atracurium, Remifentanil etc. 
 Active metabolites: The metabolites of some drugs are pharmacologically 
active being used as a source of new drug candidates. Eg: Acetaminophen 
which is an O-deethylated metabolite of Phenacetin. 9
ADME CHARACTERS 
 Absorption: It is a process in which the unchanged proceeds from 
site of administration to the site of measurement with in the body. 
Eg Bisphosphonates 
 Distribution: The transfer of drug from blood to the extravascular 
fluids (i.e extracellular and intra cellular water) and tissues. It is a 
rapid and reversible process. 
 Metabolism: it is the biochemical conversion of drug into another 
chemical form. 
 Elimination: It is the irreversible loss of drug from the site of 
measurement. 
 Excretion: It is the irreversible loss of chemically unchanged drug by 
various routes. This can occur through urine, biliary secretion, saliva. 
sweat, milk, respiratory route. 
10
PHARMACOKINETIC CHARACTERIZATION OF THE DRUG FOR 
SELECTION OF SUITABLE DELIVERY SYSTEMS 
 Compartment model 
 Elimination rate constant and terminal half life (t1/2 ) 
 Area under the concentration-time curve (AUC) 
 Total clearance (ClT) 
 Apparent volume of distribution (Vd ) 
 Mean steady state concentration (CSS ) 
 Mean residence time 
 First-pass effect 
 Intrinsic absorption rate constant 
 Relative areas 
 Dosage form index 11
DESIGN OF CONTROLLED RELEASE FORMULATION 
 CT is the target concentration to be maintained for T hour. 
 Rate of elimination = K.CT.Vd or CT.Vd 
1/2 
 Where K is the eliminnation rate constant of the drug. 
 V is the apparent volume of distribution. 
 Rate of absorption, Ka Xa should be equal to the rate of elimination to 
maintain constant concentration. So , 
Ka Xa = K. CT Vd 
 Then rate of release should be equal to the rate of absorption and rate 
of elimination. So, 
Rate of release, Kr = K. CT Vd 12
So, 
Maintainence dose = rate of release x duration to be maintained 
= K. CT Vd T 
tmax = Log Ka 
K 
Where Ka is absorption rate constant 
Loading dose = CT Vd e-Ktmax 
F 
 Where F is bioavailability (fraction) 
 Above is on the basis that drug confers one compartment distribution 
13 
a
 Equation to express plasma concentration of controlled release 
product administered 
C = K0 (e-KT -1) e-Kt 
K Vd 
 Where K0 is zero order release rate 
 ‘T’ is time of total release 
 ‘t’ is anytime at which concentration is measured 
 ‘t’ can be less than or equal or more than ‘T’ 
14
APPLICATIONS OF PHARMACOKINETICS IN NDDS 
 To understand the process of absorption, distribution, elimination of 
drug, which affects onset and intensity of biological response. 
 To access plasma drug concentration response to given dose which is 
considered as more appropriate parameter than intrinsic pharmacological 
activity. 
 In design and utilization of In-vitro model that can evaluate dissolution 
characteristics of new compound formulated as new drug formulations 
and establish meaningful IVIVC. 
 In design and development of new drug and their appropriate dosage 
regimen. 
 In safe and effective management of patients by improving drug therapy. 15
 To understand the concept of bioavailability which has been used to 
evaluate and monitor in vivo performance of new dosage forms and 
generic formulations. 
 To carry out the bioavailability and bioequivalence tests. 
 We can use the pharmacokinetic principles in the development of the 
various NDDS. 
Eg: The drug with short half life about 2-6 hrs can be formulated as 
controlled release drugs by using polymers. 
The lower bioavailability of the drugs can be increased by using 
several components like ß-cyclodextrin. 
 List of drug carriers in NDDS: 
Nanosomes, Liposomes, Niosomes, Proniosomes, Vesicular drug 
delivery system, Cubisomes, Aquasomes, Pharmacosomes, Miscelles, 
Nanoparticles, Nanosphere, Microsphere, Microparticle, Dendrimer, 
Microemulsion, Transferosomes, Nanosuspension, Dendrosomes etc.16
DESIGN OF DOSAGE REGIMENS 
 Dosage regimen is defined as the manner in which a drug is taken. 
 An optimal multiple dosage regimen is the one in which the drug is 
administered in suitable doses (by a suitable route), with sufficient 
frequency that ensures maintenance of plasma concentration within 
the therapeutic window(without excessive fluctuations and drug 
accumulation) for the entire duration of therapy. 
17
APPROACHES TO DESIGN OF DOSAGE REGIMEN 
1.Empirical Dosage Regimen: It is designed by physician based on 
empirical clinical data, personal experience and clinical observations. 
2.Individualised Dosage Regimen: it is based on the pharmacokinetics 
of drug in the individual patient. 
Suitable for hospitalised patients. 
3.Dosage Regimen on population Averages: It is based on one of the 
two models-i) 
Fixed model: Population average pharmacokinetic parameters are used 
directly to calculate the dosage regimen. 
ii)Adaptive model: Based on both population average pharmacokinetic 
parameters of the drug as well as patient variables such as weight, 18
age, sex, body surface area and known patient pathophysiology such as 
renal disease. 
 DOSE SIZE: 
 The magnitude of both therapeutic and toxic responses depends on dose 
size. 
 Dose size calculation also requires knowledge of amount of drug 
absorbed after administration of each dose. 
 Greater the dose size, greater the fluctuations between Css,max and 
Css,min during each dosing interval,greater chances of toxicity. 
Plasma 
conc. 
19
DOSING FREQUENCY: 
 The dosing interval (inverse of dosing frequency) is calculated on the 
basis of half life of the drug. 
 If the interval is increased and the dose is unchanged, Cmax, Cmin & 
Cav decrease but the ratio Cmax/Cmin increases. 
 Opposite is observed when dosing interval is reduced or dosing 
frequency increased. 
Plasma 
conc. 
20
MONITORING DRUG THERAPY 
 Depending upon the drug and the disease to be treated, management of 
drug therapy in individual patient can be accomplished by: 
 Monitoring therapeutic effect-therapeutic monitoring 
 Monitoring pharmacologic actions- pharmacodynamic monitoring . 
 Monitoring plasma drug concentration - pharmacokinetic monitoring. 
21
PHARMACOKINETICS OF DRUG INTERACTIONS 
 Bioavailability 
Complexation / chelation: Calcium, magnesium, or aluminum and 
iron salts with tetracycline complexes with divalent cations, causing 
a decreased bioavailability. 
 Distribution 
Protein binding of Warfarin – phenylbutazone leads to displacement 
of warfarin from binding. 
22
INDIVIDUALIZATION OF DRUG DOSAGE 
REGIMENS: 
 Therapeutic Drug Monitoring: 
In administering potent drugs to patients, the physician must 
maintain the plasma drug level within a narrow range of therapeutic 
concentrations. 
The functions of a TDM service are listed below: 
 Select drug. 
 Design dosage regimen. 
 Evaluate patient response. 
 Determine need for measuring serum drug concentrations. 
 Assay for drug concentration in biological fluids. 
 Perform pharmacokinetic evaluation of drug concentrations. 
 Readjust dosage regimen, if necessary. 
 Monitor serum drug concentrations. 
23
 Drug Selection: 
 The choice of drug and drug therapy is usually made by the physician. 
 Pharmacokinetics and pharmacodynamics are part of the overall 
considerations in the selection of a drug for inclusion into the drug 
formulary (DF). 
 Drugs with similar therapeutic indications may differ in dose and 
pharmacokinetics. 
 Dosage Regimen Design: 
 The overall objective of dosage regimen design is to achieve a target 
drug concentration at the receptor site. 
 The usual pharmacokinetics of the drug—including its absorption, 
distribution, and elimination profile—are considered in the patient. 
 Pathophysiologic conditions, such as renal dysfunction, hepatic disease, 
or congestive heart failure, may change the normal pharmacokinetic 
24 
profile of the drug, and the dose must be carefully adjusted.
 Drug Dosage Form (Drug Product): 
 Affect drug bioavailability. 
 The rate of absorption. 
 The route of drug administration and the desired onset will affect the 
choice of drug dosage form. 
 Patient Compliance: 
 Cost of the medication. 
 Complicated instructions. 
 Multiple daily doses. 
 Difficulty in swallowing. 
 Adverse drug reactions. 
 Evaluation of Patient's Response: 
 Practitioner should evaluate the patient's response clinically. 
 If the patient is not responding to drug therapy as expected, then the 
drug and dosage regimen should be reviewed. 25
 Measurement of Serum Drug Concentrations: 
 A major assumption made by the practitioner is that serum drug 
concentrations relate to the therapeutic and/or toxic effects of the 
drug. 
 A single blood sample gives insufficient information. Several blood 
samples are often needed to clarify the adequacy of the dosage 
regimen. 
 The pharmacokineticist should be aware of the usual therapeutic 
range of serum concentrations from the literature. 
 Dosage Adjustment: 
 The new dosage regimen should be calculated using the 
26 
pharmacokinetic parameters derived from the patient's serum drug 
concentrations.
DOSING OF DRUG IN OBESE PATIENTS 
 Ideal body weight (IBW) is calculated as follows: 
IBW Men= 50 kg ± 1 kg /2.5 cm above or below 150cm in 
height … [1] 
IBW Women= 45 kg ± 1 kg/2.5 cm above or below 150cm in 
height…[2] 
Any person is considered as obese if the body weight is more 
than 25% above the IBW. 
27
DOSAGE CALCULATION IN NEONATES INFANTS AND 
CHILDREN: 
Formula: 
 Young’s rule (For children 2 years and above ): 
( Age (yr) ) × adult dose 
Age (yr)+12 
 Clark’s rule: 
( Weight (lb) ) × Adult dose 
150 
 Fried’s rule (For infants upto 2 years old): 
( Age (month) ) × adult dose 
150 
 Square meter surface area OR Mosteller’s equation 
SA in m2 = ( height × weight ) ½ 
60 28
 The child’s maintenance dose can be calculated from adult dose by 
using the following equation : 
Child’s Dose = SA of Child in m2 × Adult dose 
1.73 
Where 1.73 is surface area in m2 of an average 70 Kg adult . 
 Since the surface area of a child is in proportion to the body weight 
according to equation, 
SA ( in m2 ) = Body weight (in Kg )0.7 
 The following relationship can also be written for child’s dose : 
Child’s Dose = [Weight of child in Kg ] 0.7 × Adult dose 
70 
29
DOSING OF DRUG IN ELDERLY 
 A general equation that allows calculation of maintenance dose for a 
patient of any age (except neonates and infants ) when maintenance of 
same Css,av is desired is : 
 Patient’s Dose : 
= (weight in Kg )0.7 (140 - Age in years) × Adult dose 
1660 
DOSING OF DRUG IN HEPATIC DISEASE 
 The influence of hepatic disorder on drug availability and disposition 
in unpredictable as of the multiple effect that liver disease produce 
effects on the drug metabolizing enzyme, binding and hepatic blood 
flow. 
30
DOSING OF DRUGS IN RENAL DISEASE 
Dose adjustment based on total body clearance : 
The parameters to be adjusted in renal Insufficiency are shown below: 
Css,av = F × 1 × ( X0 ) 
ClT 
τ 
To be kept assumed decrease needs 
Normal constant due to disease adjustment 
31
CONCLUSION 
 It is very important to have complete knowledge of pharmacokinetic 
characters of drug and factors effecting them for designing an effective 
and useful drug delivery systems. 
 Pharmacokinetic study is also important to identify variables that are 
important in determining the potential success of drug delivery systems 
 It can be used to evaluate the products or delivery systems. 
 Selection/design of proper experimental protocol is very important. 
Suitable analytical method is necessary for proper estimation. 
 Iv-Iv correlation and PK /PD relationship are useful for better design. 
32
REFERENCES 
 Biopharmaceutics & Pharmacokinetics a Treatise 
D.M. Brahmankar & Sunil b. Jaiswal,Vallabh Prakashan Pitampura, 
Delhi. 
 Biopharmaceutics & clinical pharmacokinetics by Milo Gilbaldi 4th 
edition , Philadelphia lea & Febiger 1991. 
 Text book of Biopharmaceutics & pharmacokinetics by Dr.shobha 
rani R.Hiremath, prism books Pvt Ltd, 
bangalore,2002 
 Application of drug metabolism and pharmacokinetics in new drug 
development by yoon Gyoon Kim1 and KeonWook Kang 
 Role of metabolism and pharmacokinetics in drug discovery and 
development by Jiunn.H Lin Fna and Anthony Y.H.Lu. 
 Novel drug delivery systems, Ed.Y.W. Chien, Marcel Dekker Inc; 
USA 2nd edition 1992. 33
34 
Thank 
you…

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Applications of pharmacokinetics in new drug development,dosage form design & ndds

  • 1. APPLICATIONS OF PHARMACOKINETICS IN NEW DRUG DEVELOPMENT,DOSAGE FORM DESIGN & NDDS PRESENTATION BY ROJA THOGUTA ROLL NO: 256212886025 1
  • 2. CONTENTS  Introduction  New drug development Pharmacokinetic principles  Novel drug delivery system  Pharmacokinetic applications  Pharmacokinetic parameters  Pharmacokinetic characterization  Dosage form design  Conclusion  References 2
  • 3. INTRODUCTION  Drug research encompasses several diverse disciplines united by a common goal, namely the development of novel therapeutic agents.  The search for new drugs can be divided functionally into two stages: discovery and development.  The former consists of setting up a working hypothesis of the target enzyme or receptor for a particular disease, establishing suitable models (or surrogate markers) to test biological activities, and screening the new drug molecules for in vitro and/or in vivo biological activities.  In the development stage, efforts are focused on evaluation of the toxicity and efficacy of new drug candidates. 3
  • 4. PHARMACOKINETICS  Study and characterization of the time course of drug absorption, distribution, metabolism and excretion, and relationship of these processes to the intensity and time course of therapeutic and toxicology effects of drug.  It describes the process where by a specific mode and by a specific dose is handled by the body, leading to the specific drug concentrations in different tissues/organs.  Part of drug will reach the site(s) of action and exerts its pharmaco dynamic action.  Another way it can be said as what body does to drug. Pharmacokinetics is used in the clinical setting to enhance safe and effective therapeutic management of the individual patient. This application is termed as Clinical pharmacokinetics. 4
  • 5. PRINCIPLES:  Design and development of new drugs for improving therapeutic effectiveness.  Design and development of an optimum formulation for better use of the drug.  Design and development of controlled/targeted release formulation.  Select the appropriate route for drug administration.  Select the right drug for a particular illness. 5
  • 6.  Predict and explain drug-food and drug-drug interactions.  Design an appropriate multiple dosage regimen.  Therapeutic drug monitoring in individual patients.  Dosage adjustments in situations of altered physiology and drug interactions. 6
  • 7. APPLICATIONS OF PHARMACOKINETICS  Drug Development  Formulation Development  Deciding Dosage Regimen  Designing Rational Dose, Frequency and Duration  Rational Drug Design (QSPKR)  Clinical Pharmacy  ADME study, Bioavailability and Bioequivalence studies  In Vitro –In Vivo correlation studies  Pharmacokinetics, Pharmacodynamics Relationship 7
  • 8. PHARMACOKINETIC PARAMETERS  Overall first order elimination rate constant(K)  Half life(t1/2)  Clearance (Total. Renal, Hepatic etc.(Cl)  Effective concentration range  Absorption rate constant(Ka)  Extent of bioavailability(F) α)  Fraction of dose excreted unchanged in urine (Xu  Blood -Plasma concentration ratio  Apparent volume of distribution (Vd)  Fraction of protein binding(Fb)  Peak concentration(Cp)  Time to reach peak concentration(tp)  Toxic concentrations 8
  • 9. APPROACHES FOR DESIGN OF SAFER DRUGS  From toxicological and pharmacological points of view, it is desirable to design a “safer” drug that undergoes no metabolism.  Hard drugs: The concept of nonmetabolisable drugs called hard drugs. Drugs are excreted primarily through either bile or kidney. Eg: Bisphosphonates, enalaprilat, lisinopril  Soft drugs: It is pharmacologically active, it undergoes a predictable and controllable metabolism to nontoxic and inactive metabolites.  The main concept is to avoid oxidative metabolism as much as possible and to use hydrolytic enzymes to achieve predictable and controllable drug metabolism. Eg: Atracurium, Remifentanil etc.  Active metabolites: The metabolites of some drugs are pharmacologically active being used as a source of new drug candidates. Eg: Acetaminophen which is an O-deethylated metabolite of Phenacetin. 9
  • 10. ADME CHARACTERS  Absorption: It is a process in which the unchanged proceeds from site of administration to the site of measurement with in the body. Eg Bisphosphonates  Distribution: The transfer of drug from blood to the extravascular fluids (i.e extracellular and intra cellular water) and tissues. It is a rapid and reversible process.  Metabolism: it is the biochemical conversion of drug into another chemical form.  Elimination: It is the irreversible loss of drug from the site of measurement.  Excretion: It is the irreversible loss of chemically unchanged drug by various routes. This can occur through urine, biliary secretion, saliva. sweat, milk, respiratory route. 10
  • 11. PHARMACOKINETIC CHARACTERIZATION OF THE DRUG FOR SELECTION OF SUITABLE DELIVERY SYSTEMS  Compartment model  Elimination rate constant and terminal half life (t1/2 )  Area under the concentration-time curve (AUC)  Total clearance (ClT)  Apparent volume of distribution (Vd )  Mean steady state concentration (CSS )  Mean residence time  First-pass effect  Intrinsic absorption rate constant  Relative areas  Dosage form index 11
  • 12. DESIGN OF CONTROLLED RELEASE FORMULATION  CT is the target concentration to be maintained for T hour.  Rate of elimination = K.CT.Vd or CT.Vd 1/2  Where K is the eliminnation rate constant of the drug.  V is the apparent volume of distribution.  Rate of absorption, Ka Xa should be equal to the rate of elimination to maintain constant concentration. So , Ka Xa = K. CT Vd  Then rate of release should be equal to the rate of absorption and rate of elimination. So, Rate of release, Kr = K. CT Vd 12
  • 13. So, Maintainence dose = rate of release x duration to be maintained = K. CT Vd T tmax = Log Ka K Where Ka is absorption rate constant Loading dose = CT Vd e-Ktmax F  Where F is bioavailability (fraction)  Above is on the basis that drug confers one compartment distribution 13 a
  • 14.  Equation to express plasma concentration of controlled release product administered C = K0 (e-KT -1) e-Kt K Vd  Where K0 is zero order release rate  ‘T’ is time of total release  ‘t’ is anytime at which concentration is measured  ‘t’ can be less than or equal or more than ‘T’ 14
  • 15. APPLICATIONS OF PHARMACOKINETICS IN NDDS  To understand the process of absorption, distribution, elimination of drug, which affects onset and intensity of biological response.  To access plasma drug concentration response to given dose which is considered as more appropriate parameter than intrinsic pharmacological activity.  In design and utilization of In-vitro model that can evaluate dissolution characteristics of new compound formulated as new drug formulations and establish meaningful IVIVC.  In design and development of new drug and their appropriate dosage regimen.  In safe and effective management of patients by improving drug therapy. 15
  • 16.  To understand the concept of bioavailability which has been used to evaluate and monitor in vivo performance of new dosage forms and generic formulations.  To carry out the bioavailability and bioequivalence tests.  We can use the pharmacokinetic principles in the development of the various NDDS. Eg: The drug with short half life about 2-6 hrs can be formulated as controlled release drugs by using polymers. The lower bioavailability of the drugs can be increased by using several components like ß-cyclodextrin.  List of drug carriers in NDDS: Nanosomes, Liposomes, Niosomes, Proniosomes, Vesicular drug delivery system, Cubisomes, Aquasomes, Pharmacosomes, Miscelles, Nanoparticles, Nanosphere, Microsphere, Microparticle, Dendrimer, Microemulsion, Transferosomes, Nanosuspension, Dendrosomes etc.16
  • 17. DESIGN OF DOSAGE REGIMENS  Dosage regimen is defined as the manner in which a drug is taken.  An optimal multiple dosage regimen is the one in which the drug is administered in suitable doses (by a suitable route), with sufficient frequency that ensures maintenance of plasma concentration within the therapeutic window(without excessive fluctuations and drug accumulation) for the entire duration of therapy. 17
  • 18. APPROACHES TO DESIGN OF DOSAGE REGIMEN 1.Empirical Dosage Regimen: It is designed by physician based on empirical clinical data, personal experience and clinical observations. 2.Individualised Dosage Regimen: it is based on the pharmacokinetics of drug in the individual patient. Suitable for hospitalised patients. 3.Dosage Regimen on population Averages: It is based on one of the two models-i) Fixed model: Population average pharmacokinetic parameters are used directly to calculate the dosage regimen. ii)Adaptive model: Based on both population average pharmacokinetic parameters of the drug as well as patient variables such as weight, 18
  • 19. age, sex, body surface area and known patient pathophysiology such as renal disease.  DOSE SIZE:  The magnitude of both therapeutic and toxic responses depends on dose size.  Dose size calculation also requires knowledge of amount of drug absorbed after administration of each dose.  Greater the dose size, greater the fluctuations between Css,max and Css,min during each dosing interval,greater chances of toxicity. Plasma conc. 19
  • 20. DOSING FREQUENCY:  The dosing interval (inverse of dosing frequency) is calculated on the basis of half life of the drug.  If the interval is increased and the dose is unchanged, Cmax, Cmin & Cav decrease but the ratio Cmax/Cmin increases.  Opposite is observed when dosing interval is reduced or dosing frequency increased. Plasma conc. 20
  • 21. MONITORING DRUG THERAPY  Depending upon the drug and the disease to be treated, management of drug therapy in individual patient can be accomplished by:  Monitoring therapeutic effect-therapeutic monitoring  Monitoring pharmacologic actions- pharmacodynamic monitoring .  Monitoring plasma drug concentration - pharmacokinetic monitoring. 21
  • 22. PHARMACOKINETICS OF DRUG INTERACTIONS  Bioavailability Complexation / chelation: Calcium, magnesium, or aluminum and iron salts with tetracycline complexes with divalent cations, causing a decreased bioavailability.  Distribution Protein binding of Warfarin – phenylbutazone leads to displacement of warfarin from binding. 22
  • 23. INDIVIDUALIZATION OF DRUG DOSAGE REGIMENS:  Therapeutic Drug Monitoring: In administering potent drugs to patients, the physician must maintain the plasma drug level within a narrow range of therapeutic concentrations. The functions of a TDM service are listed below:  Select drug.  Design dosage regimen.  Evaluate patient response.  Determine need for measuring serum drug concentrations.  Assay for drug concentration in biological fluids.  Perform pharmacokinetic evaluation of drug concentrations.  Readjust dosage regimen, if necessary.  Monitor serum drug concentrations. 23
  • 24.  Drug Selection:  The choice of drug and drug therapy is usually made by the physician.  Pharmacokinetics and pharmacodynamics are part of the overall considerations in the selection of a drug for inclusion into the drug formulary (DF).  Drugs with similar therapeutic indications may differ in dose and pharmacokinetics.  Dosage Regimen Design:  The overall objective of dosage regimen design is to achieve a target drug concentration at the receptor site.  The usual pharmacokinetics of the drug—including its absorption, distribution, and elimination profile—are considered in the patient.  Pathophysiologic conditions, such as renal dysfunction, hepatic disease, or congestive heart failure, may change the normal pharmacokinetic 24 profile of the drug, and the dose must be carefully adjusted.
  • 25.  Drug Dosage Form (Drug Product):  Affect drug bioavailability.  The rate of absorption.  The route of drug administration and the desired onset will affect the choice of drug dosage form.  Patient Compliance:  Cost of the medication.  Complicated instructions.  Multiple daily doses.  Difficulty in swallowing.  Adverse drug reactions.  Evaluation of Patient's Response:  Practitioner should evaluate the patient's response clinically.  If the patient is not responding to drug therapy as expected, then the drug and dosage regimen should be reviewed. 25
  • 26.  Measurement of Serum Drug Concentrations:  A major assumption made by the practitioner is that serum drug concentrations relate to the therapeutic and/or toxic effects of the drug.  A single blood sample gives insufficient information. Several blood samples are often needed to clarify the adequacy of the dosage regimen.  The pharmacokineticist should be aware of the usual therapeutic range of serum concentrations from the literature.  Dosage Adjustment:  The new dosage regimen should be calculated using the 26 pharmacokinetic parameters derived from the patient's serum drug concentrations.
  • 27. DOSING OF DRUG IN OBESE PATIENTS  Ideal body weight (IBW) is calculated as follows: IBW Men= 50 kg ± 1 kg /2.5 cm above or below 150cm in height … [1] IBW Women= 45 kg ± 1 kg/2.5 cm above or below 150cm in height…[2] Any person is considered as obese if the body weight is more than 25% above the IBW. 27
  • 28. DOSAGE CALCULATION IN NEONATES INFANTS AND CHILDREN: Formula:  Young’s rule (For children 2 years and above ): ( Age (yr) ) × adult dose Age (yr)+12  Clark’s rule: ( Weight (lb) ) × Adult dose 150  Fried’s rule (For infants upto 2 years old): ( Age (month) ) × adult dose 150  Square meter surface area OR Mosteller’s equation SA in m2 = ( height × weight ) ½ 60 28
  • 29.  The child’s maintenance dose can be calculated from adult dose by using the following equation : Child’s Dose = SA of Child in m2 × Adult dose 1.73 Where 1.73 is surface area in m2 of an average 70 Kg adult .  Since the surface area of a child is in proportion to the body weight according to equation, SA ( in m2 ) = Body weight (in Kg )0.7  The following relationship can also be written for child’s dose : Child’s Dose = [Weight of child in Kg ] 0.7 × Adult dose 70 29
  • 30. DOSING OF DRUG IN ELDERLY  A general equation that allows calculation of maintenance dose for a patient of any age (except neonates and infants ) when maintenance of same Css,av is desired is :  Patient’s Dose : = (weight in Kg )0.7 (140 - Age in years) × Adult dose 1660 DOSING OF DRUG IN HEPATIC DISEASE  The influence of hepatic disorder on drug availability and disposition in unpredictable as of the multiple effect that liver disease produce effects on the drug metabolizing enzyme, binding and hepatic blood flow. 30
  • 31. DOSING OF DRUGS IN RENAL DISEASE Dose adjustment based on total body clearance : The parameters to be adjusted in renal Insufficiency are shown below: Css,av = F × 1 × ( X0 ) ClT τ To be kept assumed decrease needs Normal constant due to disease adjustment 31
  • 32. CONCLUSION  It is very important to have complete knowledge of pharmacokinetic characters of drug and factors effecting them for designing an effective and useful drug delivery systems.  Pharmacokinetic study is also important to identify variables that are important in determining the potential success of drug delivery systems  It can be used to evaluate the products or delivery systems.  Selection/design of proper experimental protocol is very important. Suitable analytical method is necessary for proper estimation.  Iv-Iv correlation and PK /PD relationship are useful for better design. 32
  • 33. REFERENCES  Biopharmaceutics & Pharmacokinetics a Treatise D.M. Brahmankar & Sunil b. Jaiswal,Vallabh Prakashan Pitampura, Delhi.  Biopharmaceutics & clinical pharmacokinetics by Milo Gilbaldi 4th edition , Philadelphia lea & Febiger 1991.  Text book of Biopharmaceutics & pharmacokinetics by Dr.shobha rani R.Hiremath, prism books Pvt Ltd, bangalore,2002  Application of drug metabolism and pharmacokinetics in new drug development by yoon Gyoon Kim1 and KeonWook Kang  Role of metabolism and pharmacokinetics in drug discovery and development by Jiunn.H Lin Fna and Anthony Y.H.Lu.  Novel drug delivery systems, Ed.Y.W. Chien, Marcel Dekker Inc; USA 2nd edition 1992. 33

Editor's Notes

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  2. ca
  3. En dose which is considered
  4. Ng themy