This document summarizes a seminar on applying pharmacokinetics in new drug development and dosage form design. [1] It discusses how pharmacokinetic parameters can be used to design dosage regimens, predict and explain drug interactions, and individualize treatment for different populations. [2] Dosage adjustment considerations for special populations like neonates, children, elderly, hepatically or renally impaired patients are also reviewed. [3] The document emphasizes that therapeutic drug monitoring is important for optimizing drug therapy for individual patients.
Introduction to dosage regimen and Individualization of dosage regimenKLE College of pharmacy
Introduction of Dosage regimen, Approaches for design of dosage regimen, Individualization, Advantages, Dosage in neonates, Geriatrics, Renal and Hepatic impaired Patients.
Individualisation and optimization of drug dosing regimenJyoti Nautiyal
Drug dosing regimen, dosing frequency, individualisation, Steps Involved in Individualization of Dosage Regimen, optimization, variability, Clinical experience with individualization and optimization based on plasma drug levels.
Clinical pharmacokinetics and its application--
1)definition
2) APPLICATIONS OF CLINICAL PHARMACOKINETICS
Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese patients.
Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.
Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability – Genetic, Age and Weight, disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug therapy.
e) TDM of drugs used in the following disease conditions: cardiovascular disease, Seizure disorders, Psychiatric conditions, and Organ transplantations
Dosage adjustment in Renal and Hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in renal disease.
d. Measurement of Glomerular Filtration rate and creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.
Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feedback.
c) Analysis of Population pharmacokinetic Data
Introduction to dosage regimen and Individualization of dosage regimenKLE College of pharmacy
Introduction of Dosage regimen, Approaches for design of dosage regimen, Individualization, Advantages, Dosage in neonates, Geriatrics, Renal and Hepatic impaired Patients.
Individualisation and optimization of drug dosing regimenJyoti Nautiyal
Drug dosing regimen, dosing frequency, individualisation, Steps Involved in Individualization of Dosage Regimen, optimization, variability, Clinical experience with individualization and optimization based on plasma drug levels.
Clinical pharmacokinetics and its application--
1)definition
2) APPLICATIONS OF CLINICAL PHARMACOKINETICS
Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese patients.
Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.
Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability – Genetic, Age and Weight, disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug therapy.
e) TDM of drugs used in the following disease conditions: cardiovascular disease, Seizure disorders, Psychiatric conditions, and Organ transplantations
Dosage adjustment in Renal and Hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in renal disease.
d. Measurement of Glomerular Filtration rate and creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.
Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feedback.
c) Analysis of Population pharmacokinetic Data
conversion from INTRAVENOUS TO ORAL DOSING----- design of dosage regimenpavithra vinayak
conversion from INTRAVENOUS TO ORAL DOSING----- TYPES OF IV TO PO THERAPY CONVERSIONS: MEDICATIONS INCLUDED IN AN IV TO PO CONVERSION PROGRAM: SELECTION OF PATIENTS FOR IV TO PO THERAPY CONVERSION: design of dosage regimen--clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
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
conversion from INTRAVENOUS TO ORAL DOSING----- design of dosage regimenpavithra vinayak
conversion from INTRAVENOUS TO ORAL DOSING----- TYPES OF IV TO PO THERAPY CONVERSIONS: MEDICATIONS INCLUDED IN AN IV TO PO CONVERSION PROGRAM: SELECTION OF PATIENTS FOR IV TO PO THERAPY CONVERSION: design of dosage regimen--clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
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
Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. Primary goals of clinical pharmacokinetics include enhancing efficacy and decreasing toxicity of a patient's drug therapy.
The success of drug therapy is highly dependent on the choice of the drug, the drug product, and the design of the dosage regimen. The choice of the drug is generally made by the physician after careful patient diagnosis and physical assessment.
The science of dosage or posology (from Greek posos, how much, and logos, study) is a branch of pharmacology and therapeutics concerned with ‘treatment dosage’ and ‘dosage regimen’. Establishing optimum dosage underpins every clinical development plan for novel therapeutic candidates. Failure to select the adequate drug dose is a leading culprit for regulatory delays or denial of initial applications for new drugs and, more generally, inadequate dose selection contributes to the high attrition rate of pivotal clinical trials.
Pediatric Drug calculations |drug calculation formulasNEHA MALIK
Most drugs in children are dosed according to body weight (mg/kg) or body surface area (BSA) (mg/m2). Care must be taken to properly convert body weight from pounds to kilograms (1 kg= 2.2 lb) before calculating doses based on body weight. Doses are often expressed as mg/kg/day or mg/kg/dose, therefore orders written "mg/kg/d," which is confusing, require further clarification from the prescriber.
1. Dosage Regimen
Dosage regimen is defined as the manner in which a drug is taken. It is the schedule of doses of a medicine including, the dosage form, the time between doses, the duration of treatment and the amount to be taken each time.
2. Designing of Dosage Regimen
For some drugs like analgesics, hypnotics or anti emetics, a single dose may provide effective treatment. However, the duration of most of the illnesses 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 depending upon the nature of illness. So for a successful drug therapy, designing of an optimal multiple dosage regimen is required.
3. Objective
The primary objective in dosage regimen design is to obtain a safe plasma drug concentration which neither exceeds the maximum safe concentration nor falls below the minimum effective concentration.
4. Criteria For Optimum Dosage Regimen
The plasma levels of drug given must be maintained within the therapeutic window. For example, the therapeutic range of theophylline is 10-20μg/L. So, the best is to maintain the CP around 15μg/L. Therapeutic window is a range of doses that produces therapeutic response without causing any significant adverse effect in patients. Generally therapeutic window is a ratio between minimum effective concentrations (MEC) to the minimum toxic concentration (MTC).
5. Factors to be Considered In Dosage Regimen Design
Numerous factors must be considered in designing a dosage regimen.
1. Pharmacokinetic Factors
These include absorption, distribution, metabolism and excretion characteristics of a drug.
2. Physiological Factors
Age, Weight, Gender and Nutritional status of a patient under treatment must be considered.
3. Pathophysiologic Factors
Existence of diseases like Renal failure, Hepatic diseases, Congestive heart failure, Myocardial infraction etc., must be considered in the patient being treated. This is because co-existence of these diseases will prolong the elimination of drugs. Therefore, the dose in such patients must be carefully adjusted.
4. Personal Lifestyle Habits
Lifestyle habits like cigarette smoking, alcohol abuse, voracious eating etc, must also be taken into consideration.
5. Exposure of patient to Long Term Medication
Chronic intake of medicines can alert the drug pharmacokinetics.
6. Other Factors
These include-
▪ Desired concentration of drug at site of action
▪ Alteration in the sensitivity of the receptors to the drug
▪ Drug dosage form
▪ Drug interactions
▪ Tolerance-dependence
▪ Pharmacogenitics – idiosyncracy
Multiple-Dosage Regimens
Why Multiple-Dosage Regimens is necessary?
After single-dose drug administration, the plasma drug level rises above and then falls below the minimum effective concentration (MEC), resulting in a decline in therapeutic effect.
Therapeutic Regimen
Dose-response Curve
Drug Toxicity
Symptoms, Diagnosis & Treatment Of Drug Toxicity
Dosage Regimen
Factors To Consider In Design Of Drug Dosage Regimens
Methods To Design A Dosage Regimen
Dosing Of Drugs In Infants And Children
Dosing Of Drugs In The Elderly
Clinical Trial
1. A SEMINAR ON APPLICATION OF
PHARMACOKINETIC IN NEW DRUG
DEVELOPMENT AND DESIGNING OF
DOSAGE FORM
GUIDED BY: PREPARED BY:
PARTH PATEL
Mr. ASHOK MAHAJAN
M.PHARM ( QA)
SEM:1
2. CONTENTS
Introduction
Application
Design of dosage regimen
Dose size
Dosing frequency
Prediction and explanation of drug food and drug-
drug interaction
Individualization
Dosing of drug in neonates, children, infants and
elderly.
Dosing of drug in various disease state
Monitoring drug therapy
3. INTRODUCTION
PHARMACOKINETIC
PARAMETERS :
C max
(Peak plasma concentration):
t max
(Time of peak concentration):
AUC (Area under the curve):
4. APPLICATIONS
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. DESIGN OF DOSAGE REGIMEN
“Dosage Regimen is defined as the manner in
which a drug is taken”.
Types Of Dosage Regimen :
Single Dosage Regimen
Multiple Dosage Regimen
7. DOSE SIZE
The magnitude of both therapeutic and toxic
responses depends upon dose size.
8. DOSING FREQUENCY
The dose interval (inverse of dosing frequency)
is calculated on the basis of half-life of the drug.
9. 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.
Hepatic elimination
Renal clearance
Diet
Virus drug interactions
10. 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.
11. 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 profile of the drug, and the dose must be
carefully adjusted.
12. 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.
13. 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
pharmacokinetic parameters derived from the patient's
serum drug concentrations.
14. Design of Dosage Regimens
The initial dosage of the drug is estimated using average population
pharmacokinetic parameters obtained from the literature.
After evaluation of the patient, adjustment of the dosage regimen using
the patient's individual pharmacokinetic parameters may be indicated,
with further therapeutic drug monitoring.
Dosage Regimens Based on Population Averages:
The fixed model assumes that population average pharmacokinetic
parameters may be used directly to calculate a dosage regimen for the
patient, without any alteration.
Usually, pharmacokinetic parameters such as absorption rate constant k a,
bioavailability factor F, apparent volume of distribution V d, and elimination
rate constant k E are assumed to remain constant.
Most often the drug is assumed to follow the pharmacokinetics of a one-
compartment model. When a multiple-dose regimen is designed, multiple-
dosage equations based on the principle of superposition are used to
evaluate the dose.
15. 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.
16. 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
17. 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
70 dose
18. 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.
19. 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 decreased needs
normal constant due to disease adjustment
20. DOSE ADJUSTMENT BASED ON
ELIMINATION RATE CONSTANT OR
HALF LIFE
The parameters to be adjusted in renal
insufficiency are :
Css,av = 1.44 F × t1/2 × ( X0 )
Vd τ
To be kept assumed decreased needs
normal constant due to adjustment
disease
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
22. REFERENCES:
D.M.Brahmankar & Sunil b. jaiswal,
―Biopharmaceutics and Pharmacokinetics‖, First
edition, Reprint 2005,Vallabh prakashan, p.p. 306-321.
Leon Shargel/Andrew B.C. Yu, ―Applied
Biopharmaceutics and Pharmacokinetics‖, Fourth
edition,A Simon & Schuster Company, p.p. 475-504.
Milo Gibaldi & Donald Perrier, ―Drugs &
Pharmaceutical Sciences; Pharmacokinetics‖, 2nd
Edition Revised & expanded; Marcel Dekker, Inc.
Volume: - 15, p.p. 385-387.