The document discusses various methods for designing dosage regimens, including individualized regimens based on pharmacokinetic measurements, population-based regimens, empirical regimens, and regimens based on partial pharmacokinetic data or nomograms. It also covers considerations for converting patients from intravenous to oral drug administration through sequential, switch, or step-down methods based on pharmacokinetic principles and calculations using steady-state drug concentrations and clearance. An example calculation is provided to determine an appropriate oral theophylline dosage based on intravenous aminophylline infusion rates.
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
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
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
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
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest
Bayesian theory was developed to improve forecast accuracy by combining subjective prediction with improvement from newly collected data.
Bayesian probability is used to improve forecasting in medicine.
Bayesian theory provides a method to weigh the prior information (e.g. physical diagnosis) and new information (e.g. results from laboratory tests) to estimate a new probability for predicting the disease.
Genetic polymorphism in drug transport and drug targets.pavithra vinayak
Genetic polymorphism in drug transport and targets.--pharmacogenetics
DRUG TRANSPORTER
Two types of transporter :
•ATP binding Cassette (ABC) – Found in ABCB, ABCD and ABCG family. Associated with multidrug resistance (MDR) of tumor cells causing treatment failure in cancer.
•Solute Carrier (SLC) – Transport varieties of solute include both charged or uncharged
P-glycoprotein
• ATP binding cassette subfamily B member- 1 (ABCB 1)
• Multidrug resistance protein 1 (MDR1)
• Transport various molecules, including xenobiotic, across cell membrane
• Extensively distributed and expressed throughout the body
Mechanism of Pglycoprotein
Substrate bind to P-gp form the inner leaflet of the membrane
ATP binds at the inner side of the protein
ATP is hydrolyzed to produce ADP and energy
Therapeutic drug monitoring (TDM) of drugs used in seizure disordersAbel C. Mathew
Therapeutic drug monitoring (TDM) of drugs used in seizure disorders- Phenytoin, Valproic acid, Carbamazepine are major drugs used in epilepsy disorders. These drug need TDM to ensure their proper usage.
THIS SLIDE GIVES AN INSIGHT TO THE DIFFERENT METHODS THAT COULD BE USED FOR THE DOSAGE ADJUSTMENT IN PATIENTS WITH RENAL DISEASE.
RENAL FUNCTION OF THE PATIENT IS ASSESSED TO DETERMINE THE DOSAGE ADJUSTMENT
Population pharmacokinetics (PopPK) is the study of variability in plasma drug concentrations between and within patient populations receiving therapeutic doses of a drug.
• Population modelling provides estimates of typical drug levels and drug effects (PK or PK/PD parameters) in a specific population by identifying sources of variability (covariates) in a population and then quantifying the impact of each covariate through a modelling system.
• Population pharmacokinetics can be used to assist with therapeutic drug monitoring (TDM) and the principles of dosage adjustments.
• Population analysis identifies and quantitates this difference, assesses whether this difference will alter the dose-concentration-effect relationship, and then consequently determines if dose adjustment is needed.
• A dosing regimen based on Pop PK or PK/PD analysis should be included in the drug label.
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.
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
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest
Bayesian theory was developed to improve forecast accuracy by combining subjective prediction with improvement from newly collected data.
Bayesian probability is used to improve forecasting in medicine.
Bayesian theory provides a method to weigh the prior information (e.g. physical diagnosis) and new information (e.g. results from laboratory tests) to estimate a new probability for predicting the disease.
Genetic polymorphism in drug transport and drug targets.pavithra vinayak
Genetic polymorphism in drug transport and targets.--pharmacogenetics
DRUG TRANSPORTER
Two types of transporter :
•ATP binding Cassette (ABC) – Found in ABCB, ABCD and ABCG family. Associated with multidrug resistance (MDR) of tumor cells causing treatment failure in cancer.
•Solute Carrier (SLC) – Transport varieties of solute include both charged or uncharged
P-glycoprotein
• ATP binding cassette subfamily B member- 1 (ABCB 1)
• Multidrug resistance protein 1 (MDR1)
• Transport various molecules, including xenobiotic, across cell membrane
• Extensively distributed and expressed throughout the body
Mechanism of Pglycoprotein
Substrate bind to P-gp form the inner leaflet of the membrane
ATP binds at the inner side of the protein
ATP is hydrolyzed to produce ADP and energy
Therapeutic drug monitoring (TDM) of drugs used in seizure disordersAbel C. Mathew
Therapeutic drug monitoring (TDM) of drugs used in seizure disorders- Phenytoin, Valproic acid, Carbamazepine are major drugs used in epilepsy disorders. These drug need TDM to ensure their proper usage.
THIS SLIDE GIVES AN INSIGHT TO THE DIFFERENT METHODS THAT COULD BE USED FOR THE DOSAGE ADJUSTMENT IN PATIENTS WITH RENAL DISEASE.
RENAL FUNCTION OF THE PATIENT IS ASSESSED TO DETERMINE THE DOSAGE ADJUSTMENT
Population pharmacokinetics (PopPK) is the study of variability in plasma drug concentrations between and within patient populations receiving therapeutic doses of a drug.
• Population modelling provides estimates of typical drug levels and drug effects (PK or PK/PD parameters) in a specific population by identifying sources of variability (covariates) in a population and then quantifying the impact of each covariate through a modelling system.
• Population pharmacokinetics can be used to assist with therapeutic drug monitoring (TDM) and the principles of dosage adjustments.
• Population analysis identifies and quantitates this difference, assesses whether this difference will alter the dose-concentration-effect relationship, and then consequently determines if dose adjustment is needed.
• A dosing regimen based on Pop PK or PK/PD analysis should be included in the drug label.
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.
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 drug monitoring (TDM) is the clinical practice of measuring specific drug at designated intervals to maintain a constant concentration in a patients blood stream, thereby optimizing individual dosage regimen.
Pharmacokinetic concepts and principles in humans in order to design individualized dosage regimens which optimize the therapeutic response of a medication while minimizing the chance of an adverse drug reaction.
Measurement of bioavailability and concept of equivalenceRavish Yadav
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Design of Dosage form
1. Design of
Dosage Regimen
Dr. Ramesh Bhandari
Assistant Professor
Department of Pharmacy Practice
KLE College of Pharmacy, Belagavi
2. Difference between dosage
form and dosage regimen
Dosage form: the way in which a therapeutic agent
in taken or administered (tablet, capsule, spray).
Dosage regimen: the schedule of doses per unit of
time ( no. of doses and interval).
3. Introduction
• Dosage regimen design is the selection of drug
dosage, route, and frequency of administration in an
informed manner to achieve therapeutic objectives.
• At the same time, the variability among patients in
pharmacodynamic response demands individualized
dosing to assure maximum efficacy.
• Planning of drug therapy is necessary because the
administration of drugs usually involves risk of
untoward effects.
4. Several Methods Used to Design a Dosage Regimen
1) Individualized Dosage Regimen
2) Dosage Regimens based on Population averages
3) Dosage Regimens based on Partial Pharmacokinetic
parameters
4) Empirical Dosage Regimen
5) Nomogram and Tabulation in Dosage Regimen
5. 1) Individualized Dosage Regimens
Most accurate approach
Dose calculated based on the pharmacokinetics of the drug
in the individual patient derived from measurement of serum
/ plasma drug levels
Not feasible for calculation of the initial dose, however, once
the patient has been medicated, readjustment of the dose
may be done.
Most dosing program record the patient’s age and weight and
calculate the individual dose based on creatinine clearance
and lean body weight.
6. 2) Dosage regimen based on population
Averages
The method most often used to calculate a dosage
regimen is based on average pharmacokinetic
parameters obtained from clinical studies published in
the drug literature.
There are 2 approaches followed:
a) Fixed model
b)Adaptive model
7. a) Fixed Model
• Assumes that population average pharmacokinetic parameters
may be used directly to calculate a dosage regimen for the
patient, without any alteration.
• The practitioner may use the usual dosage suggested by the
literature and then make a small adjustment of the dosage
based on the patient’s weight and / or age
• Usually, pharmacokinetic parameters such as Ka, F, Vd, k are
assumed remain constant and most often drug is assumed to
follow one compartment open model
• When a multiple dose regimen is designed, multiple dosage
equations based on the principle of superposition are used to
evaluate the dose.
8. b) Adaptive Model
• Attempts to adapt or modify dosage regimen according to the
need of the patient.
• Uses patient variable such as weight, age, sex, body surface
area, and known patient’s pathophysiology such as, renal
disease, as well as known population average pharmacokinetic
parameters of the drug.
• This model generally assumes that pharmacokinetic parameters
such as drug clearance do not change from one dose to the
next.
• However, some adaptive models allow for continuously adaptive
change with time in order to simulate more closely the changing
process of drug disposition in the patient, especially during a
disease state.
9. 3) Dosage regimen based on partial PK
Parameter
• For many drugs, the entire pharmacokinetic profile for the drug is
unknown or unavailable.
• Therefore, the pharmacokineticist needs to make some assumptions in
order to calculate the dosage regimen.
• These assumptions will depend on the safety, efficacy, and therapeutic
range of the drug.
• The use of population pharmacokinetics uses average patient
population characteristics and only a few serum / plasma
concentration from the patient
• Population pharmacokinetic approaches to therapeutic drug monitoring
have increased with the increased availability of computerized data
bases and development of statistical tools for the analysis of
observational data.
10. 4) Empirical Dosage Regimen
• In many cases, physician selects a dosage
regimen of the patient without using any
pharmacokinetic variables.
• The physician makes the decision based on
empirical clinical data, personal experience and
clinical observations.
11. 5) Nomograms andTabulation in Designing
Dosage Regimen
• For ease of calculation of dosage regimens, many
clinicians rely on nomograms to calculate the proper
dosage regimen for their patients.
• The use of nomogram may give a quick dosage regimen
adjustment for patients with characteristics requiring
adjustments such as age, body weight, and physiologic
state.
• In general, nomogram of a drug is based on population
pharmacokinetic data collected and analyzed using a
specific pharmacokinetic model.
12. Nomograms andTabulation in Designing
Dosage Regimen
• A nomogram typically has three scales: two scales represent
known values and one scale is the scale where the result is
read off.
• The known scales are placed on the outside; i.e. the result
scale is in the center.
• Each known value of the calculation is marked on the outer
scales and a line is drawn between each mark.
• Where the line and the inside scale intersects is the result.
• Examples include: height – BMI – weight,
total clearance – maintenance dose – lean body weight, etc.
13. Nomograms andTabulation in Designing
Dosage Regimen
• In order to keep the dosage regimen calculation simple,
complicated equations are often solved and their results
displayed diagrammatically on special scaled axes to produce
a simple dose recommendation based on patient information.
• Some nomograms make use of certain physiologic parameters,
such as serum creatinine concentration, to help modify the
dosage regimen according to renal function.
• For many marketed drugs, the manufacturer provides tabulated
general guidelines for use in establishing a dosage regimen for
patients, including loading and maintenance doses.
14. Examples of drugs for which nomograms are being used
for designing dosage regimen:
• Theophylline
• Aminoglycosides:Tobramycin sulfate
• Warfarin
• Digoxin etc.
16. Importance of IV to PO Conversion
oral formulations are easier to administer, safe, and
achieve desired therapeutic concentrations, thus making
the PO route an ideal choice.
More Comfortable
Cost Effective: reduces hidden expenses
IV therapy restrict the movement and make more
prone to IV related adverse effects.
Furthermore, IV route make portal for bacteria and
fungal infections.
17. Types of IV to PO therapy
Conversion
1) Sequential Therapy
2) Switch Therapy
3) Step-down Therapy
18. 1) SequentialTherapy
It refers to the act of replacing a parenteral version of a
medication with its oral counterpart.
There are many classes of medications that have oral
dosage forms that are therapeutically equivalent to the
parenteral form of the same medication.
E.g. conversion of famotidine 20 mg IV to famotidine
20 mg PO.
19. 2) SwitchTherapy
Used to describe a conversion from an IV medication to
the PO equivalent that may be within the same class and
have the same level of potency, but is a different
compound.
An example is the conversion of IV pantoprazole to
rapidly dissolving lansoprazole tablets omeprazole
capsules.
20. 3) Step-downTherapy
It refers to converting from an injectable medication to
an oral agent in another class or to a different medication
within the same class where the frequency, dose, and the
spectrum of activity (in the case of antibiotics) may not
be exactly the same.
Converting from ampicillin 3 g IV q 6 hr to amoxicillin
875 mg PO q 12 hr is an example of step-down therapy.
21. SELECTION OF PATIENT FOR IVTO
POTHERAPY CONVERSION
I. Intact and functioning of GI tract
II. Improving patient condition
III.Doesn't meet exclusion criteria
IV.Others
22. Pharmacokinetic Consideration
• For oral medications, bioavailability may be less due to
the variability in the rate and extent of dissolution of
the oral form and the total amount that is absorbed into
the systemic circulation.
23. • When intravenous infusion is stopped, the serum drug
concentration decreases according to first-order
elimination kinetics.
• For most oral drug products, the time to reach steady
state depends on the first-order elimination rate
constant for the drug.
• Therefore, if the patient starts the dosage regimen with
the oral drug product at the same time as the intravenous
infusion is stopped, then the exponential decline of
serum levels from the intravenous infusion should be
matched by the exponential increase in serum drug
levels from the oral drug product.
24. • Following two methods may be used to calculate an
appropriate oral dosage regimen for a patient whose
condition has been stabilized by an intravenous drug
infusion.
• Both methods assume that the patient’s plasma drug
concentration is at steady state.
25. METHOD I
C∞
av = SFD0 / k Vd τ
D0 / τ = C∞
av . k Vd / SF
Where, S is the salt form of the drug and D0 / τ is the dosing
rate
26. METHOD II
• This method assumes that the rate of intravenous
infusion (mg/hr) is the same desired rate of oral
dosage.
27. EXAMPLE
• An adult male asthmatic patient (age 55, 78 kg) has been
maintained on an IV infusion of aminophylline at a rate
of 34 mg/hr. The steady state theophylline drug
concentration was 12 µg/mL and total body clearance
was calculated as 3.0 L/hr. Calculate an appropriate oral
dosage regimen of theophylline for this patient.
(Aminophylline is a soluble salt of theophylline and
contains 85% theophylline (S = 0.85). Theophylline is
100% bioavailable (F = 1) after an oral dose.)
28. Solution by Method - I
We know, D0 / τ = C∞
av . k Vd / SF
But, total body clearance (ClT) = kVd
Therefore,
D0 / τ = C∞
av ClT/ SF
• The dose rate (34 mg/hr) was calculated on the basis of aminophylline dosing.
• The patient however will be given theophylline orally, to convert to oral
theophylline S and F should be considered
Oral theophylline dose rate = SFD0 / τ = (0.85) (1) (34) / 1 = 28.9 mg / hr
• Therefore the total daily dose is 28.9 mg/hr x 24 hr or 693.6 mg/day
• Possible theophylline schedules might be 700 mg/day.
• The dose of 350 mg every 12 hours could be given in sustained-release form to
avoid any excessive high drug concentration in the body.
29. Solution by Method - II
Rate of IV infusion is 34 mg/hr and so the daily
dose is 34 mg/hr x 24 = 816 mg/day.
The equivalent dose in terms of theophylline is
816 x 0.85 = 693.6 mg.
Thus the patient should receive approximately
700 mg of theophylline per day or 350 mg every
12 hours.