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Ivan N. Tanodra, MD, RPh
Lifegeneral area of general area of study concerned study concerned with the formulation, with the formulation, manufacture, manufacture, stability and stability and effectiveness of effectiveness of pharmaceutical pharmaceutical dosage formsdosage forms
Biopharmaceuticsstudy of the factors influencing the
bioavailability of a drug in man and animals and the use of this information to optimize pharmacological or therapeutic activity of drug products in clinical application
BiopharmaceuticsInterrelationship of the physicochemical
properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of drug absorption
BiopharmaceuticsStudy of the relationship of the
physicochemical properties and in vitro behavior of the drug & drug product on the delivery of the drug to the body under normal or pathologic conditions
PHARMACOKINETICS – a process of how the body deals with the drug, “what your body does to your drug”
PHARMACODYNAMICS – a process of how your drug deals with the body, “what your drug does to your body”
PharmacokineticsDeals with the changes of drug concentration
in a drug product inside the human or animal body following administration
PharmacokineticsInvolves the kinetics of drug absorption,
distribution, metabolism and elimination
PharmacodynamicsRelationship between the drug concentration
at the site of action (receptor) and pharmacologic response including the biochemical and physiologic effects that influence their interaction
Initiation of sequence of molecular events resulting in pharmacologic or toxic response
Drug ProductFinished dosage form that contains an
active drug ingredient generally, but not necessarily, in association with inactive ingredient (vehicle)
Formulation or matrix in which the drug is contained
Term may also include a dosage form that does not contain an active ingredient intended to be used = placebo
Physicochemical properties of drug product
Pharmacologic/clinical effect
Factors Stability of the drug within a drug productThe release of the drug from the drug
productRate of dissolution/release of the drug at the
absorption siteThe systemic absorption of the drug
RationaleApply biopharmaceutic principles in
developing a rational design of a drug product which would enhance the delivery of active drug and provide optimal therapeutic efficacy of the drug in the patient
AIM:To deliver the right amount of drug that is
EFFECTIVEand SAFE at the right place (site of action) and
at the right time (oral, SL or IV/ fast or slow-release)
In-vivo & in-vitro methodsBe able to assess the impact of the physical
and chemical properties of the drug, drug stability and large-scale production of the drug and drug product on the biologic performance of the drug
Mometasone cream AND Mometasone (Nasonex) nasal spray
Methylprednisolone tablet AND Fluticasone spray
Salbutamol nebules, Salbutamol MDI and Salbutamol syrup
Nitroglycerin patch AND Nitroglycerin sprayLactacyd facial wash AND Lactacyd feminine
washAtropine eyedrops AND Atropine ampuleLidocaine spray, Epinephrine ampule and
Lidocaine:Epinephrine carpule
Drug dispositionDescription of drug distribution and
elimination
Let’s discuss the disposition of a drugDOSAGE FORM
ROUTE OF ADMINISTRATION
Bioavailability of the drug (active ingredient) is the primary concern of biopharmaceutics
- Remember you AIM
L A D M E R T
How do you measure the bioavailability of a drug?
How do you measure the bioavailability of a drug?1. Blood = plasma level concentration2. Urine3. Feces – reflect a drug that has not been
absorbed after an oral dose or a drug that has been biliary secreted after systemic absorption
4. Clinical outcome/Pharmacologic effect/pharmacodynamic effect
Which is the most direct measurement?
Plasma Level – Time Curve
Time (mins.)
Plasma level (mg/mL)
Identify….Peak plasma level (cmax)– max drug
concentration related to the dose & the rate constants for absorption & elimination of the drug
AUC (Area Under the Curve)- related to the amount of drug absorbed systemically
Time of peak plasma level (tmax)– time of max drug conc. in plasma roughly proportional to the average rate of drug absorption
Determine the route of administrationIVOral
Higher plasma level concentration = ___________? bioavailability
Bioavailability = Therapeutic Efficacy ???
EstablishMinimum effective concentration (MEC)Minimum toxic concentration (MTC)
Let us go back to the plasma-level time curve……
You will be able to determine….Onset time of actionDuration of actionIntensity of drug action
Higher plasma concentration of a drug = Therapeutic Efficacy ???
Most of the time……..Plasma level concentration of a drug =
concentration of drug at the receptor sites = intensity of a pharmacologic effect
Is measuring plasma concentrations of a drug enough to determine its therapeutic efficacy?
Pharmacodynamic ResponseDigoxin = ECG tracingsWarfarin = Prothrombin timeInsulin = Blood glucose levelsSimvastatin = Blood cholesterol levelsNifedipine (anti-hypertensive) =
___________________Paracetamol = ___________________
Plasma drug concentrations do not accurately predict pharmacodynamic response
Action of warfarin is dependent on the clotting factors II, VII, IX & X
Having the same trend of plasma level concentration of Warfarin…..
Will the intensity of the activity of Warfarin in a hemophiliac be the same with a normal person?
Pharmacodynamic response OR Plasma level concentration????
IQA 64 year-old male, diabetic patient with a poor
creatinine clearance is being given Gentamycin 80mg (aminoglyocside) IV once daily as a treatment for sepsis. Which is important:
a. Blood culture and sensitivity to determine his response to treatment
b. Plasma level concentration to determine the blood level of the drug
c. A and B
Why?
Pharmacokinetic ModelsDrugs are in a dynamic state within the bodyIt is a hypothesis conceived using
mathematical termsDescribe drug concentrations in the body as
a function of unit time
Pharmacokinetic ModelsConcentration of drug in the tank would be
governed by two parameters which are CONSTANT:
1. Fluid volume of the tank2. Elimination of drug per unit of time
Let us correlate the LADMER System with Pharmacokinetic Models
Pharmacokinetic ModelsIf a known set of drug concentrations in the
tank were determined at various intervals volume of fluid in the tank & rate of drug elimination would be established
Pharmacokinetic Models• A compartment is a tank containing a
volume of fluid• In the human body, a fraction of drug is
continually eliminated as a function of time
Pharmacokinetic Models• Concentration of drug in the tank
(compartment) after a given dose (Ab) is governed by two parameters:1. Fluid volume of the tank (Vd)2. Elimination of drug per unit of time (kel, CL)
this could be established by knowing a set of drug concentrations in the tank (Cp) at various time intervals
Pharmacokinetic ModelsThe number of parameters needed to
describe the model depends on:1. Complexity of the process (ADME)2. route of drug administration
Uses of Pharmacokinetic ModelsPredict plasma, tissue and urine drug levels
with any dosage regimenCalculate the optimum dosage regimen for
each patient individually Estimate possible accumulation of drug
and/or metabolitesCorrelate drug concentrations with
pharmacologic or toxicologic activity
Uses of Pharmacokinetic ModelsEvaluate differences in the rate or extent of
availability between formulations (bioequivalence)
Describe how changes in physiology or disease affect the absorption, distribution and elimination of the drug
Explain drug interactions
Pharmacokinetic ModelsA. Compartment Model (Mammillary Model) B. Physiologic Pharmacokinetic Model (Flow
Model)
Compartment (Mammillary) ModelOne or more peripheral compartment
connected to a central compartment like satellites
DRUG IN THE BODY = CENTRAL COMPARTMENT + TISSUE COMPARTMENT
Compartment (Mammillary) ModelCompartment is not a real physiologic or
anatomic regionUsed when there is little information known
about the tissues
ASSUMPTION: Compartment group of tissues that have a
similar blood flow and drug affinityWithin each compartment, drug is uniformly
distributedOPEN – drugs move in & out of the
compartment (dynamic)
Compartment (Mammillary) Model
ASSUMPTION:Drug has an equal probability of leaving the
compartment
Compartment ModelsRate constants (ka & ke) represents the
overall rate processes of drug entry into and exit from the compartments
Compartment ModelFUNCTIONS:Enables the pharmacokineticist to write
different equations to drug concentration changes inside each compartment
Visual representation of rate processesShows how many pharmacokinetic constants
are necessary to describe the process adequately
Compartment ModelsOpen-one compartment modelOpen-two compartment model
Compartment model for IV and oral
Compartment ModelCan a drug concentration data be obtained
directly from each compartment???In open two compartment data in the
peripheral compartment cannot be obtained tissues are not easily sampled & may not contain homogenous concentration of the drug only estimated mathematically (from amount of drug absorbed & eliminated per unit time)
Compartment ModelDISADVANTAGES:NOT REALISTIC because everything is based
on presumption and mathematical concept Cannot be extrapolated to humans
Physiologic Pharmacokinetic Model Blood flow or perfusion model Based on known anatomic and physiologic
data MORE REALISTIC Actual tissue volume is used Experimentally determined in ANIMALS
extrapolated to humans No data fitting required On model if there’s no perfusion, organ is
excluded (e.g. brain)
Construct the model….IV injection, Venous blood, Arterial blood,
Heart, Muscle, Slowly equilibrating tissue (SET), Rapidly equilibrating tissue (RET), Kidney, Liver, ke, km, Perfusion (Q) Qh, Qm, Qs, Qr, Qk, Ql, Urine
Physiologic Pharmacokinetic ModelDISADVANTAGE: 1.Data can be experimentally difficult to obtain2.Data can be affected by pathophysiologic
conditions
Factors Affecting Design of a Drug ProductDRUGDosage formDose (mg/kg)Physicochemical
propertiesRoute of
administration
BODYPhysiologic factors
(e.g. age, body mass)Pathologic factors
(e.g. liver and renal disease)
Application of BiopharmaceuticsGeneric equivalencyDrug availabilityTherapeutic efficacyDrug substitution
BioequivalenceAchieved if the extent and absorption of a
drug product are not statistically significantly different from the standard when administered at the same molar dose