01 Biopharmaceutics

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