Experimental & Clinical Validation of Classical and Proprietary Ayurvedic Formulations

K V GOPINATH M Pharm PhD,CPhTTirumala Tirupati Devasthanams

TIRUPATIe-mail:gopinath.karnam@gmail.com

Definitions

Proprietary Name : It is the trade name/brand name of the drug given by the manufacturer.

- designate the drug’s source of manufacture and

- to differentiate it from the similar drug from the other manufacture.

Chemical Name: It is the name used to indicate the chemical structure of the drug.

Generic Name: It is the established, non proprietary or common name or official name of the active drug in a drug product used in official compendium.

– The generic product must be a therapeutic equivalent to the reference drug product .

Drug Product: It means a finished dosage form, e.g., tablet, capsule, or solution, that contains the active drug ingredient, generally, but not necessarily, in association with inactive ingredients.

Definitions

Bioequivalent drug product: A drug is said to be bioequivalent to the reference generally brand drug if both products are pharmaceutical equivalents and its rate and extent of systemic drug absorption do not show a statistically significant difference when administered in the same dose of the active ingredient in the same chemical form, in a similar dosage form, by the same route of administration and under the same experimental conditions.

-If two drugs are bioequivalent, there is no clinically significant difference in their bioavailability

Pharmaceutical Equivalents: Drug products that contain the same therapeutically active drug ingredients(s), same salt, ester, or chemical form; are of the same dosage form; and are identical in strength and concentration and route of administration. It may differ in characteristics such as shape, scoring configuration, release mechanisms, packing, and excipients ( including colors, flavors , preservatives).

Definitions

The reference drug product: It is usually the currently marketed, brand name product with a full New Drug Application(NDA) approved by the FDA

Pharmaceutical alternatives: These are drug products that contain the same therapeutic moiety but are different salts, esters, or complexes(Tetracycline HCl vs Tetracycline PO4) or are different dosage forms( tablets vs capsule; immediate release dosage form vs controlled release dosage form); or strengths.

Clinical Trial: A clinical study is a systemic study of pharmaceutical products in human subjects to evaluate safety and efficacy of the product (pharmacological action i.e. pharmacokinetic /and pharmacodynamic /toxic effect of the drug).

Pharmacokinetics: It is a science dealing with absorption, distribution, metabolism ,excretion, and toxic study of the drug product in a biological system.

Definition

Bioavailability :It is a measurement of the rate and extent (amount) of therapeutically active drug which reaches the general circulation.

Relative bioavailability: It is important for generic drug studies. It is the systematic availability of the drug from a dosage form as compared to a reference standard given by the same route of administration.

Absolute bioavailability: It is the fraction of drug systematically absorbed form the dosage form.

_ It is calculated as the ratio of the AUC for the dosage form given orally to the AUC obtained after IV drug administration.

Supra – Bioavailability: This is a term used when a test product displays an appreciably larger bioavailability than the reference product.

Proprietary/ Classical Drug Evaluation ?

There are a number of examples of drugs products which have exhibited bioavailability problems in the past.

-Chlorpropamide: With three products tested the peak plasma concentration after one brand was less than 1/2 the peak after the other two products

-Digoxin: The text reports a number of bioavailability problems with digoxin due to change in formulation to enhance dissolution.

- Phenytoin : intoxication due to change in diluents from Calcium sulfate to Lactose

This is an indication that more attention is now being given to formulation development during drug development.

-Fig : Plot of Cp versus Time of Chlorpropamide of A,B, C Brands

Reasons for Bio equivalence

The FDA may decide to require bioavailability studies for a variety of reasons including:

-Results from clinical studies indicate that different drug products produce different therapeutics results.

-Results from bioavailability studies indicate that different products are not bioequivalent.

-Drug has a narrow therapeutic range.

-Low solubility and/or large dose.

-Absorption is considerably less than 100%

Bioavailability & Bioequivalence Determination

Plasma Drug Concentration VS Time Profile

Urinary Drug Excretion Studies

Measurements of an acute Pharmacological effect

Clinical studies (or)

In vitro measurements of Bioequivalence

Measurement of an Acute Pharmacological effect

A good correlation exists between the Pharmacologic response and plasma concentration. Over at least a limited concentration range, the intensity of pharmacologic effects should increase with plasma concentration. This relationship allows us to predict pharmacologic effects with changing plasma drug concentrations

Wide inter subject variation in plasma drug concentrations results from a given dose.

When pharmacologic effects relate to plasma drug concentrations, the latter can be used to predict the former.

The drug’s desired pharmacologic effects cannot be

assessed readily by other simple means (e.g., blood

pressure measurement for anti hypertensives).

Measurements of an Acute Pharmacological effect

Acute Pharmacological effects such as changes in heart rate, blood pressure, ECG, clotting time or FEV1 can be used to measure bioavailability

or

When the plasma drug concentration does not relate to the pharmacological response (Albuterol inhalation).

Quantitation of the pharmacological effect VS time profile can be used as a measure of bioavailability or bioequivalence.

The parameters used to known as Pharmacodynamic Parameters Pharmacodynamics : It is the study of the relation of the drug concentration

or amount at the site of action (receptor) and its pharmacological response

Pharmacodynamic Parameters : Onset of Action

Onset time Intensity Duration of Action Therapeutic window

Onset Time

It is the time required for the drug to start producing pharmacological response. It corresponds to the time for the plasma concentration to reach MEC after administration of drug.

Onset of Action

The beginning of pharmacological response is called as on set of action. It occurs when the plasma drug concentration just exceeds the required MEC.

Pharmacodynamic Parameters

Minimum Effective Concentration (MEC)

It is defined as the minimum concentration of drug in plasma required to produce the therapeutic effect.

It reflects the minimum concentration of drug at the receptor site to elicit the desired pharmacological response. The concentration of drug below MEC is said to be in the sub‐therapeutic level.

In case of antibiotics, the term minimum inhibitory concentration(MIC) is used. It describes the minimum concentration of antibiotic in plasma required to kill or inhibit the growth of microorganisms.

Pharmacodynamic Parameters

Intensity It is the maximum pharmacological response produced by the peak

plasma concentration of drug. It is also called as peak response. It is proportional to the number of receptors occupied by the drug up

to a maximum pharmacological effect.

Duration of Action The time period for which the plasma concentration of drug remains

above the MEC level is called as duration of drug action. It is also defined as the difference between on set time and time for

the drug to decline back to MEC.

Maximum Safe Concentration (MSC) / Minimum Toxic Concentration (MTC) :It is the concentration of drug in plasma above which adverse or unwanted effects are precipitated. Concentration of drug above MSC is said to be in the toxic level.

Pharmacodynamic Parameters

Therapeutic Range/therapeutic window The drug concentration between MEC and MTC

Therapeutic Index The ratio of MTC to MEC is called as therapeutic index. It is also defined as the ratio of dose required to produce toxic or

lethal effects to do so required to produce therapeutic effect.

- The therapeutic index of a drug is a relative measure of the safety and effectiveness in laboratory studies.

- The therapeutic index is the ratio of the minimum dose that is toxic for 50% of the population (TD 50 or median toxic dose) to the minimum dose that is effective for 50% of the population (ED 50% or median effective dose)

Margin of safety: Ratio of the minimum toxic for 0.1% of the population to the minimum effective dose for 99.9% of the population

Plasma Drug Concentration Vs Time Curve

It is most often to measure the systemic bioavailability of a drug from a drug product

Pharmacokinetic parameters used to define the plasma drug concentration vs time curve

-Time for peak plasma drug concentration (T max)

- Peak plasma drug concentration (C max ) and

-Area under the plasma drug concentration (AUC)

Pharmacokinetic Parameter

Peak plasma drug concentration (C max ) : The peal plasma drug concentration at Time T. It relates to the intensity of the pharmacological response. Ideally , C max should be within the therapeutic window

Area under the plasma drug concentration (AUC):

- It relates to the amount or extent of drug absorption.

-The amount of systemic drug absorption is directly related to the AUC.

-The AUC is usually calculated by the Trapezoids rule and expressed in units of concentration multiplied by time (mg * hr/ml)

-The AUC is directly proportional to the dose when the drug follows linear kinetics.

-The AUC is inversely proportional to the clearance of the drug.

Time for peak plasma drug concentration (T max):

It relates to the rate constant for systemic absorption and elimination.

If two oral drug products contain the same amount of active drug but different excipients, the dosage form that yields the faster rate of drug absorption has the shorter T Max because the elimination rate constant for the drug from both dosage forms is the same

Urinary Drug Excretion

Urinary Drug Excretion :Measurement of urinary drug excretion can determine bioavailability from a drug product. This method is more accurate if the active therapeutic moiety is excreted unchanged in significant quantity in the urine

The cumulative amount of active drug excreted in the urine(DU∞) is

directly related to the extent of systemic drug absorption.

The rate of drug excretion in the urine ( dDU/dt) is directly related to the rate of systemic drug absorption

The time for the drug to be completely excreted (t∞) :corresponds to the total time for the drug to be systemically absorbed and completely excreted after administration.

Clinical (Pharmacodynamic) response & In vitro measurements of bioequivalence

Clinical responses to a drug can be used to measure bioavailability quantitatively: however they are less precise than other methods and are highly variable because of individual differences in drug pharmacodynamics and subjective measurements.

In vitro measurements of bioequivalence: Especially when an in vitro test has been correlated with human in vivo bioavailability data.

_ For e.g., the rate of drug dissolution in vitro for certain drug products correlates with drug bioavailability in vivo. If the dissolution test in vitro is considered statistically adequate to predict drug bioavailability, then dissolution may be used in place of an in vivo bioavailability study.

Evaluation of a drug product bioavailability

The study involves consideration of various factors

– Drug

– Drug product

– Subjects• Health

• Age

• Weight

• Enzyme status

• Number

– Assay

– Design

– Data Analysis

Drug: Bioavailability studies are conducted to compare two or more products/dosage form containing the same chemical substance.

The apparent volume of distribution and kel can be quite different for different drug substances, thus no interpretation of the results is possible.

The only time that this rule is relaxed is in the case of pro-drug administration.

- In this case it may be appropriate to compare the delivery of a dosage form containing the drug with another dosage form containing a pro-drug. This testing is generally conducted to evaluate the usefulness of the pro-drug, rather than a strict comparison of the drug products.

Evaluation of a drug product bioavailability

The study involves consideration of various factors

– Drug

– Drug product

– Subjects• Health

• Age

• Weight

• Enzyme status

• Number

– Assay

– Design

– Data Analysis

Drug Product: Usually the comparison is made between two (or more) similar products, containing exactly the same chemical substance.

However, different dosage forms can be compared (when they contain the same drug). For example we could compare an IM dosage form with IV dosage form.

Subjects: health, age, weight, enzyme status, number.– Health: Healthy Volunteers, some times diseased population

– Age: subjects between the ages of 18 to 35 years are preferred. Kinetic changes usually aren't important until age greater than 60.

– Weight: The apparent volume of distribution is usually proportional to weight in subjects of normal weight for height

– Enzyme Status: Smokers/poly pharmacy

– Number: Usually 10 – 20 subjects

Evaluation of a drug product bioavailability

The study involves consideration of various factors

– Drug

– Drug product

– Subjects• Health

• Age

• Weight

• Enzyme status

• Number

– Assay

– Design

– Data Analysis

Assay: The same assay method should be used for all phases of the study . The assay method should be sensitive and specific.

Design: Usually a complete cross-over design is used. With this design each subject receives all products with a wash-out period between each dose administration.

Data Analysis: ANOVA Acceptance Criteria for Bioequivalence: There must

be no more than 20% difference in AUC and C max of brand name vs generic. But narrow therapeutic drugs have different range of acceptance i.e. 90% 112%