BIOAVAILABILITY : BIOAVAILABILITY Prepared by
Nilesh J. Patel HISTORY: : HISTORY: Phenytoin toxicity in epileptic patients which occurred in the year 1968 in Australia
The differences in the bioavailability observed with different digoxin formulations in the year 1971. Definition: : Definition: Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route.
To exert an optimal therapeutic action an active moiety should be delivered to its site of action in an effective concentration for the desired period. Slide 4: Route Bioavailability (%) Characteristics
Intravenous 100 (by definition) Most rapid onset
Intramuscular 75 to = 100 Large volumes often feasible; may be
Subcutaneous 75 to = 100 Smaller volumes than IM; may be painful
Oral (PO) 5 to < 100 Most convenient; first pass effects may be
Rectal (PR) 30 to < 100 Less first-pass effects than oral
Inhalation 5 to < 100 Often very rapid onset
Transdermal 80 to = 100 Usually very slow absorption; used for
lack of first-pass effects; prolonged duration
of action Objectives of bioavailability studies: : Objectives of bioavailability studies: Development of new formulation.
Determination of influence of excipients, patient related factors and possible interaction with other drugs on the efficiency of absorption.
Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage, stability on drug absorption.
Primary stages of the development of a suitable dosage form for a new drug entity. Significance of Bioavailability : Significance of Bioavailability Drugs having low therapeutic index, e.g. cardiac glycosides, quinidine, phenytoin etc.
Drugs whose peak levels are required for the effect of drugs, e.g. phenytoin, phenobarbitone, primidone, sodium valporate, anti-hypertensives,antidiabetics and antibiotics.
Drugs that are absorbed by an active transport,e.g. amino acid analogues. Purine analogues etc.
Drugs which are disintegrated in the alimentary canal and liver,e.g.chiorpromazine etc. or those which under go first pass metabolism.
Formulations that give sustained release of drug, formulations with smaller disintegration time than dissolution rate and drugs used as replacement therapy also warrant bioavailability testing. In addition, any new formulation has to be tested for its bioavailability profile. DISPOSITION OF DRUGS : DISPOSITION OF DRUGS ABSOLUTE BIOAVAILABILITY: : ABSOLUTE BIOAVAILABILITY: The systemic availability of a drug administered orally is determined in comparison to its iv administration.
Characterization of a drug's absorption properties from the e.v. site.
F = AUCev
The availability of a drug product as compared to another dosage form or product of the same drug given in the same dose.
Characterization of absorption of a drug from its formulation.
AUCB FACTORS INFLUENCING BIOAVAILABILITY: : FACTORS INFLUENCING BIOAVAILABILITY: Three distinct factors are involved to influencing bioavailability. These are:
physicochemical properties of the drug.
1. Particle size
2. Crystalline structure
3. Salt form
Formulation and manufacturing variables.
1.Disintegration and dissolution time
4.Nature and type of dosage form 2. Patient related factors: : 2. Patient related factors: Physiologic factors.
1.Variations in pH of GI fluids
2.Gastric emptying rate
3. Intestinal motility
4. Presystemic and first-pass metabolism
5. Age, sex
6. Disease states
Interactions with other substances.
2. Fluid volume
3. Other drugs
3. Route of administration:
4.Topical administration METHODS OF ASSESSING BIOAVAILABILITY: : METHODS OF ASSESSING BIOAVAILABILITY: Bioavailability testing is a means of predicting the clinical efficacy of a drug.
1. Demonstration of a clinically significant effect.
The drawbacks are complex, expensive, time-consuming and require a sensitive and quantitative measure of the desired response.
2. Quantification of pharmacologic effect.
This method is based on the assumption that a given intensity of response is associated with a particular drug concentration at the site of action.
The drawbacks are monitoring of pharmacologic data is often difficult, precision and reproducibility are difficult to establish.
And there are only a limited number of pharmacologic effects (e.g. heart rate, body temperature, blood sugar levels) that are applicable to this method. 2. Blood level studies: : 2. Blood level studies: These are based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action.
Dosing interval 7 Slide 14: The key parameters for determining bioavailability
1. AUC: The AUC is proportional to the total amount of
drug reaching the systemic circulation, and thus
characterizes the extent of absorption.
2. Cmax: Gives indication whether drug is sufficiently
absorbed systemically to provide a therapeutic
3. Tmax: The Tmax reflects the rate of drug absorption,
and decreases as the absorption rate increases. 3.Urinary Excretion Data: : 3.Urinary Excretion Data: These studies are based on the premise that urinary excretion of the unchanged drug is directly proportional to the plasma concentration of total drug.
This technique of studying bioavailability is most useful for those drugs that are not extensively metabolized prior to urinary elimination. Slide 16: The three major parameters examined in urinary excretion data are as follow:
1.(dXu/dt)max : It gives the rate of appearance of drug in the urine is proportional to its concentration in systemic circulation. Its value increases as the rate of and/or extent of absorption increases
2. (tu)max : It is analogous to the of plasma level data, its value decreases as the absorption rate increases.
3. Xu : It is related to the AUC of plasma level data and increases as the extent of absorption increases.
This studies used for certain thiazide diuretics and sulfonamides and for drugs that have urine as the site of action-for example, urinary antiseptics. DESIGN AND CONDUCT OF STUDIES: : DESIGN AND CONDUCT OF STUDIES: The design and conduct of the study should follow ICH regulations on Good Clinical Practice, including reference to an Ethics Committee.
A bioequivalence study is basically a comparative bioavailability study designed to establish equivalence between test and reference products.
The study should be designed in such a way that the formulation effect can be distinguished from other effects.
For the number of formulations the design of choice
is a two-period, two sequence crossover design.
Parallel design, single dose studies, steady-state. Slide 18: 2. Subjects:
A.Selection of subjects:
Aim to minimize variability and permit detection of differences between pharmaceutical products.
The studies should normally be performed with healthy volunteers.
They should be screened for suitability by means of clinical laboratory tests, review of medical history, and medical examination.
B.Standardization of the study:
The test conditions should be standardized in order to minimize the variability of all factors involved.
Standardization of the diet, fluid intake and exercise is recommended.
The subjects should not take other medicines during a suitable period before and during the study. Slide 19: C.Inclusion of patients:
If the investigated active substance is known to have adverse effects and the pharmacological effects or risks are considered unacceptable for healthy volunteers it may be necessary to use patients instead, under suitable precautions and supervision.
Phenotyping of subjects should be considered as well in crossover studies.
If a drug is known to be subject to major genetic polymorphism, studies could be performed in panels of subjects of known phenotype or genotype.
3. Characteristics to be investigated:
In most cases evaluation of bioavailability and bioequivalence will be based upon the measured concentrations of the parent compound. Slide 20: In some situations, measurements of an active or inactive metabolite is carried out.
The plasma concentration versus time curves are mostly used to assess extent and rate of absorption.
The use of urine excretion data may be advantageous in determining the extent of drug input in case of products predominately excreted renally.
Specificity, accuracy and reproducibility of the methods should be sufficient.
It is conducted according to the applicable principles of Good Laboratory Practice (GLP).
Determination of the active moiety and/or its biotransformation product(s) in plasma, urine or any other suitable matrix must be well characterized, fully validated and documented to yield reliable results that can be satisfactorily interpreted. Slide 21: 5 Reference and test product:
The choice of reference product should be justified by the applicant and agreed upon by the regulatory authority.
The test products used in the biostudy must be prepared in accordance with GMP-regulations.
To quantify the difference in bioavailability between the reference and test products and to demonstrate that any clinically important difference.
The statistical analysis (e.g. ANOVA) should take into account sources of variation that can be reasonably assumed to have an effect on the response variable.
Pharmacokinetic parameters derived from measures of concentration, e.g. AUC, Cmax should be analyzed using ANOVA. Slide 22: B.Acceptance range for pharmacokinetic parameters:
It should lie within an acceptance interval of 0.80-1.25.
It should lie within an acceptance interval of 0.80-1.25.
The wider interval must be 0.75-1.33.
For tmax if there is a clinically relevant claim for rapid release or action or signs related to adverse effects. The interval should lie within a clinically determined range.
C.Handling deviations from the study plan:
The protocol should also specify methods for handling drop-outs.
D.A remark on individual and population bioequivalence:
Bioequivalence studies are designed for population and individual is limited. Slide 23: 7.In vitro dissolution for bioequivalence study:
The term commonly used to describe is "in-vitro/in-vivo correlation".
The specifications for the in vitro dissolution of the product should be derived from the dissolution profile of the batch.
A. Official dissolution tests:
Apparatus 1, (basket method).
Apparatus 2 (paddle method).
1. Degree of agitation
2. Size and shape of container
3. Composition of dissolution medium
• pH, ionic strength, viscosity
4. Temperature of dissolution medium
5. Volume of dissolution medium Slide 24: 8.Reporting of results:
The report of a bioequivalence study should give the complete documentation of its protocol, conduct and evaluation complying with GCP-rules and ICH guideline.
Drop-out and withdrawal of subjects should be fully documented.
The method used to derive the pharmacokinetic parameters should be specified.
The analytical report should include the results for all standard and quality control samples. Slide 25: APPLICATIONS FOR PRODUCTS CONTAINING NEW ACTIVE SUBSTANCES:
In the case of new active substances, the systemic availability of the substance in its intended pharmaceutical form is measured in comparison with intravenous administration.
Such studies may be exempted if the absence of differences in the in vivo performance can be justified by satisfactory in vitro data.
APPLICATIONS FOR PRODUCTS CONTAINING APPROVED ACTIVE SUBSTANCES:
A. Bioequivalence studies:
In vivo bioequivalence studies are needed when there is a risk that possible differences in bioavailability may result in therapeutic in equivalence. Slide 26: oral immediate release drug formulations with systemic action
Non-oral and non-parenteral drug formulation designed to act by systemic absorption.
Sustained or otherwise modified release drug formulation.
Fixed-dose combination products.
If a product has been reformulated from the formulation initially approved, a bioequivalence study is required.
In cases where the bioavailability of the product undergoing change has been investigated and an acceptable correlation between in vivo performance and in vitro dissolution has been established, the requirements for in vivo demonstration of bioequivalence can be waived if the dissolution rate in vitro of the new product is similar to that of the already approved medicinal product under the same test conditions as used to establish the correlation.