BIOAVAILABILITY: means rate & extent of absorption of unchanged drug from its dosage form or site of administration to the systemic circulation. Order: Parentral(i,.v)>oral>rectal>topical Absolute Bioavailability: It is the systemic availability of drug after extravascular administration compared to i.v dosing of the same drug. F= [AUC]oral / [AUC]i.v*doseiv/doseoral
Relative Bioavailability: It is the systemic availability of the drug after oral administration is compared with that of an oral standard of the same drug. Fr=[AUC]test/ [AUC]std*dosetest/dosestd, where,Fr=Relative Bioavailability
Primary stages of development of a suitable dosage form for a new drug entity. Development of new formulation of existing drugs. Determination of influence of Excipient, patient related factors, drug-interaction on efficiency of absorption. Control of quality of drug prior to marketing.
A number of factors such as health, age, weight, enzyme status and number are concern. It is better to have the subjects of similar kinetics to avoid major variations. Health : Subjects should be of great health that is ascertained by various biochemical and medical examination.
Age : Elderly and children have different kinetics to adults. Subjects between 18 – 35 years are preferred.Number : Number of participants should be kept minimum required for carrying out a reliable, well designed study.
However, in overweight and underweight Vd maybe different. Hence, to better match the subject ,normal weights are preferred. Usually 140-200lbEnzyme Status : Enzyme activity can be altered by alteredkinetics of the drug in case of smokers or subjectstaking other drugs leading to drug-druginteraction.
Methods Of Bioavailability Indirect Direct Or Or Pharmacokinetic Pharmacodynamic Method method Urinary AcutePlasma-level Therapeutic Excretion Pharmacological Studies Response Studies Response
Based on assumption that 2 dosage forms that exhibit super-imposable plasma level-time profiles in a group of subjects should result in identical therapeutic activity. For a single dose studies,3 sampling points & multiple dose studies 5-6 sampling points should be taken. Requires collection of blood for a period of 2-3 biological half-lives.
Cmax : Represents maximum plasma drug concentration after oral administration of a drug. Indicates whether drug is sufficiently absorbed systemically to give a therapeutic response. Warns about toxic level of a drug.
tmax: Represents to time required to reach maximum plasma concentration after drug administration. Indicates rate of absorption. At tmax, rate of absorption equals to rate of elimination. AUC: It is a measure of extent of drug bioavailability. Independent of route of administration. Measured by trapezoidal rule method.
Based on assumption that the urinary excretion of unchanged drug is directly proportional to the plasma drug concentration. Concentration of metabolite excreted is never taken into account. Involves collection of urine for 7 biological half-lives.
(1) (dXu/dt)max: Maximum urinary excretion rate. Analogous to Cmax. It increases as rate & extent of absorption increases.(2) (tu)max: Time for maximum excretion rate. It increases as the rate of absorption decreases.(3) Xu: Cumulative amount of the drug excreted in the urine. It increases as the rate of absorption increases.
(1) Acute Phamacological Response: requires demonstration of dose-response curve. Includes determination of change in EEG or ECG readings,pupil diameter. Requires measurement of responses for at least 3 biological half-lives. Used when indirect method produce inaccurate results.
(2) Therapeutic response: Based on observing the clinical response to a drug formulation given to patient suffering from disease for which intended to be used. Disadvantages: Quantitation of response is too imprecise. Physiological status of the patient may be changed during study. Patient may not get sufficient drug for adequate treatment.
(2) Dosage form related: Disintegration time Manufacturing variables - Manufacturing process - Excipients Nature & type of dosage form: Solutions>emulsion>suspension>coarse powder>capsules>tablets
(3) Physico-chemical properties of drug: Particle size & effective surface area It can be lowered by micronization,but it is true for non-hydrophobic drug. e.g. :Griseofulvin,Chloramphenicol,etc. It is vice-versa for hydrophobic drug e.g.: Aspirin,Phenacetin,Phenobarbital.Polymorphism & Amorphous Chloramphenicol palmitate A,B,C,out of these three polymorphic forms,B shows best availability.
Pseudo polymorphism (hydrates & solvates) Anhydrous form of theophylline & ampicillin have higher aqueous solubility than monohydrate & trihydrate form. Chloroform solvate of Griseofulvin are more water- soluble than their non-solvated form.Salt form of the drug Bioavailability of novobiocin from its sodium or calcium salt, & free acid was found to be in ratio of 50:25:1. Lipophilicity of the drug
Bioavailability problems in oral controlled delivery system:(a) G.I.T transit time & regional absorption(b) Incomplete absorption(c) Increased first pass metabolism(d) Dose dumping(e) Effect of food(f) Effect of diurnal variation(g) Increased variability
Satisfactory steady-state plasma level should be obtained with test & reference product in patients. Determination of Css should be determined by comparison of Cmin on 3 or more consecutive days. Failure to achieve satisfactory steady state may indicate lack of patient compliance, failure of dosage form performance.
Comparison of pharmacokinetic parameters should be limited to subject who achieve steady-state condition. Comparison of AUC during a dosing interval is only proper if both test & reference drug are at steady state. Fluctuation greater than 15% should be closely examined or food effect, diurnal variation, achievement of steady state. Fluctuation=Cmax- Cmin/(Cmax+Cmin/2)
1.Title a. Principal investigator b. Project or protocol number & date2.Study objective
3.Study design a. Design b. Drug products -Test product -Reference product c. Dosage regimen d. Sample collection schedule e. Housing/Confinement f. Fasting meals g. Analytical method
4.Study population a. Subjects b. Subject selection -Medical history -Physical examination - Laboratory tests c. Inclusion/Exclusion criteria d Restrictions/Prohibitions
5. Clinical procedures a. Basic principles b. Biological sampling schedule & handling procedures c. Activity of subjects6. Ethical considerations: a. Basic principles b. Instituitional review board c. Informed consent d. Indications for subject withdrawal e. Adverse reactions & emergency procedures
7. Facilities8. Data analysis a. Analytical validation procedure b. Statistical treatment of data9. Drug accountability10. Appendix