Drug product performance in-vivo

The release of the drug substance from the drug product leading to the bioavailability of the drug substance. The assessment of drug product performance is imp. Since bioavailability is related both to the pharmacodynamic responses and the adverse events. The performance tests relate the quality of a drug product to clinical safety and efficacy.
Bioavailability studies are drug product performance studies used to define
the effect of changes in the physicochemical properties of the drug substance, the formulation of the drug, and the manufacturing process of the drug product.

1. Created by Ms . Darekar Sayali S. M. Pharm- Pharmaceutics (1 Year) DRUG PRODUCT PERFORMANCE, IN VIVO 1

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3. FLOW OF PRESENTATION Drug Product Performance (In vivo) Bioavailability and Bioequivalence Methods for assessing bioavailability Bioequivalence studies Design and evaluation of bioequivalence studies Study designs Crossover study designs Study submission and Drug review process References 3

4. DRUG PRODUCT PERFORMANCE (IN VIVO) The release of the drug substance from the drug product leading to bioavailability of the drug substance. The assessment of drug product performance is imp. Since bioavailability is related both to the pharmacodynamic responses and the adverse events. The performance tests relate the quality of a drug product to clinical safety and efficacy. Bioavailabilty studies are drug product performance studies used to define t he effect of changes in the physicochemical properties of the drug substance, the formulation of the drug , and the manufacture process of the drug product. 4

5. BIOEUIVALENCE STUDIES IN NEW DRUG DEVELOPMENT (NDA) Used to compare : Early and late clinical trial formulations Formulations used in clinical trials and stability studies, if different Clinical trial formulations and to be marketed drug products , if different 5

6. BIOEQUIVALENCE STUDIES IN GENERIC DRUG DEVELOPMENT (ANDA) A generic drug product is a multisource drug product that has been approved by the FDA as a therapeutic equivalent to the reference listed drug product and has proven equivalent drug product performance . The generic drug manufacturer must demonstrate that the generic drug product is pharmaceutically equivalent, bioequivalent , and therapeutically equivalent to the comparator brand-name drug product . 6

7. PURPOSE OF BIOAVAILABILITY STUDIES Bioavailability studies are performed for both approved active drug ingredients and therapeutic moieties not yet approved for marketing by the FDA . New formulations of active drug ingredients must be approved by the FDA before marketing . FDA ensures that the drug product is safe and effective for its labeled indications are use . The drug product must meet all applicable standards of identity , strength , quality , and purity . 7

8. ABSOLUTE AVAILABILITY RELATIVE AVAILABILITY When the systemic availability of a drug administered orally is determined in comparison to its intravenous administration , it is called as absolute bioavailability . It is denoted by symbol F. Its determination is used to characterize a drugs absorption properties from the e. v . site . [AUC] po / dose po [ A UC ] IV / dose IV W hen the systemic availability of a drug after oral administration is compared with that of an oral standard of the same drug , It is referred to as relative or comparative bioavailability . It is denoted by symbol Fr . It is used to characterize absorption of a drug from its formulation . Relative availability =[ AUC]a D b *100 ( Frel ) [AUC]b D a Absolute availability ( Fabs ) = 8

9. METHODS FOR ASSESSING BIOAVAILABILITY In vivo measurement of active moiety or moieties in biological fluids Plasma drug concentration tmax Cmax AUC Urinary Drug excretion In vivo pharmacodynamic comparison Clinical endpoint study In vitro studies 9

10. PLASMA DRUG CONCENTRATION URINARY EXCRETION STUDIES Measurement of drug concentration in blood , plasma , or serum after drug administration is most direct and objective way to determine systemic bioavailability . t max C max AUC This method of assessing bioavailability is based on the principle that the urinary excretion of unchanged drug is directly proportional to the plasma concentration of drug. D etermination of bioavailability using urinary excretion data should be conducted only if at least 20 % of administered dose is excreted unchanged in urine. 10

11. BIOEQUIVALENCE STUDIES Differences in the predicted clinical response or an adverse event may be due to differences in the pharmacokinetic or pharmacodynamic behaviour of the drug. Bioequivalent drug products that have the same systemic drug bioavailability will have the same predictable drug response . However, variable clinical responses among individuals that are unrelated to bioavailability may be due to differences in the pharmacodynamics of the drug. 11

12. DESIGN AN EVALUATION OF BIOEQUIVALENCE STUDIES Bioequivalence studies are performed to compare the Bioavailability of the generic drug product to the brand name product. Statistical techniques should be of sufficient sensitivity to detect differences in rate and extent of absorption that are not attributable to subject variability. Once bioequivalence is established , it is likely that both the generic and brand name dosage forms will produce the same therapeutic effect. 12

13. STUDY DESIGN For many drug products, the FDA, Division of Bioequivalence, Office of Generic Drugs, provides guidance for the performance of in-vitro dissolution and in-vivo bioequivalence studies. Similar guidelines appear in the United States Pharmacopoeia NF. Currently, three different studies may be required for solid oral dosage forms, including F asting study F ood intervention study M ultiple-dose study 13

14. 1 PARALLEL DESIGN Two Formulations either test or standard are administered to two groups of volunteers. The formulations are administered randomly to the volunteers. Disadvantages: Inter subject variation 14 Group Formulation Formulation Group 1 A A Group 2 B B

15. 2 CROSS OVER STUDY DESIGN Each Subject is administered the test and standard formulation Latin square cross over design : Each subject receives just once each formulation Each Formulation is administered just once in each study period. A. Two Period two sequence cross over design. 15

16. B. 3-period 3-sequence cross over design C. 4-period 4-sequence cross over design 16

17. STUDY SUBMISSION AND DRUG REVIEW PROCESS The contents of NDAs and ANDAs are similar in terms of the quality of manufacture . The submission for an NDA must contain safety and efficacy studies as provided by animal toxicology studies, clinical efficacy studies, and pharmacokinetic/bioavailability studies. For the generic drug manufacturer, the bioequivalence study is the pivotal study in the ANDA that replaces the animal, clinical, and pharmacokinetic studies. 17

18. REFERENCES Davit B, Conner D, Shargel L. Drug product performance, in vivo: bioavailability and bioequivalence. Applied biopharmaceutics and pharmacokinetics, 7th edn . McGraw Hill Education, New York. 2016; pp 469-528. Venkateswarlu V. Biopharmaceutics and pharmacokinetics. PharmaMed Press; 2008; pp 331-357. Pack BW, Babayan Y, Schrad MA, Stroud PA, Sperry DC, White KC, Aburub A. Development of an in vivo-relevant drug product performance method for an amorphous solid dispersion. Journal of pharmaceutical and biomedical analysis. 2017 Aug 5;142:307-14. 18

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