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Evaluation of In Vitro and In Vivo Equivalence Data - Coggle Diagram
Evaluation of In Vitro and In Vivo Equivalence Data
BCS-based Biowaiver
a regulatory drug approval process when the dossier (application) is approved based on evidence other than through in vivo equivalence testing
in vitro instead of in vivo BE testing
comparison of test and reference
a biowaiver based on BCS considers
solubility and intestinal permeability (BCS) class
similarity of dissolution profiles
excipients
risk assessment
BCS-based biowaiver guidelines
when the in vivo dissolution of an IR solid oral dosage form is rapid or very rapid in relation to gastric emptying and the drug has high solubility, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or GI transit time
combining the dissolution of the pharmaceutical product with these two properties of the drug (solubitliy and permeability), takes the three major factors that govern the rate and extent of drug absorption form immediate-release solid dosage forms into account.
Dissolution Profiles Comparison
BCS Class 1
the multisource and comparator product are very rapidly dissolving or similarly rapidly dissolving
if rapidly dissolving
dissolution profile of the generic product must be similar to that of the reference product in pH 1.2, 4.5 & 6.8 buffer
if both products are very rapidly dissolving, profile comparison is not necessary
BCS Class 2
the multisource and comparator product are very rapidly dissolving
both the reference are very rapidly dissolving in all 3 media
Comparative dissolution testing
dissolution test that includes comparison of the dissolution profiles between a mutlisource product (test) and the comparator produce (reference) in three media (pH 1.2, 4.5 and 6.8)
multipoint dissolution testing
last time point
a maximum of one-tiome point should be considered after 85% dissolution of the reference (comparator) product has been reached
Statistical Evaluation of In Vivo Bioequivalence Data
Generic products
a generic drug is BE to the listed drug if the rate and extent of the absorptiion (BA) of the generic drug do not show a significant difference from the BA of the listed drug when administered at the same molar dose under similar experimental conditions in either a single dose or multiple doses
Review of In Vivo Equivalence Studies
Conventional Design: 2x2
a two-period, two sequence, single-dose, cross-over, randomized design in healthy human volunteers
Cross over Design
In Vivo Equivalence Studeis
What are the parameters being assessed?
measures of BA are based upon measures of the concentration of drug in the blood and we must assume that there is a direct relationship between the concentration of drug we detect in the blood and the concentration of the drug at the site of action
area under plasma concentration-time curve (AUC)
peak plasma concentration
time to reach the peak concentration
Statistical Approaches
the determination of the 90% confidence interval around the ratio of the log transformed population means (test and reference) for the pharmacokinetic paramenters under consideration
the 90% CI should lie between 80-125%
if the API has narrow therapeutic index -> the range is 90-111%
carrying out two one-sided tests ate the 5% level of significance
point estimates
in the early 1990s, the add-on design (AOD) was very popular and was mentioned by many regulatory documents