get_profile_portion: Profile portion determination

In disprofas: Non-Parametric Dissolution Profile Analysis

Description

The function get_profile_portion() determines, depending on the value of use_EMA, which part of the profile will be used for the similarity assessment (EMA: European Medicines Agency).

Usage

get_profile_portion(data, tcol, groups, use_EMA = "yes", bounds = c(1, 85))

Arguments

data	A data frame with the dissolution profile data in wide format.
tcol	A vector of indices specifying the columns in data that contain the % release values. The length of tcol must be two or longer.
groups	A logical vector specifying different groups.
use_EMA	A character string indicating if the similarity factor f_2 should be calculated following the EMA guideline “On the investigation of bioequivalence” ("yes", the default) or not ("no"). A third option is "ignore". If use_EMA is "yes" or "no" the appropriate profile portion is determined on the basis of the values of the parameter bounds. If it is "ignore", the complete profiles are used as specified by the parameter tcol.
bounds	A numeric vector of the form c(lower, upper) specifying the “lower” and “upper” limits, respectively, for the % drug release given that use_EMA is "no". The default is c(1, 85). Mean % release values of any of the two groups being compared that are smaller than or equal to the lower bound are ignored and only the first mean % release value that is greater than or equal to the upper bound is included while all the subsequent values are ignored. If use_EMA is "yes" the bounds are c(1, 85) per definition.

Details

The function get_profile_portion() determines which part of a dissolution profile is used for comparison based on the recommendations of the European Medicines Agency's guideline “On the investigation of bioequivalence”. It says that profile similarity testing and any conclusions drawn from the results can be considered valid only if the dissolution profile has been satisfactorily characterised using a sufficient number of time points. For immediate release formulations comparison at 15 minutes is essential to know if complete dissolution is reached before gastric emptying. Where more than 85% of the drug is dissolved within 15 minutes, dissolution profiles may be accepted as similar without further mathematical evaluation. In case more than 85% is not dissolved at 15 minutes but within 30 minutes, at least three time points are required: the first time point before 15 minutes, the second at 15 minutes, and the third time point when the release is close to 85%. For modified release products, the advice given in the relevant guidance should be followed. Dissolution similarity may be determined using the f_2 statistic as follows:

f_2 = 50 log(100 / (sqrt(1 + (sum((R.bar(t) - T.bar(t))^2) / n)))) .

In this equation

f_2

is the similarity factor,

n

is the number of time points,

R.bar(t)

is the mean percent reference drug dissolved at time t after initiation of the study, and

T.bar(t)

is the mean percent test drug dissolved at time t after initiation of the study.

For both the reference and the test formulations, percent dissolution should be determined. The evaluation of the similarity factor is based on the following conditions (called “EMA Rules”, from the European Medicines Agency (EMA) guideline “On the investigation of bioequivalence”):

1. A minimum of three time points (zero excluded).

2. The time points should be the same for the two formulations.

3. Twelve individual values for every time point for each formulation.

4. Not more than one mean value of > 85% dissolved for any of the formulations.

5. The relative standard deviation or coefficient of variation of any product should be less than 20% for the first time point and less than 10% from the second to the last time point.

An f_2 value between 50 and 100 suggests that the two dissolution profiles are similar.

Value

The function returns a logical vector defining the appropriate profile portion.

References

European Medicines Agency (EMA), Committee for Medicinal Products for Human Use (CHMP). Guideline on the Investigation of Bioequivalence. 2010; CPMP/EWP/QWP/1401/98 Rev. 1.
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf

disprofas documentation built on Dec. 8, 2021, 5:10 p.m.