Assessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive?
Purpose: In order to evaluate the permissiveness of current bioequivalence requirements for antiepileptic drugs we investigated how accurate Cmax and AUC0-t of generic antiepileptic drugs approved in Brazil are in comparison to reference products. Methods: Data collected from assessment reports of a...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2014-05-01
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| Series: | Journal of Pharmacy & Pharmaceutical Sciences |
| Online Access: | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/21116 |
| _version_ | 1797722581638316032 |
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| author | Camila F Rediguieri Jorge L Zeredo |
| author_facet | Camila F Rediguieri Jorge L Zeredo |
| author_sort | Camila F Rediguieri |
| collection | DOAJ |
| description | Purpose: In order to evaluate the permissiveness of current bioequivalence requirements for antiepileptic drugs we investigated how accurate Cmax and AUC0-t of generic antiepileptic drugs approved in Brazil are in comparison to reference products. Methods: Data collected from assessment reports of approved bioequivalence studies archived in the Brazilian regulatory agency in 2007-2012 were: geometric mean ratios and 90% confidence intervals (CI) for Cmax and AUC0-t, intra-subject variability (CV) of Cmax and AUC0-t and number of subjects. Results: The average difference in Cmax and AUC0-t between generic and reference products was 5% and 3%, respectively. Maximum deviation from 1.00 of the CI of Cmax can achieve 15-20% (demonstrated in 27% of studies); for AUC0-t, 25% of studies showed the deviation can be >10%. All studies that used adequate number of subjects for a 90% CI of 0.90-1.11 complied with it for AUC0-t, except one of carbamazepine, but only 33% complied with it for both AUC0-t and Cmax. The CV was strongly correlated to the maximum CI deviation for AUC0-t (CV of approximately 15% corresponding to deviation of 10%). Studies that presented maximum CI deviation ≤ 10 % together with CV ≤ 15% for AUC0-t represented 65% of the total. Weaker correlation was observed for Cmax and no correlation was seen between maximum CI deviation and number of subjects. Conclusions: Modification in legislation for bioequivalence of antiepileptic drugs is suggested, not only with constraint of AUC0-t 90% CI to 0.90-1.11, but also with limitation of the CV to 15%, as to assure similar variance in pharmacokinetics and diminish the risk of critical plasma-level fluctuation when switching between generic and reference formulations. Although most generics presented differences ≤ 10% in AUC0-t compared to their references, some narrow therapeutic index drugs displayed differences that could be clinically significant after product substitution.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page. |
| first_indexed | 2024-03-12T09:49:24Z |
| format | Article |
| id | doaj.art-c2558845a29d47ce97a17a681935fbf1 |
| institution | Directory Open Access Journal |
| issn | 1482-1826 |
| language | English |
| last_indexed | 2024-03-12T09:49:24Z |
| publishDate | 2014-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Journal of Pharmacy & Pharmaceutical Sciences |
| spelling | doaj.art-c2558845a29d47ce97a17a681935fbf12023-09-02T12:39:27ZengFrontiers Media S.A.Journal of Pharmacy & Pharmaceutical Sciences1482-18262014-05-0117210.18433/J3659ZAssessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive?Camila F Rediguieri0Jorge L Zeredo1Brazilian Health Surveillance Agency - ANVISAUniversity of BrasiliaPurpose: In order to evaluate the permissiveness of current bioequivalence requirements for antiepileptic drugs we investigated how accurate Cmax and AUC0-t of generic antiepileptic drugs approved in Brazil are in comparison to reference products. Methods: Data collected from assessment reports of approved bioequivalence studies archived in the Brazilian regulatory agency in 2007-2012 were: geometric mean ratios and 90% confidence intervals (CI) for Cmax and AUC0-t, intra-subject variability (CV) of Cmax and AUC0-t and number of subjects. Results: The average difference in Cmax and AUC0-t between generic and reference products was 5% and 3%, respectively. Maximum deviation from 1.00 of the CI of Cmax can achieve 15-20% (demonstrated in 27% of studies); for AUC0-t, 25% of studies showed the deviation can be >10%. All studies that used adequate number of subjects for a 90% CI of 0.90-1.11 complied with it for AUC0-t, except one of carbamazepine, but only 33% complied with it for both AUC0-t and Cmax. The CV was strongly correlated to the maximum CI deviation for AUC0-t (CV of approximately 15% corresponding to deviation of 10%). Studies that presented maximum CI deviation ≤ 10 % together with CV ≤ 15% for AUC0-t represented 65% of the total. Weaker correlation was observed for Cmax and no correlation was seen between maximum CI deviation and number of subjects. Conclusions: Modification in legislation for bioequivalence of antiepileptic drugs is suggested, not only with constraint of AUC0-t 90% CI to 0.90-1.11, but also with limitation of the CV to 15%, as to assure similar variance in pharmacokinetics and diminish the risk of critical plasma-level fluctuation when switching between generic and reference formulations. Although most generics presented differences ≤ 10% in AUC0-t compared to their references, some narrow therapeutic index drugs displayed differences that could be clinically significant after product substitution. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/21116 |
| spellingShingle | Camila F Rediguieri Jorge L Zeredo Assessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive? Journal of Pharmacy & Pharmaceutical Sciences |
| title | Assessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive? |
| title_full | Assessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive? |
| title_fullStr | Assessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive? |
| title_full_unstemmed | Assessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive? |
| title_short | Assessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive? |
| title_sort | assessing bioequivalence of antiepileptic drugs are the current requirements too permissive |
| url | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/21116 |
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