Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union
Bioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in the European Union is currently established by demonstrating that the 90% confidence interval for the ratio of the population geometric means of the test compared to the reference product’s AUC, and in certain cases C...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/14/11/2349 |
| _version_ | 1797466808723177472 |
|---|---|
| author | Paulo Paixão Nuno Silva Rita Bento Guerreiro Kevin Blake Milton Bonelli José Augusto Guimarães Morais Alfredo García-Arieta Luís Filipe Gouveia |
| author_facet | Paulo Paixão Nuno Silva Rita Bento Guerreiro Kevin Blake Milton Bonelli José Augusto Guimarães Morais Alfredo García-Arieta Luís Filipe Gouveia |
| author_sort | Paulo Paixão |
| collection | DOAJ |
| description | Bioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in the European Union is currently established by demonstrating that the 90% confidence interval for the ratio of the population geometric means of the test compared to the reference product’s AUC, and in certain cases Cmax, is included within the tighter acceptance range of 90.00–111.11%. An alternative criterion, consisting of narrowed limits based on the within-subject variability of the reference product, was recently proposed. Its performance for a three-period partial replicate design was tested by simulation in terms of power to show BE, type I error (T1E) and sample size requirements. A new condition, a constraint on the test-to-reference geometric mean ratio (cGMR) to be contained within the range of 90.00–111.11%, was also tested. The probability of showing BE when the products differ more than 10% was increased, but only if the reference product’s within-subject variability was moderate-to-high. The inclusion of the additional cGMR limited this. An increase in the T1E (<7%) was observed. The inclusion of the additional cGMR did not change the highest inflation of the T1E. Finally, a significant sample size reduction was observed and the inclusion of the cGMR usually did not increase the required sample size. |
| first_indexed | 2024-03-09T18:44:56Z |
| format | Article |
| id | doaj.art-4a97e846e7ef467d9ec29b4ff1382fc4 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T18:44:56Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-4a97e846e7ef467d9ec29b4ff1382fc42023-11-24T06:20:46ZengMDPI AGPharmaceutics1999-49232022-10-011411234910.3390/pharmaceutics14112349Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European UnionPaulo Paixão0Nuno Silva1Rita Bento Guerreiro2Kevin Blake3Milton Bonelli4José Augusto Guimarães Morais5Alfredo García-Arieta6Luís Filipe Gouveia7Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, PortugalEuropean Medicines Agency (EMA), 1083 HS Amsterdam, The NetherlandsEuropean Medicines Agency (EMA), 1083 HS Amsterdam, The NetherlandsResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, PortugalEMA’s Pharmacokinetics Working Party, 1083 HS Amsterdam, The NetherlandsResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, PortugalBioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in the European Union is currently established by demonstrating that the 90% confidence interval for the ratio of the population geometric means of the test compared to the reference product’s AUC, and in certain cases Cmax, is included within the tighter acceptance range of 90.00–111.11%. An alternative criterion, consisting of narrowed limits based on the within-subject variability of the reference product, was recently proposed. Its performance for a three-period partial replicate design was tested by simulation in terms of power to show BE, type I error (T1E) and sample size requirements. A new condition, a constraint on the test-to-reference geometric mean ratio (cGMR) to be contained within the range of 90.00–111.11%, was also tested. The probability of showing BE when the products differ more than 10% was increased, but only if the reference product’s within-subject variability was moderate-to-high. The inclusion of the additional cGMR limited this. An increase in the T1E (<7%) was observed. The inclusion of the additional cGMR did not change the highest inflation of the T1E. Finally, a significant sample size reduction was observed and the inclusion of the cGMR usually did not increase the required sample size.https://www.mdpi.com/1999-4923/14/11/2349narrow therapeutic indexbioequivalencemedicines regulationgeneric medicinal products |
| spellingShingle | Paulo Paixão Nuno Silva Rita Bento Guerreiro Kevin Blake Milton Bonelli José Augusto Guimarães Morais Alfredo García-Arieta Luís Filipe Gouveia Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union Pharmaceutics narrow therapeutic index bioequivalence medicines regulation generic medicinal products |
| title | Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union |
| title_full | Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union |
| title_fullStr | Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union |
| title_full_unstemmed | Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union |
| title_short | Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union |
| title_sort | evaluation of a proposed approach for the determination of the bioequivalence acceptance range for narrow therapeutic index drugs in the european union |
| topic | narrow therapeutic index bioequivalence medicines regulation generic medicinal products |
| url | https://www.mdpi.com/1999-4923/14/11/2349 |
| work_keys_str_mv | AT paulopaixao evaluationofaproposedapproachforthedeterminationofthebioequivalenceacceptancerangefornarrowtherapeuticindexdrugsintheeuropeanunion AT nunosilva evaluationofaproposedapproachforthedeterminationofthebioequivalenceacceptancerangefornarrowtherapeuticindexdrugsintheeuropeanunion AT ritabentoguerreiro evaluationofaproposedapproachforthedeterminationofthebioequivalenceacceptancerangefornarrowtherapeuticindexdrugsintheeuropeanunion AT kevinblake evaluationofaproposedapproachforthedeterminationofthebioequivalenceacceptancerangefornarrowtherapeuticindexdrugsintheeuropeanunion AT miltonbonelli evaluationofaproposedapproachforthedeterminationofthebioequivalenceacceptancerangefornarrowtherapeuticindexdrugsintheeuropeanunion AT joseaugustoguimaraesmorais evaluationofaproposedapproachforthedeterminationofthebioequivalenceacceptancerangefornarrowtherapeuticindexdrugsintheeuropeanunion AT alfredogarciaarieta evaluationofaproposedapproachforthedeterminationofthebioequivalenceacceptancerangefornarrowtherapeuticindexdrugsintheeuropeanunion AT luisfilipegouveia evaluationofaproposedapproachforthedeterminationofthebioequivalenceacceptancerangefornarrowtherapeuticindexdrugsintheeuropeanunion |