Predictive Potential of C<sub>max</sub> Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ<sub>2</sub> Similarity Factor Method
Pilot bioavailability/bioequivalence (BA/BE) studies are downsized trials that can be conducted prior to the definitive pivotal trial. In these trials, 12 to 18 subjects are usually enrolled, although, in principle, a sample size is not formally calculated. In a previous work, authors recommended th...
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| Format: | Article |
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MDPI AG
2023-10-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/10/2498 |
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| author | Sara Carolina Henriques Paulo Paixão Luis Almeida Nuno Elvas Silva |
| author_facet | Sara Carolina Henriques Paulo Paixão Luis Almeida Nuno Elvas Silva |
| author_sort | Sara Carolina Henriques |
| collection | DOAJ |
| description | Pilot bioavailability/bioequivalence (BA/BE) studies are downsized trials that can be conducted prior to the definitive pivotal trial. In these trials, 12 to 18 subjects are usually enrolled, although, in principle, a sample size is not formally calculated. In a previous work, authors recommended the use of an alternative approach to the average bioequivalence methodology to evaluate pilot studies’ data, using the geometric mean (G<sub>mean</sub>) ƒ<sub>2</sub> factor with a cut off of 35, which has shown to be an appropriate method to assess the potential bioequivalence for the maximum observed concentration (C<sub>max</sub>) metric under the assumptions of a true Test-to-Reference Geometric Mean Ratio (GMR) of 100% and an inter-occasion variability (IOV) in the range of 10% to 45%. In this work, the authors evaluated the proposed ƒ<sub>2</sub> factor in comparison with the standard average bioequivalence in more extreme scenarios, using a true GMR of 90% or 111% for truly bioequivalent formulations, and 80% or 125% for truly bioinequivalent formulations, in order to better derive conclusions on the potential of this analysis method. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling, accounting for different IOV levels. A redefined decision tree is proposed, suggesting a fixed sample size of 20 subjects for pilot studies in the case of intra-subject coefficient of variation (ISCV%) > 20% or unknown variability, and suggesting the assessment of study results through the average bioequivalence analysis, and additionally through G<sub>mean</sub> ƒ<sub>2</sub> factor method in the case of the 90% confidence interval (CI) for GMR is outside the regulatory acceptance bioequivalence interval of [80.00–125.00]%. Using this alternative approach, the certainty levels to proceed with pivotal studies, depending on G<sub>mean</sub> ƒ<sub>2</sub> values and variability scenarios tested (20–60% IOV), were assessed, which is expected to be helpful in terms of the decision to proceed with pivotal bioequivalence studies. |
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| issn | 1999-4923 |
| language | English |
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| publishDate | 2023-10-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-bc73f0ada8b64ca2a340f7b840d0d5ec2023-11-19T17:45:23ZengMDPI AGPharmaceutics1999-49232023-10-011510249810.3390/pharmaceutics15102498Predictive Potential of C<sub>max</sub> Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ<sub>2</sub> Similarity Factor MethodSara Carolina Henriques0Paulo Paixão1Luis Almeida2Nuno Elvas Silva3Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, PortugalBlueClinical Ltd., Senhora da Hora, 4460-439 Matosinhos, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, PortugalPilot bioavailability/bioequivalence (BA/BE) studies are downsized trials that can be conducted prior to the definitive pivotal trial. In these trials, 12 to 18 subjects are usually enrolled, although, in principle, a sample size is not formally calculated. In a previous work, authors recommended the use of an alternative approach to the average bioequivalence methodology to evaluate pilot studies’ data, using the geometric mean (G<sub>mean</sub>) ƒ<sub>2</sub> factor with a cut off of 35, which has shown to be an appropriate method to assess the potential bioequivalence for the maximum observed concentration (C<sub>max</sub>) metric under the assumptions of a true Test-to-Reference Geometric Mean Ratio (GMR) of 100% and an inter-occasion variability (IOV) in the range of 10% to 45%. In this work, the authors evaluated the proposed ƒ<sub>2</sub> factor in comparison with the standard average bioequivalence in more extreme scenarios, using a true GMR of 90% or 111% for truly bioequivalent formulations, and 80% or 125% for truly bioinequivalent formulations, in order to better derive conclusions on the potential of this analysis method. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling, accounting for different IOV levels. A redefined decision tree is proposed, suggesting a fixed sample size of 20 subjects for pilot studies in the case of intra-subject coefficient of variation (ISCV%) > 20% or unknown variability, and suggesting the assessment of study results through the average bioequivalence analysis, and additionally through G<sub>mean</sub> ƒ<sub>2</sub> factor method in the case of the 90% confidence interval (CI) for GMR is outside the regulatory acceptance bioequivalence interval of [80.00–125.00]%. Using this alternative approach, the certainty levels to proceed with pivotal studies, depending on G<sub>mean</sub> ƒ<sub>2</sub> values and variability scenarios tested (20–60% IOV), were assessed, which is expected to be helpful in terms of the decision to proceed with pivotal bioequivalence studies.https://www.mdpi.com/1999-4923/15/10/2498bioequivalencegeneric medicinal productspilot studiesƒ<sub>2</sub> factorpharmacokineticsmodelling and simulation |
| spellingShingle | Sara Carolina Henriques Paulo Paixão Luis Almeida Nuno Elvas Silva Predictive Potential of C<sub>max</sub> Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ<sub>2</sub> Similarity Factor Method Pharmaceutics bioequivalence generic medicinal products pilot studies ƒ<sub>2</sub> factor pharmacokinetics modelling and simulation |
| title | Predictive Potential of C<sub>max</sub> Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ<sub>2</sub> Similarity Factor Method |
| title_full | Predictive Potential of C<sub>max</sub> Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ<sub>2</sub> Similarity Factor Method |
| title_fullStr | Predictive Potential of C<sub>max</sub> Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ<sub>2</sub> Similarity Factor Method |
| title_full_unstemmed | Predictive Potential of C<sub>max</sub> Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ<sub>2</sub> Similarity Factor Method |
| title_short | Predictive Potential of C<sub>max</sub> Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ<sub>2</sub> Similarity Factor Method |
| title_sort | predictive potential of c sub max sub bioequivalence in pilot bioavailability bioequivalence studies through the alternative f sub 2 sub similarity factor method |
| topic | bioequivalence generic medicinal products pilot studies ƒ<sub>2</sub> factor pharmacokinetics modelling and simulation |
| url | https://www.mdpi.com/1999-4923/15/10/2498 |
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