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Predictive Potential of C_max Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ₂ Similarity Factor Method.

ABSTRACT: 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_mean) ƒ₂ 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_max) 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 ƒ₂ 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_mean ƒ₂ 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_mean ƒ₂ 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.

SUBMITTER: Henriques SC

PROVIDER: S-EPMC10610255 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Predictive Potential of Cmax Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ2 Similarity Factor Method.

Henriques Sara Carolina SC Paixão Paulo P Almeida Luis L Silva Nuno Elvas NE

Pharmaceutics 20231020 10

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 (Gmean) ƒ2 factor with a cut off of 35, which ...[more]

PMID: 37896259

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Project description:Introduction: Rifapentine, a potent semi-synthetic member of the rifamycin class, is approved for the treatment of tuberculosis due to its effective bactericidal properties. It is essential to assess the bioequivalence and bioavailability of different rifapentine formulations to ensure consistent clinical outcomes. This study compares the pharmacokinetic profiles of test and reference rifapentine capsules in healthy male volunteers.MethodsIn this single-dose, randomized, crossover study, 19 healthy male volunteers aged 18-40 received 0.6 g of either the test or reference rifapentine capsules. The reference is an NMPA-approved product, while the test is a modified version intended to match it in safety and efficacy; both contain the same active ingredient but may differ in excipients or manufacturing processes. Blood samples were collected at predefined intervals over a 84-h period following administration to measure rifapentine plasma concentrations using UPLC. Key pharmacokinetic parameters, including maximum concentration (Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC), were calculated and analyzed for bioequivalence.ResultsThe pharmacokinetic analysis demonstrated that both formulations of rifapentine had similar absorption rates and extent of exposure. The mean Cmax, Tmax, and AUC values were closely aligned between the two formulations. Statistical analysis, including ANOVA and bioequivalence testing, confirmed that the 90% confidence intervals for the primary pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-∞) fell within the acceptable range of 80%-125% for bioequivalence. Both formulations were well-tolerated with no serious adverse events reported.DiscussionThe results of this study confirm the bioequivalence of the test and reference formulations of rifapentine under the conditions tested. These findings support the interchangeable use of these formulations in clinical practice for the treatment of tuberculosis. This study contributes to the body of evidence needed to ensure that patients receive a consistent therapeutic effect when administered either formulation of rifapentine.ConclusionThe bioequivalence demonstrated between the test and reference rifapentine capsules supports their use in clinical settings where rifapentine is indicated for tuberculosis therapy. This study provides a robust foundation for the regulatory approval of generic formulations of rifapentine, ensuring that patients have access to effective and lower-cost medication options.

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Predictive Potential of C_max Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ₂ Similarity Factor Method.

Publications

Predictive Potential of C<sub>max</sub> Bioequivalence in Pilot Bioavailability/Bioequivalence Studies, through the Alternative ƒ<sub>2</sub> Similarity Factor Method.

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