Limits of 80%-125% for AUC and 70%-143% for Cmax. What is the impact on bioequivalence studies?
| Autor: | Mei-Ling Chen, Lawrence J. Lesko, A Parekh, Roger Williams, W W Hauck |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Pharmacology
Therapeutic equivalency United States Food and Drug Administration Cmax Fasting Bioequivalence Confidence interval United States Bioavailability Food and drug administration Pharmacokinetics Therapeutic Equivalency Sample size determination Reference Values Research Design Area Under Curve Sample Size Statistics Humans Pharmacology (medical) Mathematics |
| Zdroj: | International journal of clinical pharmacology and therapeutics. 39(8) |
| ISSN: | 0946-1965 |
| Popis: | Objective: The US Food and Drug Administration (FDA) currently uses bioequivalence (BE) limits for fasting BE studies that are based on the 90% confidence interval for the ratio of difference of the test and reference products C max and AUC falling within 80% to 125%. The FDA has also proposed that BE limits be used similarly for AUC and C max measurements from fed BE studies. In some cases, regulatory agencies have considered a wider BE limit for C max , because of the typically higher variability of C max compared to AUC. We investigated the consequences of changing from an 80%/ 125% limit for both pharmacokinetic measures to one that uses a limit of 80%/125% for AUC and 70%/143% for C max . Methods: We computed the sample sizes required for BE studies using 80%/ 125% for AUC and 70%/143% for C max as BE limits. We also determined the range of the ratios of C max and AUC values in a study that could meet the 70%/143% and 80%/125% BE limits. Results: The sample size for the study, in order to have adequate power with 80%/125% for AUC and 70%/143% for C max , will be determined primarily by the intrasubject variability of AUC, though with a substantial proportion of studies (about one third) still determined by the variability of C max . The ratio of mean C max values that can pass a wider 70%/143% BE limit could easily be as high as 128%. Conclusion: Without further scientific or clinical rationale, we find it difficult to justify widening the bioequivalence limit for C max to 70%/143% for either fasting or fed BE studies. |
| Databáze: | OpenAIRE |
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