The Suitability of an in Situ Perfusion Model for Permeability Determinations: Utility for BCS Class I Biowaiver Requests

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• 作者：Jae-Seung Kim ; Stefanie Mitchell ; Paul Kijek ; Yasuhiro Tsume ; John Hilfinger ; Gordon L. Amidon
• 刊名：Molecular Pharmaceutics
• 出版年：2006
• 出版时间：December 2006
• 年：2006
• 卷：3
• 期：6
• 页码：686 - 694
• 全文大小：219K
• 年卷期：v.3,no.6(December 2006)
• ISSN：1543-8392

文摘

The FDA has published recommendations for sponsors who wish to request a waiverof in vivo bioavailability (BA) or bioequivalence (BE) studies for immediate release (IR) solidoral dosage forms based on the Biopharmaceutics Classification System (BCS). Biowaiverscan be requested for IR formulations in which the active ingredient is shown to be a BCS classI drug: that is, a drug showing high permeability and high solubility over a pH range of 1-7.5.For permeability determinations, a variety of experimental methods can be used, such as therat in situ single pass perfusion or Caco-2 cell culture models, once the suitability of the particularmethod is established. Following the recommended procedure for assessing the suitability ofpermeability determinations, we determined the permeability of 20 test drugs using the in situsingle pass perfusion model in rats. The test compounds were coperfused through jejunalintestinal segments with an internal permeability reference standard (metoprolol) over a 90 mintime period. Sample analysis was performed by HPLC, and the ratio of the effective permeability,P_eff (cm/s), of test compound to that of metoprolol was determined. To address the question oftest drug permeabilities that approach that of the internal standard, we propose that a statisticalanalysis such as the "0.8-1.25 rule" used for in vivo or in vitro bioequivalence studies provideguidance for permeability classification using the in situ single pass perfusion model. Wedeveloped a method using the 90% confidence interval of the permeability ratio of the test tointernal reference standard in order to differentiate between high and low permeabilitycompounds. This analysis allowed for the proper permeability classification of all of the testcompounds and suggests a robust means for assessing drug permeability classification.