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The suitability of an in situ perfusion model for permeability determinations: utility for BCS class I biowaiver requests.
Mol Pharm. 2006 Nov-Dec; 3(6):686-94.MP

Abstract

The FDA has published recommendations for sponsors who wish to request a waiver of in vivo bioavailability (BA) or bioequivalence (BE) studies for immediate release (IR) solid oral dosage forms based on the Biopharmaceutics Classification System (BCS). Biowaivers can be requested for IR formulations in which the active ingredient is shown to be a BCS class I 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 the rat in situ single pass perfusion or Caco-2 cell culture models, once the suitability of the particular method is established. Following the recommended procedure for assessing the suitability of permeability determinations, we determined the permeability of 20 test drugs using the in situ single pass perfusion model in rats. The test compounds were coperfused through jejunal intestinal segments with an internal permeability reference standard (metoprolol) over a 90 min time period. Sample analysis was performed by HPLC, and the ratio of the effective permeability, Peff (cm/s), of test compound to that of metoprolol was determined. To address the question of test drug permeabilities that approach that of the internal standard, we propose that a statistical analysis such as the "0.8-1.25 rule" used for in vivo or in vitro bioequivalence studies provide guidance for permeability classification using the in situ single pass perfusion model. We developed a method using the 90% confidence interval of the permeability ratio of the test to internal reference standard in order to differentiate between high and low permeability compounds. This analysis allowed for the proper permeability classification of all of the test compounds and suggests a robust means for assessing drug permeability classification.

Authors+Show Affiliations

TSRL, Inc., Ann Arbor, Michigan 48108, USA. jkim@tsrlinc.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Evaluation Study
Journal Article

Language

eng

PubMed ID

17140256

Citation

Kim, Jae-Seung, et al. "The Suitability of an in Situ Perfusion Model for Permeability Determinations: Utility for BCS Class I Biowaiver Requests." Molecular Pharmaceutics, vol. 3, no. 6, 2006, pp. 686-94.
Kim JS, Mitchell S, Kijek P, et al. The suitability of an in situ perfusion model for permeability determinations: utility for BCS class I biowaiver requests. Mol Pharm. 2006;3(6):686-94.
Kim, J. S., Mitchell, S., Kijek, P., Tsume, Y., Hilfinger, J., & Amidon, G. L. (2006). The suitability of an in situ perfusion model for permeability determinations: utility for BCS class I biowaiver requests. Molecular Pharmaceutics, 3(6), 686-94.
Kim JS, et al. The Suitability of an in Situ Perfusion Model for Permeability Determinations: Utility for BCS Class I Biowaiver Requests. Mol Pharm. 2006 Nov-Dec;3(6):686-94. PubMed PMID: 17140256.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The suitability of an in situ perfusion model for permeability determinations: utility for BCS class I biowaiver requests. AU - Kim,Jae-Seung, AU - Mitchell,Stefanie, AU - Kijek,Paul, AU - Tsume,Yasuhiro, AU - Hilfinger,John, AU - Amidon,Gordon L, PY - 2006/12/5/pubmed PY - 2007/3/27/medline PY - 2006/12/5/entrez SP - 686 EP - 94 JF - Molecular pharmaceutics JO - Mol Pharm VL - 3 IS - 6 N2 - The FDA has published recommendations for sponsors who wish to request a waiver of in vivo bioavailability (BA) or bioequivalence (BE) studies for immediate release (IR) solid oral dosage forms based on the Biopharmaceutics Classification System (BCS). Biowaivers can be requested for IR formulations in which the active ingredient is shown to be a BCS class I 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 the rat in situ single pass perfusion or Caco-2 cell culture models, once the suitability of the particular method is established. Following the recommended procedure for assessing the suitability of permeability determinations, we determined the permeability of 20 test drugs using the in situ single pass perfusion model in rats. The test compounds were coperfused through jejunal intestinal segments with an internal permeability reference standard (metoprolol) over a 90 min time period. Sample analysis was performed by HPLC, and the ratio of the effective permeability, Peff (cm/s), of test compound to that of metoprolol was determined. To address the question of test drug permeabilities that approach that of the internal standard, we propose that a statistical analysis such as the "0.8-1.25 rule" used for in vivo or in vitro bioequivalence studies provide guidance for permeability classification using the in situ single pass perfusion model. We developed a method using the 90% confidence interval of the permeability ratio of the test to internal reference standard in order to differentiate between high and low permeability compounds. This analysis allowed for the proper permeability classification of all of the test compounds and suggests a robust means for assessing drug permeability classification. SN - 1543-8384 UR - https://www.unboundmedicine.com/medline/citation/17140256/The_suitability_of_an_in_situ_perfusion_model_for_permeability_determinations:_utility_for_BCS_class_I_biowaiver_requests_ L2 - https://doi.org/10.1021/mp060042f DB - PRIME DP - Unbound Medicine ER -