iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes

被引：15

作者：

Baeckman, Per

Cabal, Antonio ^{[1
]}

Clark, Andy ^{[2
]}

Ehrhardt, Carsten ^{[3
]}

Forbes, Ben ^{[4
]}

Hastedt, Jayne ^{[5
]}

Hickey, Anthony ^{[6
,7
]}

Hochhaus, Guenther ^{[8
]}

Jiang, Wenlei ^{[9
]}

Kassinos, Stavros ^{[10
]}

Kuehl, Philip J. ^{[11
]}

Prime, David ^{[12
]}

Son, Yoen-Ju ^{[13
]}

Teague, Simon P. ^{[14
]}

Tehler, Ulrika ^{[15
]}

Wylie, Jennifer ^{[16
]}

机构：

[1] Eisai, Woodcliff Lake, NJ 07677 USA

[2] Aerogen Pharma, San Mateo, CA 94402 USA

[3] Trinity Coll Dublin, Dublin 2, Ireland

[4] Kings Coll London, London WC2R 2LS, England

[5] JDP Pharma Consulting, San Carlos, CA 94070 USA

[6] Univ N Carolina, Chapel Hill, NC 27599 USA

[7] RTI Int, Res Triangle Pk, NC 27709 USA

[8] Univ Florida, Gainesville, FL 32611 USA

[9] US FDA, Ctr Drug Evaluat & Res, Off Gener Drugs, Off Res & Stand, Silver Spring, MD 20993 USA

[10] Univ Cyprus, CY-1678 Nicosia, Cyprus

[11] Lovelace Biomed, Albuquerque, NM 87108 USA

[12] Pulm Drug Delivery Consultant, Ware SG12, Herts, England

[13] Genentech Inc, San Francisco, CA 94080 USA

[14] GlaxoSmithKline, Stevenage SG1 2NY, Herts, England

[15] AstraZeneca, Sci R&D, Adv Drug Delivery Pharmaceut Sci, S-43183 Gothenburg, Sweden

[16] Merck & Co Inc, Kenilworth, NJ 07033 USA

来源：

MOLECULAR PHARMACEUTICS | 2022年

关键词：

biopharmaceutics classification system; inhaled drugs; iBCS; mechanistic modeling; critical product attributes; pulmonary availability; FLUTICASONE PROPIONATE; PHARMACOKINETICS; DISSOLUTION; INHALATION; EXPOSURE; HEALTHY;

D O I：

10.1021/acs.molpharmaceut.2c00112

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed (F-abs) and (ii) drug half-life in lumen (t(1/2)) to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (P-eff). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes. Drugs with Do < 1 and P-eff > 1 x 10(-6 )cm/s show rapid (t(1/2) < 20 min) and complete (F-abs > 85%) absorption from lung lumen into lung tissue. At Do > 1, dissolution becomes a critical drug product attribute and F-abs becomes dependent on regional lung deposition. The input attributes used here, Do and P-eff, thus enabled the classification of inhaled drugs into parameter spaces with distinctly different biopharmaceutic risks. The implications of these findings with respect to the design of an inhalation-based biopharmaceutics classification system (iBCS) and to the need for experimental methodologies to classify drugs need to be further explored.

引用

页码：2040 / 2047

页数：8

共 33 条

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