PBPK模拟药物经眼鼻肺部给药后的体内行为

PBPK模拟药物经眼鼻肺部给药后的体内行为

Topical drug delivery systems

1.safe and efficacious, duration

2.reduced onset time and increased

therapeutic ratio,minimize

systemic side effects

3.drug levels in the relevant effect

compartment cannot be easily

assessed.

4.clinical performance is not easy to

predict or assess from in vitro or

systemic PK data.

Dosage form

Ocular drug delivery

Nasal-

Pulmonary drug

delivery OC: Topical Soln/ Susp OC: Vitreal Soln/ Susp OC: Vitreal Impt OC: SubConj Impt

PL: Soln/ Powder PL: Inf Soln/ Powder PL:IT Soln/ Powder PL: Nasal Soln/ Powder

PBPK of Ocular model in FDA

☐据最近的报告，2012年全球眼科用药市场销售额为160亿美金，预计到2018年将达到216亿美金。全球眼科用药显著增长源于眼科疾病快速增加，例如糖尿病导致的视网膜病变、黄斑变性。所以眼科用药市场预计在

2013-2018年每年将以5.2%的速率升涨。

☐2014年FDA资助美国Simulations Plus进行“开发建模与模拟在眼部给药剂型设计的应用能力”项目开发。

吸收模型

A C A T 模

型(

)

(

肝肠循环)

肾、胆汁排泄

胆囊

肝代谢

随粪排出

肠代谢

处置模型

(经典房室模型或PBPK 模型)

ACAT & PBPK Model

Why PBPK?

Pulmonary

Compartmentalization of the Lung

Parameters

☐Drug-dependent parameters

☐Can be edited and saved into

the database

☐Default values of selected

parameters based on

correlations published in the

literature and internal studies

☐Physiology parameters,

independent of drug molecule

☐Can be edited and saved into

custom pulmonary physiology

files

☐The fractions (f ET1to f AI ) can be

●Calculated (dependent, e.g., on particle radius) –option “ICRP66”

●Manually specified by the user (independent of radius) –option “User Defined”

Distribution of Dose into Pulmonary

Dose

Amt in ET1 =f ET1*Dose Amt in ET2 =f ET2*Dose Amt in BB =f BB *Dose

Amt in bb =f bb *Dose

Amt in AI =f AI *Dose

Nose Extra-thoracic

Thoracic

Bronchiolar Alveolar

Radius, shape factor, density

ICRP 66

f ET1to f AI

☐Regional lung deposition can be predicted (from particle size distribution using the ICRP66 deposition model) or specified manually by the user ☐Size distribution and additional information for drug carrier (excipient) can be incorporated in calculation of regional deposition

Regional Deposition Calculation

Carrier-coated API

Specific Nasal-Pulmonary Capabilities

☐Evaluation of the independent contribution of pulmonary and gut absorption after inhaled administration

☐Evaluation of formulation effects (dosage form, particle size, distribution, density, shape factor, presence of excipient,

etc...)

☐Additional mechanisms and functionality to be incorporated •Enzymes and transporters in the lung compartments

•Phagocytosis, lysosomal trapping

•New deposition models and physiologies