基于体外数据模拟和预测体内PK
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直接放大，误差极大
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IVIVE vs. Allometric scaling
Old Paradigm：
Use in vivo animal model as the predictor of human behavior (eg. allometric scaling)
New Paradigm
Muscle Skin
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Absorption
Absorption term in compartment number i:
Ka’
Mdiss(i)
ASFtrans,I and ASFpara,i = transcellular and paracellular absorption scale factor in compartment i (nominal value is surface/volume, which is 2/Ri) Absorption R scale factors Ri = radius of compartment i i (ASF) account for changes in Ptrans,i and Ppara,i= transcellular and paracellular permeability in compartment i* absorption due to regional Vlum,i = volume of lumen for compartment i differences in radius, C(t)lum,i = lumen concentration in compartment i ionization, tight junction gap, C(t)entU,i = unbound enterocyte concentration in compartment i Li and carrier-mediated C(t)pvU = unbound portal vein concentration
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Allometric scaling
PK决定因素不同
生理解剖体系 代谢基因型和表型 组织成分如蛋白种类
To obtain “a” and “b”: plot the body weight of the species (at least 3 species) vs parameter of interest such as clearance
Distribution
Steady state volume of distribution is estimated using the tissue volumes and tissue:plasma partition coefficients according to Poulin:
∗ : ∗ ∗
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Clearance
In GastroPlus, the total clearance, CL, is the sum of clearance from every eliminating organ;
But mainly hepatic (CLH), renal (CLR), and biliary (CLB):
transport.
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Solubility, Dissolution, and Permeability
Three primary properties of a drug/dosage form can limit absorption in the gastrointestinal tract:
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Parameters describe PK profile
Absorption
Volume of distribution
Clearance
Half-life
Bioavailability
Dosing regimen： How often？
Dosing regimen： How much？
ACAT Model
Each physiology includes default values for: •pH in each compartment •Transit time for each compartment •Lengths & radii of each compartment •SEFs of each compartment •Stomach volume •Bile salt concentration in each compartment •Pore size in each compartment •Porosity/PoreLength in each compartment •Hepatic blood flow rate •Gut enzyme and transporter Brain distributions Adipose
Use predictive, relevant in vitro data that will feed the model for predicting in vivo behavior
IVIVE: 体外体内转化 （In Vitro In Vivo Extrapolation）
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Empirical method vs. PBPK:
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Clearance：hepatic
Step 1. In vitro incubation of drug with microsomes/hepatocytes/liver slices to obtain enzyme kinetic constants Vmax and Km and the in vitro intrinsic clearance Step 2. Scale in vitro enzyme kinetic constants to in vivo conditions based on species-specific physiological scale factors.
Solubility Dissolution rate Intestinal permeability
GastroPlus™ simulation ：
Input data required would be preformulation information (solubility, permeability, pKa·····) Structure-property predictions (from ADMET Predictor™) provide estimates for: pKa, logP, solubility, permeability, etc. Accurate physiological situations are taken into consideration
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Absorption
Total amount dissolved Total amount absorbed Total amount into portal vein
Total amount into systemic circulation (bioavailability)
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CLint in vitro
CLint (whole organ) in vivo
Step 3. Based on a hepatic blood flow model (e.g. Venous equilibrium model), determine in vivo hepatic clearance. Rate of drug elimination = CLh × Concentration
投入资金高 研发周期长 药物研发的成功率较低
Mark E Bunnage. Getting pharmaceutical R&D back on target. Nature Chemical Biology. 2011, 7: 335–339.
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Methods to predict pharmacokinetics
基于体外数据模拟和预测体内PK
In Vitro In Vivo Extrapolation
page1
How to Predict PK with GastroPlus IVIVE approach
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Why predict pharmacokinetics?
Combined R&D survival by development phase for 14 large pharmaceutical companies (Abbott, AstraZeneca, Bayer, BristolMyers Squibb, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Pfizer, Roche, SanofiAventis and Schering-Plough)
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What is Fraction Absorbed (Fa) ?
Modern (FDA) Definition of Absorption
Fa
Absorption
FDp
(not Fa!)
F
(not Fa!)
D
A
PV
SC
Metabolism
Metabolism page9
* Modified from van de Waterbeemd, H, and Gifford, E. ADMET In Silico Modelling: Towards Prediction Paradise? Nat. Rev. Drug Disc. 2003, 2:192-204
