Biopharmaceutics 5-6

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  • Created by: LBCW0502
  • Created on: 12-04-18 10:30
Describe features of acidic drugs with log P > 0
Absorbed from stomach and SI
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Describe features of drugs with MW < 270
Might have some paracellular absorption
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Describe features of basic drugs with log P > 0
Absorbed mainly from the SI via transcellular route
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Describe features of drugs with log P < 0
Not well absorbed via the transcellular route. If MW < 270 paracellular route predominates. If MW > 270 get poor absorption unless absorbed via active transport - higher MW (>500 g/mol), lower rate of absorption via transcellular route
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Drug solubility affects what?
The rate of absorption
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What is the Biopharmaceutics Classification System?
Categorises drug molecules based on intestinal permeability and aqueous solubility. Prognostic tool to facilitate oral drug product development. Extensively used by PI to predict in vivo data from in vitro assays of drug products for oral ROA
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The BCS categorises drugs into how many biopharmaceutical classes?
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What is the most desirable class?
Class I drugs
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What is the least desirable class?
Class IV drugs
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Is it possible to modify drugs in Classes II, II and IV so they fit into Class I?
Yes e.g. change pH, use of salts, co-solvents, micelles etc.
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Over how many of the marketed drugs qualify under Class II and IV?
Over 90%
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How many new investigational drugs suffer from poor aqueous solubility?
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Poor solubility prevents what?
Drugs from achieving clinically-meaningful plasma concentrations
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What does the FDA define the highest solubility point as?
The largest dose strength dissolving in 250 mL of aqueous medium within the pH range of 1-7.5 at 37 degrees Celsius (threshold)
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How is a drug considered highly permeable?
If the extent of oral absorption is greater than 90%
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What are the main objectives of the BCS?
Use of in vitro methodology to focus on permeability and solubility (as a function of pH) - leads to qualifying drug products for in vivo bio-equivalent studies. Regulatory mechanism used by drug developers/generic companies (obtain waiver)
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Describe features of Class I: High Solubility and High Permeability
Dissolve quickly in gastric/intestinal fluids, readily cross intestinal wall via passive diffusion, don't show F, eligible BCS waivers, absorption not affected by dissolution/GI residence time, excellent oral absorption
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What might exist beyond the scope of the BCS?
Addition absorption barriers e.g. luminal complexation and degradation can limit amount of drug available for absorption. Even after drug cross intestinal membrane, it may be metabolised within hepatocytes/pumped out of cells due to efflux mechanism
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Describe features of Class II: Poor Solubility and High Permeability
Poor solubility/slow dissolution, rate-limiting steps for oral absorption, very large dose-solubility ratio, compound dissolved to reach equilibrium solubility but solubility is too slow to achieve conc. gradient to drive passive diffusion
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What formulations can be designed to overcome solubility and dissolution rate problems?
Salt formation, particle size reduction, metastable forms, solid dispersion, complexation, lipid based formulations, precipitation inhibitors
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Describe features of Class III: High Solubility and Low Permeability
Passive diffusion is the rate-limiting step for oral absorption, the most effect way to improve absorption and F is to increase membrane permeability (approaches - prodrugs or permeation enhancers)
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Describe features of Class IV: Low Solubility and Low Permeability
Poor solubility/permeability, substantial investment in dosage form development with no guarantee of success. Combination of class II/III technologies can be used (low success rate) e.g. use of nano, complexes or co-crystals
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What is a major limitation of the BCS?
Does not produce an in-depth understanding of how drug metabolism and drug transport may impact PK performance of drug products
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What is the modified version of the classification system called?
The Biopharmaceutical Drug Disposition Classification System (BDDCS)
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Describe features of the BDDCS (link between BCS and drug metabolism)
Higher permeability of classes I and II allows readily access to metabolising enzymes with hepatocytes so classes I/II are eliminated via metabolism. Classes III/IV have low permeability, eliminated unchanged into urine and bile
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What are the advantages of BDDCS?
Useful framework to predict effects of food/enzyme transporter interplay, drug-drug interactions on PK of drug products. Easier to obtain accurate metabolism data than permeability data. Drug deposition profiles, expand class I for in vivo studies
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How is the BDDCS used to predict transported effect on oral absorption for class I?
High solubility/permeability of class I compounds allows high concentration in gut to saturated both absorptive and efflux transporter. Transporters play no significant role affecting oral absorption of class I compounds
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How is the BDDCS used to predict transported effect on oral absorption for class II?
High permeability allows access across gut membrane, absorptive transporters will not effect absorption. Low solubility prevents saturation of efflux transporter, resulting in dominant effect of efflux transporters on oral absorption
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How is the BDDCS used to predict transported effect on oral absorption for class III and class IV?
Absorptive transport will affect extent of oral F and rate of absorption. Both absorptive and efflux transports could have a significant effect on oral absorption of class IV compounds
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Describe rules of Lipinski 'rule of five' (to indicate poor absorption/permeation)
Contains > 5 H bond donors (NH/OH), MW > 500 D, log P > 5, the sum of N and O (H bond acceptors) > 10
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What is the obvious exception?
Substrates for active transport
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Why do we need experimental models?
Physicochemical models/hypotheses are unreliable predictors, need to study mechanisms, provide data for design of clinical trials, satisfy regulatory authorities
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Give examples of models for GI drug absorption
Physicochemical models, membrane models, isolated/cultured cells, in vitro techniques, in vivo techniques, human studies (mechanisms, drug permeability, clinical relevance)
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When choosing models, what needs to be considered?
Information required, cost, complexity and type/number of samples
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What are drug absorption prediction tools?
Experimental models with the capacity to predict how drug absorption plays an important part in the process of drug development
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Give examples of drug absorption prediction tools
In vitro epithelial cell culture models, parallel artificial membrane permeability assay, in silico systems, ex vivo tissue, in vivo animal studies and human studies
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Describe features of the epithelia model for prediction of drug absorption
Used as a screening tool in the PI for prediction of intestinal drug absorption. Observed good correlation between passive drug transport through epithelial cell monolayers (observed across SI in vivo) - Caco-2 model
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What are the advantages of cell monolayers?
Biological system allowing study of most aspects of drug transport. Similar to transporting epithelia in vivo. Much data now available from uptake of a variety of drugs
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What are the disadvantages of cell monolayers?
Cost and requires expertise. Paracellular route doesn't function as well as expected. Cell lines are different to normal cells growing in vivo
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Describe features of human studies (1)
Scintigraphy (gamme camera). Transit dosage form through intended site of delivery can be non-invasively imaged in vivo using short-lived gamma emitting radioisotope
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Describe features of human studies (2)
Used on conjunction with blood sample to give absorption sites, rate of transit and disposition of dosage form. Non-invasive. Human clinical or animal studies. Clinically relevant
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