Estudios de Permeability In Vitro. Ismael J. Hidalgo, Ph.D. Absorption Systems Exton, PA
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1 Estudios de Permeability In Vitro Ismael J. Hidalgo, Ph.D. Absorption Systems Exton, PA
2 OUTLINE Organization and architecture of the small intestinal mucosa Barrier function of the intestinal epithelium In vitro models for studying permeability Artificial membranes Cellular models Excised tissues Perfused rat intestine Final Thoughts
3
4
5 Factors influencing gastrointestinal drug absorption Physicochemical Physiological Formulation Solubility Log P pka H-bonding potential Molecular size Polar surface area Gastric emptying rate Intestinal motility Membrane surface area Intestinal metabolism Transport mechanism(s) Native surfactants Intestinal blood/lymph flow Disintegration rate Dissolution rate Drug release mechanism Excipients
6 Transepithelial transport pathways
7 Models of Drug Intestinal Permeability Log P (or Log D) Rule of 5 Artificial membranes (IAM, PAMPA) Subcellular preparations (BBMV, BLMV) Cultured Cells (Caco-2, MDCK, HT29) Intestinal mucosa Perfused intestine
8 The Rule of Five Molecular weight > 500 MLog P > 4.15 clog P > 5 H-bond donors (OH s + NH s) > 5 H-bond acceptors (N s+o s) > 10 Adv. Drug Del. Rev. 1997, 23, 3-29.
9 Immobilized Artificial Membranes (IAM)
10 Log (Papp) Correlation for 40 drugs Log (k' IAM )
11 Pararell Artificial Membrane Permeation Assay (PAMPA)
12 Correlation for 25 Drugs J. Med. Chem. 41:1007, 1998
13 Artificial membranes Advantages Disadvantages Higher throughput Potential for miniaturization, automation Amount of compound Relatively inexpensive No paracellular transport No metabolism No transporters Membrane retention Dependent on lipid composition and ph
14 Intestinal Permeability Techniques Excised Tissue Intestinal Perfusion Cell Monolayers
15 Excised Tissue Permeability
16 Excised Tissue Permeability
17 Excised Tissue Permeability
18 Transport Permeability Coefficient (Papp) C T Time
19 Permeability coefficient (P app ) P app = V r. dc/dt A. C o
20 Correlation to Human Fabs Human Jejunum Apparent Permeability Ratio Rat Jejunum Apparent Permeability Ratio NHP Jejunum Apparent Permeability Ratio
21 Intestinal mucosa Advantages Disadvantages Multiple species Segmental differences Excipients and formulations Tissue organization Labor-intensive Viability Tissue availability
22 Cellular Models used in drug transport studies T84 Caco-2 TC7 MDCK LLC-PK1 2/4/A1 HT29
23
24 Transport Permeability Coefficient (Papp) C T Time
25 Permeability Barriers
26 Determination of Papp components V r. dc/dt 1 P app = = A. C o 1/P aq + 1/P m P aq = D aq /h P m = P trans. X s + P para
27 Intestinal mucosa
28 Advantages of Caco-2 cells Enterocytic morphology (tigh junctions, microvilli) Intestinal enzymes (peptidases, S-I, CYP 1A1, 1A2, 3A5, PST, esterases) Human origin Efflux mechanisms (Pgp, MRP2/cMOAT, MRP3) Intestinal carriers (AAs, BAs, PEPT1, nucleosides, carboxylic acids, fatty acids, intrinsic factor, biotin)
29 Disadvantages of Caco-2 cells Different expression level of transporters and enzymes Lack mucus layer Cannot represent multiple regions Tight junctions too tight
30 Rat Intestinal Perfusion (with or without vascular cannulation)
31
32 Models of intestinal absorption: Intestinal Perfusion Relationship between nonsteady state absorption and blood levels Mass balance for steady-state perfusion
33 Assay Formats for Intestinal Perfusion Closed Loop Static dose over 2h P eff = -dc/dt V / 2πrL Open Loop: Single Pass Dosing solution pumped for 90 min post 30 min preincubation P eff = Q x [1-(C out /C in )]/2πrL Open Loop: Recirculating Dosing solution cyclically pumped for 90 min post 30 min pre-incubation P eff = -dc/dt V/2πrL
34 Consideration and Solutions: Water flux correction Co-perfusion with a non-absorbed marker (FD- 4, Phenol Red, PEG400) C corrected out = C out x [CM out ]/[CM in ]
35 Perfused Intestinal Segments Advantages Disadvantages Segmental differences Excipients and formulations Tissue organization Tissue availability Labor intensive Time-consuming Drug disappearance
36 Variability of Various Non- Clinical Intestinal Techniques Permeability Method %CV Excised Tissue 24-40% Perfusion 33-63% Caco-2 ~30%
37 FINAL THOUGHTS Physicochemical PAMPA; discovery only Cellular Caco-2; discovery & development Absorption potential BCS Classification Transported-Mediated Drug-Drug Interactions Formulation development Intestinal Perfused rat intestine; primarily in development BCS Classification Formulation development Great potential for troubleshooting/elucidating unexpected clinical findings not feasible in animals or humans.
38 THE END
39 Considerations and Solutions: Solubility Challenge Poor solubility Unreliable permeability estimate Potential misclassification Class II vs. IV Solution Excipients that enhance solubility without affecting permeability Implications Fewer SUPAC constraints up to Level 2 changes Waive bio studies based on in vitro dissolution and proportional similarity
40 Considerations and Solutions: Instability Challenge Instability Challenge P eff = Q x [1-(C out /C in )] 2πrl Due to instability, C out is underestimated and P eff is overestimated Solution Alter buffer composition Change ph Truncate assay duration
41 Caco-2 Papp (nm/sec) MDCK versus Caco MDCK Papp (nm/sec)
42 Characteristics of MDCK cells Advantages Disadvantages MDR/MDCK clone TJ s not too tight Short culture times Less heterogeneous Not from tumor Canine kidney origin Lacks carriers Not enterocytic Lacks mucus layer
43 Bioavailability Correlation: Rats vs Dogs Adv. Drug Deliv. Rev 23: 199, 1997
44 Absorption Correlation: Rat vs Human Oral absorption of 64 drugs in humans and rats with absorption ranging from 0 to 100% Oral absorption of 20 drugs in humans and rats with < 90% absorption Pharm. Res. 15: 1792, 1998
45 Oral Absorption: Human vs Rat and Dog % Absorbed M.W. Human Rat Dog Sumatriptan Ranitidine Chlorothiazide Atenolol Nadolol Acyclovir Iothalamate Pharm. Res. 17, 135, 2000
46 Consideration and Solutions: Sensitivity Average Plasma Concentrations Following Single Pass Intestinal Perfusion
47 Applications: Correlation to Average Perfusate Concentrations Following Recirculating Intestinal Perfusion Human Fabs P eff (x 10-4 cm/s) Rat F abs Human Antipyrine % Minoxidil % Pregabalin % Metoprolol % Atenolol %
48 Case Study: Convergence of Techniques Tolerability of Various Excipients in Caco-2 Permeability of Compound A in Caco-2 Human Colonic Permeability in the Presence of Excipients Strategy Tolerated? P app Donor 1 Donor 2 Tween 80 TPGS Labrafil Permeation Enhancer Permeation Enhancer Permeation Enhancer No Yes Yes Control 0.15 TPGS 0.38 Labrafil 0.34 Chitosan 0.15 (Compound/ Atenolol Ratio) (Compound/ Atenolol Ratio) Control TPGS Disodium EDTA Ion Pairing No Labrafil Chitosan Ion Pairing Yes
49
50
51 In Vitro Human Intestinal Permeability
52 Applications for Excised Tissue: Assessing Interactions with PEPT1 Human Jejunum Permeability With and without the PEPT1 inhibitor GlySar ph gradient (ph 5.5/pH 7.4) is used to optimize PEPT1 functionality * * * p<0.05
53 Advantages of Caco-2 cells Enterocytic morphology (tigh junctions, microvilli) Intestinal enzymes (peptidases, S-I, CYP 1A1, 1A2, 3A5, PST, esterases) Human origin Efflux mechanisms (Pgp, MRP2/cMOAT, MRP3) Intestinal carriers (AAs, BAs, PEPT1, nucleosides, carboxylic acids, fatty acids, intrinsic factor, biotin)
54 Disadavantages of Caco-2 cells Under-expressed carriers and enzymes Lack important enzymes (CYP 3A4, 2D6) Over-expressed P-gp Tumor cell line Lack mucus layer Heterogeneous Tight junctions too tight
55 Applications: Pro-drug Metabolite Appearance in Perfusate Buffer Activation Metabolite Appearance in Plasma
56 BCS Data Received by FDA for Biowaiver Applications Caco-2 accounts for ~90% of non-clinical experimental data submitted. Adapted from: Mehta, Sept. 2010; AAPS Webinar: Application of Biopharmaceutical Classification System (BCS) in Regulatory Submissions
57 Economic Impact: Biowaivers Direct savings (up to $150 million) Indirect savings ($50-$150 milliion per drug) Resource allocation and redeployment Drug A Patent Price ~ $16/dose Drug B Patent Price ~ $220/dose Class I and Class III compounds make up ~60% of drugs that have been classified Cook, JA, et al. Impact of Biopharmaceutics Classification System-Based Biowaivers, Mol Pharm Generic ~ $2/dose 2011 Generic ~ $0.13/dose 99%?
58 Acceptance Criteria for Tissue Minimum two-fold separation between atenolol and antipyrine in e
59 Applications: Site-Specific Intestinal Permeability P eff (X10-4 cm/s) - Jejunum Treatment Atenolol Antipyrine Compound B AVG SD AVG SD AVG SD Base Succinate Base + Succinic Acid P eff (X10-4 cm/s) - Ileum Treatment Atenolol Antipyrine Compound B AVG SD AVG SD AVG SD Base Succinate Base + Succinic Acid
60 BCS Beyond Biowaivers Text Introduction and Acceptance of Permeability Techniques Comparison Text Text Conclusions
61
62 ABSORPTION MODELS: nonexperimental Lipinski s rule of 5 QSTR Physiologic Modeling Molecular Modeling Number of hydrogen bonds Polar surface area (PSA) calculations
63 Subcellular preparations: Brush Border Membrane Vesicles
64 Subcellular preparations Advantages Disadvantages Amount of compound Versatility BBMV or BLMV Only uptake Lack cellular metabolism No paracellular transport
65 Cultured epithelial cells used in drug transport studies T84 Caco-2 MDCK HT29
66 Considerations and Solutions for Excised Tissue Studies Consideration Solubility Stability Non-specific binding Tissue thickness Mass balance Variability Solution Similar to Caco-2 (excipients, ph conditions, truncated duration) Pre-incubation, BSA Multiple donor and receiver time points Tissue accumulation, mucosal scraping Atenolol: Antipyrine ratio better than P app
67 Perfused Intestinal Segments Advantages Disadvantages Segmental differences Excipients and formulations Tissue organization Tissue availability Viability Labor intensive Time-consuming Drug disappearance
68 Fabs (%) Prediction of Fabs: Papp? BBRC (1991) 175: E E E E-04 Papp (cm/s)
69
70 4. Caco-2 control: PC pathway integrity
71 TRANSEPITHELIAL ELECTRICAL RESISTANCE (TEER) OF CACO-2 MONOLAYERS FROM SEVERAL LABORATORIES TEER (.cm 2 ) REFERENCE 1200 Biochem. Pharmacol. 48 (1994) In Vitro Toxicol. 7 (1994) Int. J. Pharm. 83 (1992) Am. J. Physiol. 247 (1984) C Gastroenterology 96 (1989) Antimicrob. Agents Chemother. 38 (1994) Pharm. Res. 11 (1994) Am. J. Physiol. 264 (1993) G1118 >300 J. Pharm. Pharmacol. 46 (1994) Pharm. Res. 12 (1995) Eur. J. Pharm. Sci. 3 (1995) Eur. J. Pharm. Sci. 3 (1995) Eur. J. Pharm. Sci. 3 (1995) J. Pharmacol. Exp. Ther. 270 (1994) J. Pharmacol. Exp. Ther. 267 (1993) J. Pharm. Sci. 79 (1990) J. Pharm. Sci. 88 (1999) Pharm. Res. 15 (1998) 726
72 Caco-2 cells: Inter-laboratory variability in mannitol Papp Papp (cm/s, x10 6 ) REFERENCE 0.18 BBRC 175 (1991) In Vitro Cell. Dev. Biol. 28A (1992) Pharm. Res. 10 (1993) Pharm. Res. 12 (1995) Antimicrob. Agent Chemother. 36 (1992) Pharm. Res. 8 (1991) Eur. J. Pharm. Sci. 3 (1995) Eur. J. Pharm. Sci. 3 (1995) Eur. J. Pharm. Sci. 3 (1995) 215 ~3.4 Pharm. Res 14 (1997) Pharm. Res. 16 (1999) 55
73 Fabs (h) Caco-2 data from 5 laboratories E E E E-04 Papp (cm/s)
74 Factors that influence cell permeability values Biologic factors Seeding density Passage number Attachment factors Days in culture Cell viability Permeable support Trypsinization process Culture conditions Carrier systems Efflux systems Metabolizing enzymes
75 Factors that influence cell permeability values (Cont.) Study Design factors Stirring vs stagnant Sampling schedule Transport solution ph Drug concentration Analytical methods Data analysis Use of co-solvents
76 Inter-laboratory variability Controls must be established for: Phenotypic drift Batch-to-batch variability Pre-experiment monolayer integrity Post-experiment monolayer integrity
77 Characteristics of MDCK cells Advantages Disadvantages MDR/MDCK clone TJ s not too tight Short culture times Less heterogeneous Not from tumor Canine kidney origin Lacks carriers Not enterocytic Lacks mucus layer
78 % Absorption (Humans) IVIVC: Caco-2 monolayers Papp (nm/sec)
79 % Absorption (humans) IVIVC: MDCK monolayers Papp (nm/sec)
80 Caco-2 Papp (nm/sec) MDCK versus Caco MDCK Papp (nm/sec)
81 Applications: Testing Permeation Enhancers Rat Jejunum Permeability in the Presence of Excipients Treatment Test Compound Atenolol Antipyrine Control EGTA C Known tight junction modifiers resulted in an increase in test compound and atenolol permeability Excipients did not affect antipyrine as its permeability is transcellular
82 Applications: Pro-drug Metabolite Appearance in Perfusate Buffer Activation Metabolite Appearance in Plasma
83 Applications: Sustained Release Feasibility Average Plasma Concentrations Following Single Pass Intestinal Perfusion Segment P eff (x 10-4 cm/s) Duodenum 0.65 Jejunum 0.10 Ileum 0.55 Colon 0.19
84 Case Study: Convergence of Techniques Tolerability of Various Permeability of Human Colonic Permeabilit Excipients in Caco-2 Compound A in Caco-2 in the Presence of Excipien Tween 80 TPGS Labrafil Disodium EDTA Strategy Permeation Enhancer Permeation Enhancer Permeation Enhancer Ion Pairing Tolerated? No Yes Yes No P app Control 0.15 TPGS 0.38 Labrafil 0.34 Chitosan 0.15 Donor 1 (Compound/ Atenolol Ratio) Donor 2 (Compound/ Atenolol Ratio) Control TPGS Labrafil Chitosan Ion Pairing Yes
85 Economic Impact: Biowaivers Direct savings (up to $150 million) Indirect savings ($50-$150 milliion per drug) Resource allocation and redeployment Drug A Patent Price ~ $16/dose Drug B Patent Price ~ $220/dose Class I and Class III compounds make up ~60% of drugs that have been classified Cook, JA, et al. Impact of Biopharmaceutics Classification System-Based Biowaivers, Mol Pharm Generic ~ $2/dose 2011 Generic ~ $0.13/dose 99%?
86 Consideration and Solutions: Water flux correction Co-perfusion with a non-absorbed marker (FD- 4, Phenol Red, PEG400) C corrected out = C out x [CM in ] [CM out ]
87
88 Composition of the small intestinal epithelium Epithelium composed mostly of absorptive villus cells and undifferentiated crypt cells. One-cell thick sheet that regulates exchange between lumen and blood. Other cell types (goblet cells, Paneth cells, and M cells) are specialized
89 Barrier function of the intestinal epithelium Physical component Tight intercellular junctions Lipid characteristics of the membrane Biochemical component Enzymes Transporters (absorptive processes) Counter transporters (efflux processes)
90 Undifferentiated crypt cells Major functions: proliferation and secretion Appearance: columnar with basophilic nuclei, shorter and more sparse MV s, TJ s show less depth and complexity Composition: less alkphos, disaccharidases and dipeptidases
91 Ussing Chamber
92 Goblet cells Location: throughout the intestine, highest in the ileum. Characteristics: dense basophilic cytoplasm, basally located nuclei, sparse, irregular in size and shape, low apical membrane protein content. Function: mucus secretion
93 Goblet Cell
94 Potential exploitation: drug absorption Microfold (M) cells Location: contained in Peyer s patches Characteristics: surface microfolds, less abundant glycocalyx, not columnar Functions: luminal sampling undegraded particles
95 Microfold (M) cell
96 Absorptive (Villus) cells Apical membrane Closely packed microvilli about µm. Apical membrane ~ nm wide High (1.7:1) protein-to-lipid molar ratio Abundance of cholesterol and glycolipids
97 Absorptive (Villus) cells Basolateral membrane Basolateral membrane ~ 7 nm wide Separation of lateral membrane depends of hydration Na+-K+-ATPase located on this membrane Cholesterol content lower than apical membrane
98 Biochemical barrier Peptidases: aminopeptidase N/P/W, dipeptidyl peptidase IV. BB membrane (seg); cytosolic (nonseg); lysosomal (highest in caecum) Cyt P450: 1A1, 1A2, 2D6, 3A4, 2C9, 2C19. Esterases Phenol sulfotransferase (PST) UDP glucuronyltransferase (UDPGT)
99
100 Working model of PEPT1
101 Efflux Mechanisms MDR1 gene Member of superfamily of transport genes Located on chromosome 7 at position 21.1 Cloned and sequenced in 1986 Gene is translated as 140 kda protein Postranslationally modified to a 170 kda protein (P-gp)
102 Efflux mechanisms P-gp Is activated by protein kinase C Membrane-associated protein 170 kd molecular weight 2 Units with 6 TM domains 2 ATP binding sites 1280 amino acids Expressed in normal tissues Numerous antibodies (MRK16, C219, etc) Physiologic role unknown (cellular detoxification?)
103 Efflux mechanisms Multidrug resistance-associated protein (MRP): MRP1 MRP2/cMOAT MRP3 MRP4 MRP5 MRP6 Homology ranges from 45% to 75% Family exports GSH S conjugates and organic anions MRP1 and cmoat: resistance to arsenite, antimonite, and cisplatin MRP1 involved in transport of LTC4 Human duodenum: MRP1, MRP2/cMOAT, and MRP3 Human colon: MRP1, MRP3, and MRP5 Caco-2 cells: MRP2/cMOAT and MRP3
104 Advantages of Caco-2 cells Enterocytic morphology (tigh junctions, microvilli) Intestinal enzymes (peptidases, S-I, CYP 1A1, 1A2, 3A5, PST, esterases) Human origin Efflux mechanisms (Pgp, MRP2/cMOAT, MRP3) Intestinal carriers (AAs, BAs, PEPT1, nucleosides, carboxylic acids, fatty acids, intrinsic factor, biotin)
105 Disadavantages of Caco-2 cells Under-expressed carriers and enzymes Lack important enzymes (CYP 3A4, 2D6) Over-expressed P-gp Tumor cell line Lack mucus layer Heterogeneous Tight junctions too tight
106 Fabs (%) Prediction of Fabs: Papp? BBRC (1991) 175: E E E E-04 Papp (cm/s)
107
108 4. Caco-2 control: PC pathway integrity
109 TRANSEPITHELIAL ELECTRICAL RESISTANCE (TEER) OF CACO-2 MONOLAYERS FROM SEVERAL LABORATORIES TEER (.cm 2 ) REFERENCE 1200 Biochem. Pharmacol. 48 (1994) In Vitro Toxicol. 7 (1994) Int. J. Pharm. 83 (1992) Am. J. Physiol. 247 (1984) C Gastroenterology 96 (1989) Antimicrob. Agents Chemother. 38 (1994) Pharm. Res. 11 (1994) Am. J. Physiol. 264 (1993) G1118 >300 J. Pharm. Pharmacol. 46 (1994) Pharm. Res. 12 (1995) Eur. J. Pharm. Sci. 3 (1995) Eur. J. Pharm. Sci. 3 (1995) Eur. J. Pharm. Sci. 3 (1995) J. Pharmacol. Exp. Ther. 270 (1994) J. Pharmacol. Exp. Ther. 267 (1993) J. Pharm. Sci. 79 (1990) J. Pharm. Sci. 88 (1999) Pharm. Res. 15 (1998) 726
110 Caco-2 cells: Inter-laboratory variability in mannitol Papp Papp (cm/s, x10 6 ) REFERENCE 0.18 BBRC 175 (1991) In Vitro Cell. Dev. Biol. 28A (1992) Pharm. Res. 10 (1993) Pharm. Res. 12 (1995) Antimicrob. Agent Chemother. 36 (1992) Pharm. Res. 8 (1991) Eur. J. Pharm. Sci. 3 (1995) Eur. J. Pharm. Sci. 3 (1995) Eur. J. Pharm. Sci. 3 (1995) 215 ~3.4 Pharm. Res 14 (1997) Pharm. Res. 16 (1999) 55
111 Fabs (h) Caco-2 data from 5 laboratories E E E E-04 Papp (cm/s)
112 Factors that influence cell permeability values Biologic factors Seeding density Passage number Attachment factors Days in culture Cell viability Permeable support Trypsinization process Culture conditions Carrier systems Efflux systems Metabolizing enzymes
113 Factors that influence cell permeability values (Cont.) Study Design factors Stirring vs stagnant Sampling schedule Transport solution ph Drug concentration Analytical methods Data analysis Use of co-solvents
114 Inter-laboratory variability Controls must be established for: Phenotypic drift Batch-to-batch variability Pre-experiment monolayer integrity Post-experiment monolayer integrity
115
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