Prof - Red "Biofarma"

Transcripción

1er Curso Metodologías Biofarmacéuticas. 2011 Córdoba, Argentina
Clasificación BCS- Esenciales OMS
Primer Taller de Capacitación en Metodologías
Biofarmacéuticas:
Red Biofarma
Clasificación Biofarmacéutica Provisional de los fármacos
esenciales de la OMS y de los 200 productos principales
en US GB ES y JP
Marival Bermejo
Farmacia y Tecnología Farmacéutica
Facultad de Farmacia.
Universidad Miguel Hernández, Elche
[email protected]
Área Farmacia y Tecnología Farmacéutica.
Marival Bermejo
1
Marival Bermejo
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Bioequivalencia BE



Estándar imprescindible para garantizar la
eficacia.
Equivalencia terapéutica: equivalencia
farmacéutica + bioequivalencia.
¿Cúal es el mejor test para demostrar
BE?
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Dissol in Vivo
Formulation B
Dissol in Vivo
Absorption
Absorption
Intestinal Membrane
Distribution
Metabolism
Excretion
Distribution
Metabolism
Excretion
Drug substance
Formulation A
Drug Formulation
BE: puntos de vista
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G.L. Amidon et.al., Pharm. Res. 12, 413 (1995).
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Extensiones del BCS

Incluir en las bioexenciones fármacos clase III
 Todos los de alta solubilidad.
 Criterio de disolución en función de la permeabilidad.



Definicion de alta permeabilidad Fabs 90% ->
85%
Ensayos de disolución BE más complejos que los
de Control de calidad. (QC).
¿Cúantos fármacos serían candidatos a
bioexenciones?
Marival Bermejo
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Clasificación lista fcos esenciales OMS



Readily available data (solubility)
Easily Implemented Estimation (permeability)
Provisional Classification
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WHO and US Drugs




WHO
325 Medicines
260 Drugs
123 Oral IR




US
200 Drug Products
141 Oral
43 on WHO List
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8
Merck Solubilities
Descriptive Term
Parts of solvent
required for
Solubility range,
(Solubility Definition)
1 part of solute
mg/ml
mg/ml
Very soluble (vs)
Less than 1
1000 and over
1000
Freely soluble (fs)
From 1 to 10
100 to 1000
100
Soluble (s)
From 10 to 30
33 to 100
33
Sparingly soluble (sps)
From 30 to 100
10 to 33
10
Slightly soluble (ss)
From 100 to 1000
1 to 10
1
Very slightly soluble (vss)
From 1000 to 10,000
0.1 to 1
0.1
Practically insoluble (pi)
10,000 and over
Less than 0.1
0.01
Solubility
assigned,
Marival Bermejo
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44
Anti-infective Drugs
Percentage of drugs
40
36
32
28
% WHO
24
% US
20
16
12
8
4
0
L
A
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O
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b
A
A
Tu
Marival Bermejo
10
20
18
Percentage of drugs
16
Therapeutic Classes
14
12
% WHO
10
% US
8
6
4
2
0
e
t
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c
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Marival Bermejo
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Percentage of immediate-release oral drugs
80.0
Solubility Classification
70.0
WHO
High Solubility Drugs
60.0
US
D
50.0
Do 
40.0
30.0
250
Cs
20.0
10.0
0.0
Dose numbe r ≤ 1.0
Solubility ≤ 0.1 mg/ml Solubility ≤ 0.01 mg/ml
No solubility
information
12
Marival Bermejo
Solubility Conclusions

Majority of Drugs of the WHO list are High
Solubility (Do<1)
Marival Bermejo
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Human Jejunal Permeability Data Base
Human fraction absorbed (%)
120
100
80
60
40
20
0
0
2
4
6
8
10
Human jejunumpermeability (x10-4 cm/s)
12
D-glucose
Verapamil
Piroxicam
Phenylalanine
Cyclosporin
Enalapril
Cephalexin
Losartan
Lisinopril
Amoxicillin
Methyldopa
Naproxen
Antipyrine
Desipramine
Propanolol
Amiloride
Metoprolol
Terbutaline
Mannitol
Cimetidine
Ranitidine
Enalaprilate
Atenolol
Hydrochlorothiazide
Trend line
Marival Bermejo
14
Metoprolol: Reference Compound
OH
O
H
N
CH3
CH3
H3CO
Log P: 2.18
CLogP: 1.4864
Marival Bermejo
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Partition Coefficient Estimates: ChemDraw
Marival Bermejo
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Permeability Estimation
2
passive y = 1.1619x - 0.3606 r = 0.884
active
Peff x 10 (cm/sec)
12.0
2
y = 1.8627x + 3.0283 r = 0.932
HIGH PERMEABILITY
4
8.0
4.0
0.0
-4.0
-2.0
0.0
LOW PERMEABILITY
2.0
4.0
Metoprolol
6.0
8.0
Log P (ChemDraw)
-4.0
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Permeability Classification




Based on Metoprolol
Correct Classification for 18 of 20
passively absorbed drugs
Carrier mediated drugs are classified as
low permeability (false negatives)
Exceptions antipyrine and piroxicam (false
negatives) (high P classified as Low P)
Marival Bermejo
18
BCS Class Distribution
Log P
CLogP
Percentage of Immediate-release
Oral Drugs
40
35
30
25
20
15
10
5
0
Class l
Class ll
Class lll
Class lV
Unclassified
BCS Class
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WHO Essential Drugs




67% of WHO IR drugs are High Solubility
68% of US Top 200 drugs are HS
In Vitro Dissolution BE standard is
applicable to the majority of WHO
Drugs
Easily implemented, routinely
conducted
Marival Bermejo
20
Further references




Yu LX et al. Biopharmaceutics Classification System: The
scientific basis for biowaiver extensions. Pharm Res 2002
19(7).
Polli J.E et al. Summary Workshop Report:
Biopharmaceutics Classification System- Implementation
Challenges and Extension Opportunities. J Pharm Sci
2004 93(6)
Vogelpoel H. et al. Biowaiver monographs for IR solid oral
dosage forms based on BCS literature data: Verapamil HCl,
Propranolon HCL and Atenolol. 2004 J Pharm. Sci. 93(8)
Lindenberg et al.: Classification of orally administered drugs
on the WHO model list of essential medicines according to
the biopharmaceutics classification system. Eur. J. Pharm.
Biopharm. 58: 265-278, 2004
Marival Bermejo
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Acknowledgements


Prof. G. Amidon.
University of Michigan
Assoc Prof. J. Polli
University of Maryland
Marival Bermejo
22
Are WHO Drugs Representeative of US-GB-ES-JP
Drugs?
Marival Bermejo
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Marival Bermejo
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US-GB-ES-JP Drugs




Top 200 Drug Products
2003 Based on Sales
102-113 Oral IR
55-59% are High Solubility Drugs
Marival Bermejo
25
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Ant
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i nal
Percentage of IR oral drugs
20
15
Therapeutic Class Distribution
US
GB
ES
JP
10
5
0
Marival Bermejo
26
Solubility Distribution
Percentage of IR oral drugs
45
US
40
GB
35
ES
30
JP
25
20
15
10
5
0
ry
e
v
le
b
lu
so
fr
ly
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le
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tly
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Marival Bermejo
27
Maximum/Lowest Dose
240
Maximum dose strength
Lowest dose strength
Average dose strength (mg)
200
188.1
173.5
171.1
160
120
80
76.7
76.8
80.4
65.2
49.5
40
0
US
GB
ES
JP
Marival Bermejo
28
Distribution of Drugs Based on Maximum
Dose
US
40
GB
Number of IR drugs
35
ES
JP
30
25
20
15
10
5
0
≤1
1–3
3–10
10–30
30–100
Maximum dose strength (mg)
100–300
300–1000
Marival Bermejo
29
Dose Number Classification:
High Solubility
Do using maximum dose strength
100
Do using lowest dose strength
Percentage of drugs with
Dose number ≤ 1
90
80
70
60
68.6
66.4
54.9
55.9
69.9
67.0
61.9
58.5
60.2
54.9
50
40
30
20
10
0
US
GB
ES
JP (150 mL)
JP (250 mL)
Marival Bermejo
30
JP Drugs


Dosis máxima en JP (en promedio) mitad
de la usada en US.
Volumen de agua en los estudios BE
100-200 ml. (Vref = 150 ml.)
Marival Bermejo
31
Peff (Human) vs. CLogP
12.0
: Correctly classified
: False negative
: False positive
10.0
Peff ×10 4 (cm/s)
8.0
6.0
4.0
2.0
0.0
-4.0
-3.0
-2.0
-1.0
0.0
1.0
2.0
3.0
4.0
5.0
CLogP
Marival Bermejo
32
CLogP Falsos Positivos

Losartan: Lipophyllic, Just
barely low human
permbeability

Furosemide: pKa~4,
ionized at pH 6.5, pH
dependant permeability?
Marival Bermejo
33
Peff (Human) vs. LogP
12.0
: Correctly classified
: False negative
10.0
Peff × 10 4 (cm/s)
8.0
6.0
4.0
2.0
0.0
-3.0
-2.0
-1.0
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
Log P
Marival Bermejo
34
CLogP Exceptions: Losartan and Furosemide
Drug
Possible reason for misclassification
CLogP-based
False negative
antipyrine
cephalexin
D-glucose
enalapril
levodopa
L-leucine
phenylalanine
valacyclovir
no evidence of carrier-mediated transport
substrate for peptide transporters 22
substrate for glucose transporters 23
substrate for amino acid transporters 25
False positive
furosemide
losartan
secretion in rat jejunum and caco-2 cells 27
secretion by p-glycoprotein 28
Log P-based
False negative
antipyrine
cephalexin
D-glucose
levodopa
L-leucine
phenylalanine
piroxicam
valacyclovir
Área Farmacia
y
substrate for glucose transporters 23
26
substrate
for peptide transporters
Tecnología
Farmacéutica.
Marival Bermejo
35
CLogP y LogP


No Falsos Positivos con LogP
Falsos negativos: sustratos transportadores.
 Permeabilidad humana superior a la estimada en base
a su lipofilia.
Marival Bermejo
36
High Permeability Drugs
CLogP-based
100
Log P-based
Percentage of high-permeabilty
IR Oral drugs
90
80
70
60
69.0
63.7
62.8
56.6
59.8
63.2
59.4
58.4
50
40
30
20
10
0
US
GB
ES
JP
Marival Bermejo
37
Provisional BCS Classification (CLogP)
40
US
Percentage of IR Oral drugs
35
GB
ES
30
JP (150 mL)
JP (250 mL)
25
20
15
10
5
0
Class 1
Class 2
Class 3
Class 4
Unclassified
Marival Bermejo
38
Provisional BCS Classification (LogP)
40
US
GB
Percentage of IR Oral drugs
35
ES
JP (150 mL)
30
JP (250 mL)
25
20
15
10
5
0
Class 1
Class 2
Class 3
Class 4
Unclassified
Marival Bermejo
39
Fármacos US-GB-ES-JP






Top 200 medicamentos (ventas)
>50 % (102-113/200) Oral
55-59% Alta solubilidad
62-70 % Alta Permeabilidad (CLogP)
56-60% Alta Permeabilidad (LogP)
>55% son Clase I + Clase III
Marival Bermejo
40
BCS and Dissolution: A Comprehensive
Proposal





In Vivo Dissolution Controls BE
All BCS Classes
Dissolution specification depends on
Class
Media change required in some cases
Reflect the In Vivo rate controlling process
Marival Bermejo
41
Aplicaciones BCS : Conclusiones


Aplicable a más de la mitad de productos
orales IR
Extensible al 80-90%
 Class II

Disolución puede asegurar BE
Marival Bermejo
42
Aplicaciones BCS : Conclusiones





Nueva perspectiva de BE
Reduce estudios In Vivo innecesarios
Asegura la calidad de los productos orales
Basado en principios cientificos y extensible.
BE con Disolución aplicable al 60-90% de
medicamentos.
Marival Bermejo
43

Prof - Red "Biofarma"

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