Clasificación Biofarmacéutica Provisional de los fármacos esenciales de la OMS y de los 200 productos principales en US GB ES y JP.

Transcripción

1 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 Farmacia y Tecnología Farmacéutica Facultad de Farmacia. Universidad Miguel Hernández, Elche mbermejo@umh.es 1

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3 Bioequivalencia BE Estándar imprescindible para garantizar la eficacia. Equivalencia terapéutica: equivalencia farmacéutica + bioequivalencia. Cúal es el mejor test para demostrar BE? 3

4 BE: puntos de vista Formulation A Dissol in Vivo Absorption Distribution Metabolism Excretion Intestinal Membrane Formulation B Dissol in Vivo Absorption Distribution Metabolism Excretion Drug substance Drug Formulation 4

5 G.L. Amidon et.al., Pharm. Res. 12, 413 (1995). 5

6 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? 6

7 Clasificación lista fcos esenciales OMS Readily available data (solubility) Easily Implemented Estimation (permeability) Provisional Classification 7

8 WHO and US Drugs WHO US 325 Medicines 200 Drug Products 260 Drugs 141 Oral 123 Oral IR 43 on WHO List 8

9 Merck Solubilities Descriptive Term Parts of solvent required for Solubility range, Solubility assigned, (Solubility Definition) 1 part of solute mg/ml mg/ml Very soluble (vs) Less than and over 1000 Freely soluble (fs) From 1 to to Soluble (s) From 10 to to Sparingly soluble (sps) From 30 to to Slightly soluble (ss) From 100 to to 10 1 Very slightly soluble (vss) From 1000 to 10, to Practically insoluble (pi) 10,000 and over Less than

10 44 40 Anti-infective Drugs 36 Percentage of drugs % WHO % US TOTAL Antibacterial Leprostatic Tuberculostatic Antiprotozoal Antiviral Anthelminthic Antifungal 10

11 20 Percentage of drugs Therapeutic Classes % WHO % US Antianginal; Antihypertensive Antidepressant 0 Anxiolytic; Antipsychotic Oral contraceptive Antiinflammatory Anticonvulsant Antihistaminic Antidiabetic Narcotic analgesic Antiulcerative Antihyperlipoproteinemic 11

12 Percentage of immediate-release oral drugs Solubility Classification High Solubility Drugs Do D 250 C WHO US Dose numbe r 1.0 Solubility 0.1 mg/ml Solubility 0.01 mg/ml No solubility information 12 s

13 Solubility Conclusions Majority of Drugs of the WHO list are High Solubility (Do<1) 13

14 Human Jejunal Permeability Data Base Human fraction absorbed (%) Human jejunum permeability (x cm/s) 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 14

15 Metoprolol: Reference Compound O OH H N CH 3 H 3 CO Log P: 2.18 CLogP: CH 3 15

16 Partition Coefficient Estimates: ChemDraw 16

17 Permeability Estimation 12.0 passive active y = x r 2 = y = x r 2 = Peff x 10 4 (cm/sec) HIGH PERMEABILITY Metoprolol LOW PERMEABILITY -4.0 Log P (ChemDraw) 17

18 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) 18

19 BCS Class Distribution 40 Log P CLogP Percentage of Immediate-release Oral Drugs Class l Class ll Class lll Class lv Unclassified BCS Class 19

20 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 20

21 Further references Yu LX et al. Biopharmaceutics Classification System: The scientific basis for biowaiver extensions. Pharm Res (7). Polli J.E et al. Summary Workshop Report: Biopharmaceutics Classification System- Implementation Challenges and Extension Opportunities. J Pharm Sci (6) Vogelpoel H. et al. Biowaiver monographs for IR solid oral dosage forms based on BCS literature data: Verapamil HCl, Propranolon HCL and Atenolol 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: ,

22 Acknowledgements Prof. G. Amidon. University of Michigan Assoc Prof. J. Polli University of Maryland 22

23 Are WHO Drugs Representeative of US-GB-ES-JP Drugs? 23

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25 US-GB-ES-JP Drugs Top 200 Drug Products 2003 Based on Sales Oral IR 55-59% are High Solubility Drugs 25

26 Percentage of IR oral drugs Therapeutic Class Distribution US GB ES JP Antianginal; Antihypertensive Antiviral Antibacterial Antidepressant Anxiolytic, Antipsychotic Antihyperlipoproteinemic Antidiabetic Anticonvulsant Antihistaminic Analgesic Antiosteoporotic Antiinflammatory Immunosuppressant Contraceptive CNS stimulant Antineoplastic Antifungal Antimigraine Antiulcerative Antithrombotic Antiasthmatic Antiparkinsonian Vitamin Others 26

27 Percentage of IR oral drugs 1 er Curso Metodologías Biofarmacéuticas Córdoba, Argentina Solubility Distribution US GB ES JP 0 very soluble freely soluble soluble sparingly soluble slightly soluble very slightly soluble practically insoluble* not available 27

28 Maximum/Lowest Dose 240 Maximum dose strength Lowest dose strength Average dose strength (mg) US GB ES JP 28

29 Distribution of Drugs Based on Maximum Dose Number of IR drugs US GB ES JP Maximum dose strength (mg) 29

30 Dose Number Classification: High Solubility Do using maximum dose strength Do using lowest dose strength Percentage of drugs with Dose number US GB ES JP (150 ml) JP (250 ml) 30

31 JP Drugs Dosis máxima en JP (en promedio) mitad de la usada en US. Volumen de agua en los estudios BE ml. (Vref = 150 ml.) 31

32 Peff (Human) vs. CLogP : Correctly classified : False negative : False positive Peff 10 4 (cm/s) CLogP 32

33 CLogP Falsos Positivos Losartan: Lipophyllic, Just barely low human permbeability Furosemide: pka~4, ionized at ph 6.5, ph dependant permeability? 33

34 Peff (Human) vs. LogP : Correctly classified : False negative Peff 10 4 (cm/s) Log P 34

35 CLogP Exceptions: Losartan and Furosemide Drug Possible reason for misclassification CLogP-based False negative antipyrine no evidence of carrier-mediated transport cephalexin substrate for peptide transporters 22 D-glucose substrate for glucose transporters 23 enalapril substrate for peptide transporters 24 levodopa substrate for amino acid transporters 25 L-leucine substrate for amino acid transporters 25 phenylalanine substrate for amino acid transporters 25 valacyclovir substrate for peptide transporters 26 Log P-based False positive furosemide secretion in rat jejunum and caco-2 cells 27 losartan secretion by p-glycoprotein 28 False negative antipyrine no evidence of carrier-mediated transport cephalexin substrate for peptide transporters 22 D-glucose substrate for glucose transporters 23 levodopa substrate for amino acid transporters 25 L-leucine substrate for amino acid transporters 25 phenylalanine substrate for amino acid transporters 25 piroxicam no evidence of carrier-mediated transport valacyclovir substrate for peptide transporters 26 35

36 CLogP y LogP No Falsos Positivos con LogP Falsos negativos: sustratos transportadores. Permeabilidad humana superior a la estimada en base a su lipofilia. 36

37 High Permeability Drugs CLogP-based Log P-based Percentage of high-permeabilty IR Oral drugs US GB ES JP 37

38 Provisional BCS Classification (CLogP) Percentage of IR Oral drugs US GB ES JP (150 ml) JP (250 ml) 5 0 Class 1 Class 2 Class 3 Class 4 Unclassified 38

39 Provisional BCS Classification (LogP) Percentage of IR Oral drugs US GB ES JP (150 ml) JP (250 ml) 5 0 Class 1 Class 2 Class 3 Class 4 Unclassified 39

40 Fármacos US-GB-ES-JP Top 200 medicamentos (ventas) >50 % ( /200) Oral 55-59% Alta solubilidad % Alta Permeabilidad (CLogP) 56-60% Alta Permeabilidad (LogP) >55% son Clase I + Clase III 40

41 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 41

42 Aplicaciones BCS : Conclusiones Aplicable a más de la mitad de productos orales IR Extensible al 80-90% Class II Disolución puede asegurar BE 42

43 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. 43