Current Implementation Of Bcs Guidance For Regulatory Applications And Its

Current Implementation of BCS Guidance for Regulatory Applications and Its Extension Opportunities

Key Topics of This Presentation



Development Background of BCS Guidance



Current Implementation Status of BCS Rules



Issues and Controversies Related to BCS

Dissolution of Solid Oral Dosage Forms

Dissolution

Dissolution Absorption

Rapidly Dissolving Products Containing Highly Soluble and Highly Permeable Drugs

• Absorption will be “rapid and complete” • When dissolution is rapid in gastric fluid, the rate of absorption is primarily a function of gastric emptying • High solubility plus high permeability classification ensures extent of absorption • Dissolution tests may serve as a sensitive tool to ensure the rate of absorption

Biopharmaceutics Classification System 0.001

0.0001

Class I: HS, HP

Class II: LS, HP

Dissolution rate > Gastric emptying time

Dissolution is rate-limiting

Class III: HS, LP

Class IV: LS, LP

e mre Pl a nuj e J

Absorption is rate-limiting Problem drugs; in vitro dissolution is not reliable 0.00001 0.000001 1

10

100

1000

10000

100000 mL

Aqueous volume required (1 to 7.5 pH range)

Biopharmaceutics Classification System (BCS) Guidance



Classification of drugs based on solubility and intestinal permeability



Waiver of in vivo BE studies for IR (Immediate Release) solid oral dosage forms



Reduction in the costs of approving SUPAC

Solubility Criterion: D/S Ratio Dose Dose (mg) = = 250 mL So lub ility Aqueous Solubility (mg/mL)

(a) When D/S is < 250 mL over a pH range of 1 to 7.5; (b) When D/S is > 250 mL; D/S = 33 liters Log P = 2.18 Class 2 Drug Candidate? Griseofulvin:

S = 15 µ g/mL; Dose = 500 mg

Gastric emptying half-time (min)

Comparison of Gastric Emptying Time After Administration of 50- and 200-mL volumes 100

50 mL 200 mL

80 60 40 20 0

I

II

late II/III

Gastric Mobility (IMMC) phase Gastroenterology 99 (1990) 1275

Excipient Effect upon Bioavailability • Sodium pyrophosphate (cathartic laxative): Bioavailability of ranitidine decreased ? • Mannitol, sorbitol (cimetidine, theophylline; case studies with chewable tablets and syrups) • Myristic acid: gastric emptying time increased (nitrofurantoin) • Polysorbate 80, cremophor, and other surfactants: inhibitors of Pgp (Pgp substrates’ BE may increase) • Oleic acid-bile acids (propranolol BE increased); lymphatic uptake

Common Excipients in IR Tablets (inactive ingredient guide)

Excipients

Mg. stearate Starch Microcrystalline cellulose Lactose Silicone dioxide Sodium starch glycolate Stearic acid Povidone Hydroxypropylmethyl cellulose Titanium dioxide Croscarmellose sodium Polyethylene glycol Sodium lauryl sulfate Calcium phosphate Talc Sucrose Hydroxypropyl cellulose Carnuba wax Crospovidone Polysorbate 80 Ethyl cellulose Acacia Propylene glycol Gelatin Methyl cellulose

0

500

1000

1500

2000

Number of Submissions

2500

Key Topics of This Presentation



Development Background of BCS Guidance



Current Implementation Status of BCS Rules



Issues and Controversies Related to BCS

Examples of Class I Drugs O

O CH3

C NH

H3C

OH

N

O

N

Acetaminophen, Paracetamol CN CH3O CH3O

CH3

CCH2CH2CH2NCH2CH2

H N N

CH3

Theophylline (NTI)

OCH3 OCH3

HCl

CH(CH3)2

OCH2CHCH2NHCH OH

Verapamil

CH3 CH3

HCl

Propranolol H N CH3

Metoprolol

Pindolol

OCH2CHCH2NH C H OH

CH3

Examples of Class I Drugs (continued) December 26

Fluoxetine

Effect of Rotational Speed on Dissolution of Acetaminophen from IR Dosage Forms

100 % Release

80 Panadol tablets (50 rpm)

60

Panadol tablets (100 rpm)

40 20 0

0

10

20 Time (rpm)

30

40

Dissolution Data of Metoprolol Reference Drug Product (ANDA & UMAB)

% Drug Released

105 90 75 60 45 30 15 0

0

5

10

15

20

Time (Min)

25

30

35

Examples of Class II Drugs

Ketoconazole (pKa = 6.5, 2.9)

Danazol

Dipyridamole (pKa = 6.4)

Atovaquone Carbamazepine Glibenclamide Griseofulvin Troglitazone Ibuprofen

Examples of Class III Drugs

Acyclovir

Atenolol (F = 0.5)

Neomycin

Cimetidine (F = 0.84)

Lisinopril

Ranitidine (F = 0.52)

Examples of Class III Drugs (continued) O

O

S

H2N S O

O NH

N H

Cl

Hydrochlorothiazide (0.71) H

Doxazosin

CH3

HS

O N

H O OH

Amiloride

Captopril (0.37) H2N H2N

N

C N

CH2SCH2CH2

S

Famotidine (0.45)

NH2

O

C N

S

NH2

O

Enalapril

ytili bae mre P na mu H

Formulation Approaches (1)

(2)

(3)

(4)

Mucoadhesion Absorption-enhancer Efflux inhibitors

Liquid-filled capsules with absorptionenhancer

D/S 1

100

250

Nanoparticles Salt/polymorph derivatives Liquid-filled capsules Self-emulsifying vehicles Addition of surfactants Solid dispersions

500

1,000

10,000

100,000

Unknown

BCS Waiver Candidates: NCE (NDA)

HS, HP (24%)

60

40

10 0

0

1

2

LS, HP

20

HS, LP

30

LS, LP

% Frequency

50

3

Drug Class

4

5

6



NDA approvals over the period of 1998 to 2001



PO IR formulation (N = 54)

Direct Cost Savings: Industry Sample packaging/maintenance: $15,000 Clinical cost: $125,000 Bioanalytical cost: $70,000 Data analysis, report generation: $20,000 Internalization: $20,000 Total BE study cost = $250,000

Savings = # BE studies/yr x $250,000 x 24% (390 ㅡ 630)

BCS Waiver Candidates: ANDA

Current Rules (1.5%)

With Extensions Infeasible



In-vivo studies to be waived by BCS guidance are small.



Drugs qualified for BCS requirement are very few.



So far, very few submissions were made to FDA.

Key Topics of This Presentation



Development Background of BCS Guidance



Current Implementation Status of BCS Rules



Issues and Controversies Related to BCS

Are BCS Criteria Too Conservative? Statement of Advisory Committee for Pharm. Sci. (11/16/2000): “The public concerns are that FDA appraoch relevant to BCS is overly conservative, and people have argued that FDA should extend the application of biowaivers for Class II and III drugs. We felt that it was more prudent at this time to take a more conservative step because this is such a significant paradigm shift, in terms of risk. It was felt more prudent to be more conservative at this time.”

Are there any biowaiver extension opportunities for Class II and III drugs?

Extension Opportunities for Class II Drugs: Solubility Issue (pH)



Some class 2 drugs with pKa <4.5 and instrinsic solubility of > 0.01 mg/mL are consistently and completely absorbed after oral administration These drugs will have solubility of >1 mg/mL in the jejunum (pH 6.5), resulting in fast and reliable dissolution of the drug. However, they can’t fulfill the BCS solubility criteria (poorly soluble at gastirc pH)!

CH3

8 Ibuprofen solubility (mg/mL)



CH3

CH3 CHCO2H

CHCH2

Intrinsic solubility: 0.064 mg/mL pKa = 4.39

6 4 2 0

0

2

4 pH

6

Other Class II Drugs: Solubility (pH) Compound

pKa

Human BA (%)

Sol, pH 1.2 (mg/mL)

Sol, pH 7.4 (mg/mL)

Dose (mg)

Fenoprofen

4.5

85

0.1

> 3.1

200

Flurbiprofen

4.3

92

0.007

2.6

100

Ibuprofen

4.4

> 80

0.06

2.3

200

Ketoprofen

4.6

100

0.13

> 1.4

75

Naproxen

4.2

99

0.005

> 2.5

200

Oxaprozin

4.3

0.004

1.7

600

95

ㅡ

100

Extension Opportunities for Class II Drugs: Solubility Issue (Dissolution Medium) SDS effect upon drug dissolution (0.5 ㅡ 2.0%)  Medroxyprogesterone acetate tablet  Danazol capsule  Carbamazepine tablet  Flutamide tablet

FaSSIF effect upon drug dissolution (Micellar solubilization) KH2PO4

3.9 g

Na taurochlolate Lecithin KCl NaOH q.s. Distilled water q.s. (Ibuprofen, naproxen)

3 mM 0.75 mM 7.7 g pH 6.5 1 Liter

The necessity of developing dissolution media simulating physiologically relevant in vivo situation!

Extension Opportunities for Class III Drugs: (HS, LP)

  

Permeability-limited absorption Absorption is less dependent upon IR formulation If drug dissolution is rapid ( > 85% in 15-min), IR form will act as an oral solution in vivo.

If two IR dosage forms with a class III drug dissolve rapidly and drug absorption is not affected by excipients, their bioequivalence is assured. Biowaiver can be granted!

Extension Opportunities for Class III Drugs: (HS, LP) Solution vs Tablet Solution vs Tablet AUCinf Ratio Cmax Ratio Acebutolol

0.91 ㅡ 1.01

0.96 ㅡ 1.04

Captopril

0.88 ㅡ 1.03

0.88 ㅡ 1.17

Doxazosin

0.94 ㅡ 1.08

0.91 ㅡ 1.05

(IR tablets with various formulations)

Expert Opinion Based on Atenolol Database

Solubility

Permeability

Dissolution

Biowaiver is justified, if IR products meet rapidly dissolving FDA requirements (NLT 85% in 15 min,900 mL of 0.1 N-HCl, 50 rpm, paddle)

Permeability Determination for BCS

Pharmacokinetic Studies

Intestinal Permeabililty Studies

• Absolute bioavailability studies

• Jejunal perfusion method

• Mass balance studies with use of radiolabeled drug

• In vitro Caco-2 permeability study

Comparison of Drug Permeability (Caco-2 cell) 

High Permeability (F > 0.9) Acetaminophen Caffeine Naproxen Theophylline



Moderate Permeability (F = 0.5 Amiloride Ranitidine



Acetylsalicylic acid Labetalol Pindolol Ibuprofen

ㅡ

Antipyrine Metoprolol Propranolol Ketoprofen

0.89)

Atenolol Hydrochlorothiazide

Furosemide]

Low Permeability (F < 0.50) Chlorothiazide Nadolol

Dextran Sulfasalazine

Famotidine

Extent of Absorption (% fa)

Permeability Assay: Method Suitability

100 80 Class I

60

Class II

Class III

40 20

Class IV

0 0

20

40

60

Papp (x 10-6 cm/sec)

80

Permeability of GSK Drugs with That of Metoprolol

Drug

BA %

Permeability (cm/sec x 106) Ileum

Colon

Caco-2

GSK A

99

22

71

120

GSK B

94

1.8

6.5

48

Metoprolol

> 90

33

50

78

Acceptability of Literature Data

Current BCS Rules

Modification of BCS Rules



Solubility



Solubility



Dissolution



Dissolution



Caco-2 cell assay



Literature data on BA (Permeability ∝ BA)

Conclusions: What Will Be Next Moves? 

Implementation of industrial and academic inputs into the BCS guidance



Further research to extend BCS-based biowaivers



Taking initiatives in educating health-care professionals and the public



International harmonization efforts