excipient interactions relevant for bcs...

Excipient Interactions Relevant For BCS Biowaivers

Peter Langguth

Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg 

University Mainz, Germany

3rd Symposium on Harmonization of BE Requirements, Amman, 2018

Biowaiver definition and purpose

A waiver for in vivo bioavailability and bioequivalence studies 

•  To improve the efficiency of drug development and the review process by recommending a strategy for identifying expendable clinical bioequivalence tests.

•  To recommend a class of immediate‐release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests.

•  To recommend methods for classification according to dosage form dissolution, along with the solubility and permeability characteristics of the drug substance

CDER , US FDA

Different types of Biowaivers

•   In vitro data can be used as surrogate for in vivo bioequivalence: Biopharmaceutics Classification System: BCS based biowaiver

•   Extrapolation of in vivo results to additional strengths: Proportionality waiver

•   No in vivo data required based on In vitro / In vivo correlation (IVIVC)

BCS: Regulatory Impact EU-FDA

US-FDA Guidance for Industry. Solid Oral Dosage Forms Scale-Up and Postapproval Changes SUPAC IR: 1995; SUPAC MR: 1997).

US-FDA Guidance for Industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. 2017.

EU-EMA Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **, 2010.

EU-EMA Product specific guidancesCapecitabine, Carglumic acid, Dasatinib, Emtricitabine / Tenofovir, Disproxil, Erlotinib, Imatinib, Memantine, Miglustat, Oseltamivir, Posaconazole, Repaglinide, Sirolimus, Sorafenib, Tadalafil, Telithromycin, Voriconazole, Sunitinib

BCS based biowaivers

Generic and innovator

Variations of innovator product

Variations of genericnew generic vs. authorized and innovator

Variation during innovator developmentor before marketing

Line extensions (e.g. different strengths) in EU, WHO and selected other countries

6

BCS View of Oral Drug Absorption and Bioequivalence

Modern Biopharmaceutics CD

BCS shifts the view of BE from the plasma to the absorbing site

7

BCS: Applying Fick´s Law of Diffusion

Modern Biopharmaceutics CD

8

BCS classification

Drugs are classifiedaccording to‐ Permeability‐ Solubility

Drug products are comparedbased on‐ In vitro dissolution rate

Class 1: HS/HPPropranololMetoprololAcetaminophen

Class 2: LS/HPCarbamazepineKetoprofenNaproxen

Class 3: HS/LPAtenololRanitidineCimetidine

Class 4: LS/LPFurosemideHydrochlorothiazide

Perm

eability

Volume of aq. buffer to dissolve highest dose +

+

‐‐

Dose-Solubility Ratio, Permeability and Fraction Dose Absorbed

)(0

0LVSNONF

XPP

LF

Langguth, Fricker,Wunderli-Allenspach,Biopharmazie,Wiley-VCH (2004)Equation from Boxenbaum,1999)

D/L Quotient

Verte

ilung

skoe

ffizien

t

Abso

rbie

rter A

ntei

l [%

]

Human Gastric Emptying Rates: T50

BCS Concept: For Rapidly Dissolving IR Formulations and High PermeabilityDrugs, Absorption is Limited by Gastric Emptying Rate (approx. 15 min)

Amidon

BCS: Permeability

Absorption > 85% = high permeability(EU, WHO, US)

Literature data acceptable (EU, WHO)from investigations in humansIn vitro & animal data supportive

Experimental data required, exceptif classified in reference product labeling (US) Human, animal or in vitro studies

BCS: Solubility

Highly soluble if: Maximum dose strength (US)

Maximum clinical dose (EU, WHO)

Dissolved at 37 ºC in 250 ml; pH range:

1.0 to 6.8 (US, EU)1.2 to 6.8 (WHO)

BCS: In vitro dissolution studies

Similarity in dissolution profiles atpH 1.2, 4.5, 6.8(EU, WHO, US)+ pH of minimum solubility (EU)Similarity if >85% dissolved in 15 min in both products

Class 1: Rapid dissolution >85% in 30 min

Class 3: Very rapid dissolution>85% in 15 min

BCS: Biopharmaceutic Implications 1

Class 1: HS/HP Rapidly dissolving

Low D0<1 High An

High Dn

If dissolution is rapid underall physiological conditions,system behaves like an oralsolution, for which in vivo BEtesting can be waived

Excipients: Advisable to use similar amounts of the same excipients in the composition of test like in the reference productExcipients that might affect bio-availability should be qualitatively and quantitatively the same in thetest product and the reference product (EMA)

BCS: Biopharmaceutic Implications 2

Class 3: HS/HP Very

rapidly dissolving

Low D0<1 Low An

High Dn

Absorption of a class 3 drug islimited by its permeability & lessdependent on its formulation

If dissolution is very rapid underall physiological cond, it behaveslike an oral solution (for which in vivo BE study can be waived)

If permeability is site dependent, transit time becomes critical suggesting the need of a morestringent diss criteria.

Caution with excipients affectingTres and/or interact with carriers

Excipients have to be qualitatively the same and quantitatively very similar in order to exclude different effects on membrane transporters (EMA)

BCS: Biopharmaceutic Implications 3

Class 2: HS/HP

D0>1 High An

Dn

Absorption likely to be limited byin vivo dissolution

In vivo predictive dissolutionmethod is needed

In vivo dissolution can beestimated if there is a validatedIVIVC

Currently no BCS basedbiowaiver for class 2 compounds

BCS – excipients

When excipients are not “problematic” their effect on the absorption of class I drugs is unlikely different excipients can be used if usual for that dosage form

in usual amountsCritical excipients must be included in the same amount

as in the reference product Avoid problems by using the same excipients

as those used in the reference product insimilar amounts

Requirement for BCS class 3 drugs: Q1 & Q2

BCS – Critical excipients

Critical excipients may: - affect GI motility- interact with drugs (e.g. complex formation)- affect drug permeability (e.g. transporters)

Examples- Fillers & sweeteners (mannitol, sorbitol)- Surfactants (SLS, polysorbate 80, Cremophor, Vit E TPGS,

pluronics)- Others: Sodium acid pirophosphate, chitosans,

cyclodextrins, PEG

Chen et al. Pharm Res. (2007) 24(1):73-80; S. Grube and P. Langguth, Excipients as modulators of drug-carrier mediated absorption in the intestine, In: Drug Delivery Research Advances (Ed) B.O. Mashkevich, pp77-116 (2007)

Critical Excipients: Sorbitol

Mean plasma concentrations of ranitidine in 20 healthy volunteersfollowing administration of 150 mg ranitidine solution with addition

of 5 g of sorbitol or 5 g of sucrose

Chen et al. Pharm Res. (2007) 24(1):73-80

Risk Analysis on Excipient Effects

● Overcome/extend current limitations of guidance● Risk = incidence x 1-detectability x severity

Increased understanding of excipient effects > widen criteria? “green” list?

Additional in vitro tests: bioaccessibility, transit time, permeability, …

Fine tuning of acceptance criteria of in vitro test, …?

BCS – Increased Understanding of Excipient Effects

BCS – Detectability of Excipient Effects

Case study: Chitosan Effects on Aciclovir

Theory ● API: acyclovir

– BCS class III– Low dose: 200 mg– Safe

● Permeability modulator (enhancer): chitosan– Literature data: increase of acyclovir permeability &

bioavailability– In vitro: Caco-2 data and MDCK data– In vivo: Rat data– Selected quantities: 0.4 g and 1 g

Kubbinga M, Nguyen MA, Staubach P, Teerenstra S, Langguth P. The Influence of Chitosan on the Oral Bioavailability of Acyclovir--a Comparative Bioavailability Study in Humans. Pharm Res. (2015) 32(7):2241-9

Case study: Chitosan Effects on Aciclovir

Clinical practice● 400 mg chitosan

● 1000 mg chitosan

0

50

100

150

200

250

300

350

0 1 2 3 4 5 6 7 8 9 10 11 12

Product P P + 400mg excipient E P + 1g excipient E

t (h)

Conc(ng/ml)

PK parameter GM mean

ratio T/R

90% CI CV

(%)

AUC(0-12) 0.72 0.51-1.13 46

AUC (0-∞) 0.73 0.54-1.00 42

Cmax 0.59 0.39-0.90 57

PK parameter GM mean

ratio T/R

90% CI CV

(%)

AUC(0-12) 0.70 0.50-0.99 46

AUC (0-∞) 0.69 0.51-0.94 42

Cmax 0.58 0.38-0.88 57

Kubbinga M, Nguyen MA, Staubach P, Teerenstra S, Langguth P. The Influence of Chitosan on the Oral Bioavailability of Acyclovir--a Comparative Bioavailability Study in Humans. Pharm Res. (2015) 32(7):2241-9

Case study: Chitosan Effects on Aciclovir

In vitro models: Papp of acyclovir in the presence of chitosanModel and concentration chitosan HCl Permeation of acyclovir

Caco-2 Nr of inserts Papp in 10-6 cm/s (sd) Ratio test vs reference p-value

0 g/L 3 0.17 (0.01)

1.6 g/L 3 21 (1.08) 124 p<0.0001*

4 g/L 3 24 (1.31) 143 p<0.0001*

Caco-2+mucus Nr of inserts

0 g/L 3 0.12 (0.01)

1.6 g/L 3 0.13 (0.003) 1.08 0.96

4 g/L 3 0.28 (0.15) 2.33 0.11

Ussing type (rat) Nr of segments&

0 g/L 5 7.4 (1.5)

1.6 g/L 5 5.4 (9.3) 0.73 0.034*

4 g/L 5 6.2 (9.8) 0.84 0.23

InTESTine (pig) Nr of segments$

0 g/L 2x4 0.54 (0.30)

1.6 g/L 2x4 0.49 (0.12) 0.91 0.96

4 g/L 2x4 0.38 (0.05) 0.70 0.67

Kubbinga M, PhD Thesis University of Mainz (2016) BCS-Based Biowaivers: Risks and Opportunities

Case study: Chitosan Effects on Aciclovir

● Final risk analysis with available in vitro toolbox1. In vitro dissolution test: not necessary, acyclovir and chitosan were both in solution2. In vitro permeation test: mostly statistically insignificant results, reduced P3. In vitro bioaccessibility test: no significant effect, reduced P4. Transit time: not tested in vitro

● Detectability: unchanged as we did not validate any model● Testing= use validated comparative test method or avoid/refuse

difference in excipient; if unavailable> biostudy

Failure mode Target Incidence Detectability Severity Test?

Dissolution equivalent Zero# N/A High No

Permeability equivalent Medium Medium High Yes

Intraluminal fate equivalent Low Medium High Yes

Transit time equivalent Medium Low High No

Kubbinga M, PhD Thesis University of Mainz (2016) BCS-Based Biowaivers: Risks and Opportunities

Case study: Chitosan Effects on Aciclovir

Conclusion● Chitosan is not an inert excipient

– Hypothesis confirmed● Biostudy needed

– Position unchanged● Models

– toolbox including models for permeability testing as well as bioaccessibility testing;

– further validation studies/ simulations needed● Mechanism of interaction

– Multiple possibilities > complex – further research needed

Acknowledgements

● Prof. Marival Bermejo-Sanz● Dr. Marlies Kubbinga● Dr. Maj Nguyen