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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
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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
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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)
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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
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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
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BCS View of Oral Drug Absorption and Bioequivalence
Modern Biopharmaceutics CD
BCS shifts the view of BE from the plasma to the absorbing site
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BCS: Applying Fick´s Law of Diffusion
Modern Biopharmaceutics CD
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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 +
+
‐‐
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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 [%
]
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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
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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
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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)
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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
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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)
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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)
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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
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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
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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)
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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
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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, …?
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BCS – Increased Understanding of Excipient Effects
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BCS – Detectability of Excipient Effects
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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
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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
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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
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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
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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
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Acknowledgements
● Prof. Marival Bermejo-Sanz● Dr. Marlies Kubbinga● Dr. Maj Nguyen
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