Excipient Interactions Relevant For BCS Biowaivers Peter Langguth

Transcription

1 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

2 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

3 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)

4 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 EU-EMA Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **, EU-EMA Product specific guidances Capecitabine, Carglumic acid, Dasatinib, Emtricitabine / Tenofovir, Disproxil, Erlotinib, Imatinib, Memantine, Miglustat, Oseltamivir, Posaconazole, Repaglinide, Sirolimus, Sorafenib, Tadalafil, Telithromycin, Voriconazole, Sunitinib

5 BCS based biowaivers Generic and innovator Variations of innovator product Variations of generic new generic vs. authorized and innovator Variation during innovator development or before marketing Line extensions (e.g. different strengths) in EU, WHO and selected other countries

6 BCS View of Oral Drug Absorption and Bioequivalence BCS shifts the view of BE from the plasma to the absorbing site Modern Biopharmaceutics CD 6

7 BCS: Applying Fick s Law of Diffusion Modern Biopharmaceutics CD 7

8 BCS classification Drugsare classified according to Permeability Solubility Drug products are compared based on In vitro dissolution rate + Permeability Class 1: HS/HP Propranolol Metoprolol Acetaminophen Class 3: HS/LP Atenolol Ranitidine Cimetidine Class 2: LS/HP Carbamazepine Ketoprofen Naproxen Class 4: LS/LP Furosemide Hydrochlorothiazide Volume of aq. buffer to dissolve highest dose + 8

9 Dose-Solubility Ratio, Permeability and Fraction Dose Absorbed Absorbierter Anteil [%] F L P ( P X0 F NON S0V L ) D/L Quotient Verteilungskoeffizient Langguth, Fricker, Wunderli-Allenspach, Biopharmazie, Wiley-VCH (2004) Equation from Boxenbaum, 1999)

10 BCS Concept: For Rapidly Dissolving IR Formulations and High Permeability Drugs, Absorption is Limited by Gastric Emptying Rate (approx. 15 min) Human Gastric Emptying Rates: T50 Amidon

11 BCS: Permeability Absorption > 85% = high permeability (EU, WHO, US) Literature data acceptable (EU, WHO) from investigations in humans In vitro & animal data supportive Experimental data required, except if classified in reference product labeling (US) Human, animal or in vitro studies

12 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)

13 BCS: In vitro dissolution studies Similarity in dissolution profiles at ph 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

14 BCS: Biopharmaceutic Implications 1 Class 1: HS/HP Rapidly dissolving If dissolution is rapid under all physiological conditions, system behaves like an oral solution, for which in vivo BE testing can be waived Low D 0 <1 High A n High D n Excipients: Advisable to use similar amounts of the same excipients in the composition of test like in the reference product Excipients that might affect bioavailability should be qualitatively and quantitatively the same in the test product and the reference product (EMA)

15 BCS: Biopharmaceutic Implications 2 Class 3: HS/HP Very rapidly dissolving Low D 0 <1 Low A n High D n Absorption of a class 3 drug is limited by its permeability & less dependent on its formulation If dissolution is very rapid under all physiological cond, it behaves like 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 more stringent diss criteria. Caution with excipients affecting T res 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)

16 BCS: Biopharmaceutic Implications 3 Class 2: HS/HP D 0 >1 High A n D n Absorption likely to be limited by in vivo dissolution In vivo predictive dissolution method is needed In vivo dissolution can be estimated if there is a validated IVIVC Currently no BCS based biowaiver for class 2 compounds

17 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 amounts Critical 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 in similar amounts Requirement for BCS class 3 drugs: Q1 & Q2

18 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, pp (2007)

19 Critical Excipients: Sorbitol Mean plasma concentrations of ranitidine in 20 healthy volunteers following 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

20 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,?

21 BCS Increased Understanding of Excipient Effects

22 BCS Detectability of Excipient Effects

23 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

24 Case study: Chitosan Effects on Aciclovir Clinical practice 400 mg chitosan PK parameter GM mean ratio T/R 90% CI CV (%) AUC (0-12) AUC (0- ) C max mg chitosan PK parameter GM mean ratio T/R 90% CI CV (%) AUC (0-12 ) AUC (0- ) C max Conc (ng/ml) t (h) Product P P + 400mg excipient E P + 1g excipient E 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

25 Case study: Chitosan Effects on Aciclovir In vitro models: P app of acyclovir in the presence of chitosan Model and concentration chitosan HCl Permeation of acyclovir Caco-2 Nr of inserts P app in 10-6 cm/s (sd) Ratio test vs reference p-value 0 g/l (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 (0.01) 1.6 g/l (0.003) g/l (0.15) Ussing type (rat) Nr of segments & 0 g/l (1.5) 1.6 g/l (9.3) * 4 g/l (9.8) InTESTine (pig) Nr of segments $ 0 g/l 2x (0.30) 1.6 g/l 2x (0.12) g/l 2x (0.05) Kubbinga M, PhD Thesis University of Mainz (2016) BCS-Based Biowaivers: Risks and Opportunities

26 Case study: Chitosan Effects on Aciclovir Final risk analysis with available in vitro toolbox 1. In vitro dissolution test: not necessary, acyclovir and chitosan were both in solution 2. In vitro permeation test: mostly statistically insignificant results, reduced P 3. In vitro bioaccessibility test: no significant effect, reduced P 4. Transit time: not tested in vitro 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 Detectability: unchanged as we did not validate any model Testing= use validated comparative test method or avoid/refuse difference in excipient; if unavailable> biostudy Kubbinga M, PhD Thesis University of Mainz (2016) BCS-Based Biowaivers: Risks and Opportunities

27 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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29 Acknowledgements Prof. Marival Bermejo-Sanz Dr. Marlies Kubbinga Dr. Maj Nguyen

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