Opportunities for Regulatory Relief via In Vitro Dissolution. James E. Polli June 10, 2015

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1 Opportunities for Regulatory Relief via In Vitro Dissolution James E. Polli June 10, 2015

2 Topics Current issues with in vitro dissolution IVIVC, IVIVR, and biopharmaceutic risk Deconvolution IVIVR method BCS Class 2 (for weakly basic drugs) BCS Class 3 excipient considerations

3 Two of the Most Common Complaints about In Vitro Dissolution Too sensitive (i.e. over discrimination) Not sensitive enough (i.e. not discriminating enough) Opportunities Regulatory relief Methods development/validation/standardization of more challenging dissolution problems (e.g. BCS class 2)

4 Complications Attaining complete dissolution and sink conditions Enhanced drug solubility (e.g. via additional surfactant) tends to reduce dissolution test sensitivity. Same EVERYTHING across dose strengths Historical tendency to prefer the same test methods and same specs, even though different doses can result in a fundamental change in the dissolution problem. A higher dose may dissolve slower or to a lesser extent, than lower dose.

5 Roles of In Vitro Dissolution Product development tool QC test Clinically relevant assessment tool [a/k/a in vivo performance test] Meaning? A measure of in vivo dissolution As assessed by deconvolution of PK profile when absorption is dissolutionlimited?

6 Meaning of In Vivo Performance In vivo dissolution (profile) In vivo absorption (profile) In vivo pharmacokinetic profile Sensitive to efficacy or safety Sure, all related, but lack of clarity is a barrier. Do we want in vitro dissolution to predict first-pass metabolism? We have to be careful about what we expect of in vitro dissolution. Lack of clarity detracts from reliable utility of in vitro dissolution. IVIVR in vitro dissolution in vivo absorption relationship Absorption = dissolution + permeation

7 Beyond In Vitro Dissolution Science: Status Quo and the Confidence Game Organizations will often not pursue approaches that lack utility in drug development or lack high regulatory certainty. Status quo Stakeholder know current strength/limitations of in vitro dissolution Budget No requirement for biostudies with several formulations Uncertain elements Budget Acceptable role of modeling and simulation

8 Novel In Vitro Dissolution Methods Two major elements Apparatus and operating conditions Media Apparati Compendial Two or more lumen compartments (e.g. stomach and duodenum per ASD model) Systems with absorption compartment (e.g. biphasic systems to mimic absorption during dissolution for low solubility drugs to avoid too much surfactant)

9 Biopharmaceutic Risk Is an IVIVC/IVIVR possible or even likely for a BCS 1 IR tablet? a BCS 2 IR tablet? a BCS 3 IR tablet? a BCS 4 IR tablet? Is it possible to understand how dissolution contributes to the absorption kinetics?

10 Biopharmaceutic Risk For a SUPAC change, a IR tablet of a BCS Class 2 drug demonstrates rapid in vitro dissolution (including being in spec). Is a biowaiver possible? For a SUPAC change, a ER tablet of a BCS Class 2 drug demonstrates in vitro dissolution in spec. Is a biowaiver possible?

11 Categories of IVIVC/IVIVR Convolution (FDA Level A) Deconvolution Deconvolution (but only linear) USP Level A Summary parameters Point estimates Rank order AAA AA A B C D Polli, J.E. Analysis of In Vitro - In Vivo Data. In Amidon, G.L., Robinson, J.R., and Williams, R.L. (eds.), Scientific Foundation and Applications for the Biopharmaceutics Classification System and In Vitro - In Vivo Correlations; AAPS Press: Alexandria, VA, 1997, pp

12 Selection of IVIVC Approach interested in drug absorption interested in overall pharmacokinetics Level AA (deconvolution-based) Level AAA (convolution-based)

13 Deconvolution IVIVR Application of the nonlinear, deconvolution-based model to the in vitro-in vivo relationships metoprolol piroxicam ranitidine 1 1 F 1 1 a 1 F F fa 1 1 Hypothesis: Factor(s) controlling overall absorption kinetics and dosage form performance can be elucidated from IVIVR. Only requires one formulation. Early formulation development. d d

14 Model Development solid dosage form dissolution solution in GIT permeation drug in plasma

15 Model 1 1 F a d f 1 1 a F F F a is the fraction of the total amount of drug absorbed at time t, f a is the fraction of the dose absorbed at t = infinity, alpha is the ratio of the first-order apparent permeation rate coefficient (k p app ) to the first-order dissolution rate coefficient (k d ), and F d is the fraction of drug dose dissolved at time t. Polli, J.E., Crison, J.R., and Amidon, G.L. (1996): A novel approach to the analysis of in vitro-in vivo relationships. J. Pharm. Sci. 85: d

16 Model Assumptions Only dissolution and permeation first-order dissolution (k d ) F d in vitro = F d in vivo = F d first-order permeation (k p ) Assumptions in the determination of F a

17 Alpha k app p k d large alpha: dissolution rate-limited absorption small alpha: permeation rate-limited absorption alpha = 1: mixed rate-limited absorption

18 fraction absorbed Theoretical IVIVRs fra c tion dis s olve d Fa 1 d 1 f 1 1 a 1 F F d

19 percent dissolved Metoprolol Dissolution Profiles Lopressor fast medium slow time (min) f 2 = 19.1 r m = 0.80

20 metoprolol plasma concentration (ng/ml) Metoprolol Plasma Profiles time (hr) Lopressor fast medium slow

21 fraction metoprolol absorbed Metoprolol IVIVRs fraction metoprolol dissolved Lopressor fast medium slow

22 Metoprolol Absorption Kinetics f a Lopressor (0.025) Fast (0.024) Medium (0.034) Slow (0.030) Mean (0.015) k d k p app alpha (hr -1 ) (hr -1 ) (0.0328) (0.12) (0.268) (0.0178) (0.48) (0.139) (0.0181) (0.17) (0.068) (0.103) (0.11) (0.16) (0.098) t win (hr -1 ) 1.89 (0.16) 2.25 (0.56) 1.88 (0.26) 2.67 (0.36) 2.22 (0.18) phi (0.063) (0.042) (0.045) (0.066) (0.031) k p (hr -1 ) (0.248) (0.138) (0.048) (0.153) (0.085) Polli, J.E., Rekhi, G.S., Augsburger. L.L., and Shah, V.P. (1997): Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets. J. Pharm. Sci. 86:

23 Hypothesis Modest changes in dissolution have no in vivo consequence for IR dosage forms whose overall absorption is not dissolution controlled. When can bioequivalence studies be waived for IR products that exhibit modest differences in dissolution? Is a dissolution method acceptable if two IR products are bioequivalent, but exhibit modest differences in dissolution?

24 percent dissolved Piroxicam Dissolution Profiles time (min) Feldene fast medium slow f 2 = 23.4 r m = 0.66

25 Piroxicam Plasma Profiles

26 fraction piroxicam absorbed Piroxicam IVIVRs fraction piroxicam dissolved Feldene fast medium slow

27 Piroxicam Absorption Kinetics f a alpha k d (hr -1 ) Fast (0.018) (0.138) (0.60) Medium (0.020) (0.24) (0.10) Feldene (0.019) (0.84) (0.20) Slow (0.022) (2.17) (0.05) Mean (0.011) k app p = k p (hr -1 ) 7.26 (1.12) 7.17 (1.10) 10.7 (2.6) 11.3 (3.8) (1.14) Polli, J.E. and Ginski, M.J. (1998): Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities. Pharm. Res. 15:47-52

28 percent dissolved Ranitidine Dissolution Profiles time (min) Zantac fast medium slow f 2 = 32.1 r m = 0.44

29 Ranitidine Plasma Profiles

30 fraction ranitidine absorbed Ranitidine IVIVRs fraction ranitidine dissolved Zantac fast medium slow

31 Ranitidine Absorption Kinetics f a Fast (0.018) Zantac (0.016) Mediam (0.016) Slow (0.021) Mean (0.009) k d k p app alpha (hr -1 ) (hr -1 ) (0.0095) (1.4) (0.095) (0.0181) (0.30) (0.108) (0.0194) (0.29) (0.100) (0.020) (0.64) (0.075) (0.047) t win (hr -1 ) 2.00 (0.17) 2.10 (0.20) 2.50 (0.34) 2.14 (0.16) 2.18 (0.12) phi (0.19) (0.10) (0.18) (0.13) (0.009) k p (hr -1 ) (0.030) (0.041) (0.036) (0.031) (0.017)

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33 IVIVR Analysis and Permeability drug P (cm/sec) x 10 6 piroxicam 91.3 ( 1.2) metoprolol 10.7 ( 0.3) ranitidine ( 0.058) k p (pred) (hr -1 ) 3.49 ( 0.05) ( 0.011) ( ) k p (obs) (hr -1 ) 9.00 ( 1.14) ( 0.085) ( 0.017)

34 Summary The factor(s) controlling overall absorption kinetics and dosage form performance can be elucidated from in vitro dissolution - in vivo absorption relationships. kinetic importance of dissolution f 2 criteria (or other metrics) connection to Caco-2 permeability

35 Lamotrigine Antiepileptic drug BCS Class 2 BCS class 2b pka = 5.7 (weakly basic)

36 Lamotrigine BCS solubility ph Dose Strength (mg) C s (mg/ml) D ± ± ± Dose number (D 0 ) employed a nominal volume of 250mL.

37 BCS class distribution in ANDAs The percent approval of different classes of BCS drugs listed on WHO EML from 2000 to 2011 AK Nair, et al. Statistics on BCS Classification of Generic Drug Products Approved Between 2000 and 2011 in the USA. AAPS J. 14:664-66, 2008.

38 BCS Class 3 excipient considerations: common excipients Excipient Recommended maximum allowable amount for a class 3 biowaiver (mg) Typical excipient amount (when present) in an IR tablet or capsule with a total weight of 300mg Microcrystalline Cellulose Hydroxypropyl Methyl Cellulose Qualitatively the same and quantitatively very similar to reference product Qualitatively the same and quantitatively very similar to reference product 100mg (20%-90%) 10mg (2%-5%) Sodium Lauryl Sulfate mg (0.5%-2.5%) Corn Starch mg (25%-75%) Sodium Starch Glycolate mg (4%) Colloidal Silicon Dioxide mg (0.1%-1%) Dibasic Calcium Phosphate mg (25%-75%) Crospovidone mg (2%-5%) Lactose mg (80%) Povidone mg (0.5%-5%) Vaithianathan S, et al. Mol Pharmaceutics, in press. DOI: /acs.molpharmaceut.5b00154 Stearic Acid 80 6mg (1%-3%) Pregelatinized Starch mg (5%-75%) Croscarmellose Sodium mg (0.5%-25%) Magnesium Stearate mg (0.25% to 5%)

39 Topics Current issues with in vitro dissolution IVIVC, IVIVR, and biopharmaceutic risk Deconvolution IVIVR method BCS Class 2 (for weakly basic drugs) BCS Class 3 excipient considerations