Use of IVIVc and IVIVe to support formulation development Industrial case studies

Transcription

1 Use of IVIVc and IVIVe to support formulation development Industrial case studies Dr. Xavier Pepin, Global Head of Biopharmacy, Pharmaceutical Sciences and Operations, Sanofi R&D AAPS meeting 4 th November 2014 Xavier Pepin AAPS meeting 4 th Nov

2 Outline of the presentation Some definitions Contribution of Biopharmacy along the industrial affair value chain 4 case studies with successful application of IVIVe 1 case study where PBPK models cannot be used (today) 2

3 IVIVe vs IVIVc In vitro- in vivo correlations (IVIVc) Mathematical models relating the in vitro behavior of drug products and their bioavailability Regulatory tool used to support changes Valid for one dose, one species, one dissolution method and formulations comprised between the extremes tested Different levels to the correlations Useful for modified release BCS I and some BCS II with caution 3

4 IVIVe vs IVIVc In vitro in vivo extrapolations (IVIVe) In vitro dissolution are used to calculate in vivo release in a in silico PBPK tool representing the human physiology. Other factors are considered such as transit, solubility, permeability, precipitation, degradation, local ph Much more reliable model can be built with IR formulation and applied to MR, in vitro methods can be used as input, extrapolations can be done Not yet a regulatory tool but can be accepted to waive BE studies under certain cases 4

5 Biopharmaceutical models use along IA value chain Ideation-Feasibility LCM : Dose and release profile to reach target exposure/efficacy Definition of drug property thresholds Generics/LCM : Dissolution range for bioequivalence Case study #1 due Diligence Drugability Main sources of variability Formulation robustness evaluation Risk assessment Case study #2 Case study #3 Trouble-shooting Understand failure reasons Target drug product profile Prototyping Bioequivalence study Dossier Case study #4 Contribution to prototype selection Anticipation of bioequivalence/superiority to reference product Biowaivers Use of IVIVe to support formulation/process changes in the absence of guidance 5

6 Case study #1 Paracetamol night Define release rate and administration time to achieve maximum pain relief during the night for a 1 g tablet 6

7 PK/PD relationship Biopharmaceutical properties Physico-chemical properties pka: 9.5 (25 C, acid) Log P: around Solubility = 23.7 mg/ml at 37 C (no ph dependence) Permeability = CaCo2 cells ~ cm/sec Short half life in man (2-3 hours) Efficacy : Central PK in adults plasma + CSF 2 Distribution model CSF/Plasma 1 1: Van der Marel C.D. et al., Acetaminophen in cerebrospinal fluid in children, Eur J Clin Pharmacol (2003) 59: : Bannwarth B. et al., Plasma and cerebrospinal fluid concentrations of paracetamol after a single intravenous dose of propacetamol, Br. J. clin. Pharmac. (1992), 34,

8 PK/PD relationship Acute pain (dental surgery) Calculation of C CSF Efficacy vs Cp 1 Direct PK/PD using CSF concentrations CCSF Thresholds were defined : 4 µg/ml for chronic and 5µg/mL for acute pain Efficacy vs C CSF 1 : R. A. Seymour and M. D. Rawlins, Pharmacokinetics of Parenteral Paracetamol and its Analgesic Effects in Post- Operative Dental Pain, Eur J Clin Pharmacol (1981) 20:

9 Paracetamol : GastroPlus model PK building PK model building Use of Measured IR oral or IV PK profiles 1,2 to fit Vd, k 12 k 21 and clearance 1 : Rawlins and al., Pharmacokinetics of paracetamol after intravenous and oral administration, Eur. Clin. Journal of Pharmacology, , : Borin M.T. et al., Single dose bioavailability of Acetaminophen following oral administration IJP 54 (1989)

10 Paracetamol LP GastroPlus model PK validation (1/2) PK model Validation Use of Tylenol in vitro dissolution 3 & in vivo PK profiles 3,4 to estimate model validity Use of Weibull equation to fit vitro data 3: Journal of Controlled Release 108 (2005) : Int. J. of Current Pharm. Res. 2(4) (2010)

11 Paracetamol LP GastroPlus model PK validation (2/2) PK model Validation : Direct IVIVe Parameter Unit Value Peff human 10^-4 cm/s 7 Vd L/kg 0.44 CL T L/h/kg 0.28 Ratio blood/plasma / 1.2 Liver first pass % Adequate anticipation of PK profile Model usable 3: Journal of Controlled Release 108 (2005) : Int. J. of Current Pharm. Res. 2(4) (2010)

12 Paracetamol LP Use of model Chronic pain : Define optimal release rate Plasma concentrations transformed in CSF concentrations 1 g IR at wake up (08h00), 1g IR at lunch (14h00), 1g IR at bed-time (22h00) 1 g IR at wake up (08h00), 1g IR at lunch (14h00), 1g MR at bed-time (22h00) Gain of 1 hour analgesia at the same dose with MR formulation 12

13 Case study #2 Zolpidem ODT Define bioequivalent dissolution range for immediate release Zolpidem products 13

14 Zolpidem hemitartrate Physico-chemical and biopharmaceutical properties MW = g.mol -1 (=307.4 for active moiety) Salt to base ratio = 1.24 CaCo2 Papp = cm/s scaled to human jejunal Peff = 8, cm/s fu,p = 7.5%, B:P = Weak base pka = 6.18 Aqueous solubility ph dependent 0.2 ph ,5 mg products are BCS class I Questions to Biopharm Can the ODT formulation be bioequivalent to the reference IR tablet despite dissolution differences? 1: DMD 27(11)

15 Human data Building up a GastroPlus model In vivo PK data exist for 8 mg zolpidem IV bolus, IR formulations at 2.5, 5, 7.5, and 10 mg zolpidem hemitartrate MR formulations at 10 mg and 12.5 mg Zolpidem hemitartrate Strategy : Use IV data and check model on IR and MR product IR : Let G+ calculate the in vivo dissolution MR : use direct IVIVe One compartment PK model in agreement with literature 1 1: DRUG METABOLISM REVIEWS. 24(2) (1992) 15

16 Verification on oral IR products Good fit of IR profiles in caucasians Good fit of IR profiles in japanese 16

17 % released Model performance on modified release formulation Purpose : Investigate model performance on modified release and a potential in vitro in vivo extrapolation Zolpidem is a BCS class I drug and therefore any modification of the release rate could impact the profile Use of 10 mg MR & 12.5 MR formulation (AMBIEN CR), ph mL dissolution profile Time (H) Good estimation of tmax, Cmax and AUC with a direct IVIVe 17

18 Sensitivity analysis Stomach transit time Major reduction on Cmax and increase in tmax No anticipated effect on AUC 18

19 Cplasma (ng/ml) % dissolved Anticipation of ODT behaviour using GastroPlus Using an ODT batch dissolution profile representative of the BE study Dissolution Profile - Buffer ph 6.8-1T023 Ratios ODT/IR Batch 1T T023 ph=6.8 50rpm 50 Cp-Zolpidem 5mg IR (ng/ml) time (min) 40 Cp-ODT 5 mg 1T023 (µg/ml) Time (H) Good chance of being bioequivalent despite differences in dissolution 19

20 Definition of bioequivalent space Target for 5 mg dose IR Cmax = 0,67 µg/ml, AUC inf = 293 ng.h/ml, tmax = 1 h Variation in stomach transit time alone can lead to large Cmax variability (fasted state) Cmax (µg/ml) AUC inf (ng.h/ml) Tmax (h) Weibull time scale (h) 2,0 1,8 1,6 1,4 1,2 1,0 0,8 0,6 0,045 0,045 0,050 0,050 0,055 0,055 0,060 0,050 0,045 0,040 0,045 0,040 Weibull time scale (h) 2,0 1,8 1,6 1,4 1,2 1,0 0,8 0,6 289,5 290,0 290,5 291,0 291,5 292,0 292,5 290,5 291,0 291,5 292,0 292,5 290,5 291,0 291,5 292,0 292,5 291,0 291,5 292,0 292,5 Weibull time scale (h) 2,0 1,8 1,6 1,4 1,2 1,0 0,8 0,6 1,5 2,0 2,5 3,0 2,5 2,0 3,0 2,5 3,5 3,0 3,5 3,0 4,0 0,4 0,2 0,065 0,060 0,055 0,050 0,045 0,4 0,2 0,4 0,2 1,0 1,5 2,0 2,5 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 Stomach transit time (h) Ref A = 0.01H Test A=0.17h 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 Stomach transit time (h) BE space is large enough compared to test and reference formulations 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 Stomach transit time (h) 20

21 Case study #3 Diltiazem MR Transfer from plant A to plant B of a modified release product, BEQ failed despite comparable dissolution using QC method. Can we understand and make recommendation for future BE study? 21

22 Diltiazem extended release Transfer from plant A to plant B Extended release formulation of diltiazem comprising a mixture of IR and MR pellets MR technology : coating with Eudragit RS/RL polymer BE study failed on Cmax B/A C max 0.84 [ ] B/A AUC [ ] In vitro ph 1 data Slight difference but within specs Question to Biopharmacy Why did the BE study fail? Can we avoid similar failures in the future? 22

23 Diltiazem Biopharmaceutical properties Phys-chem properties Log P = 2.89 pka 8.02 (Base) Permeability Scaled from Caco2 data Compartment ph fasted Papp fasted Peff fasted ph fed Papp fed Peff fed Stomach Duodenum Jejunum Jejunum Ileum Ileum Ileum Caecum Asc Colon Good solubility and permeability down to the lower sections of the GI tract European Journal of Pharmaceutical Sciences 24 (2005) European Journal of Pharmaceutical Sciences, 14, (2001) Pharmaceutical Research, 14(9), , (1997) 23

24 Methodology : top-down analysis using PBPK tools Fit of plant A PK data to extract in vivo release profile using 2-phase Weibull equation and GastroPlus In vivo Significantly quicker in vivo dissolution compared to that measured at ph1 In vitro ph 1 24

25 Diltiazem extended release IVIVe with ph 1 data In vivo dissolution is ~6h quicker than in vitro dissolution 25

26 % w/w increase of Eudragit RS film Diltiazem extended release IVIVe with ph 1 data Reasons for failure Eudragit RS/RL contains chloride anions. Eudragit RS/RL ph independent prolonged release active 45 Average hydration % w t=5h Average hydration % w t=125h 40 Sugar pellet Reduced Eudragit RS film hydration in the presence of Cl- 5 0 NaCl NaH2PO4, 2H2O HCl Water HCl 0.1 M not adapted! Recommendation to use ph 6.8 phosphate buffer w/o chloride 26

27 Diltiazem extended release IVIVe with ph 6.8 data Adequate IVIVe using ph 6.8 data The reason for BE study failure is that products were different New ph 6.8 dissolution method more discriminating New ph 6.8 dissolution method is more representative & can be used to screen future batches for BE testing 27

28 Diltiazem extended release Impact of gender on BE study Majority of the drug absorbed at ICJ and ascending colon 4H more transit time per large intestinal segments for females vs males a Males CTT estimated at 12h Females CTT from 16h to 20h Longer transit times in lower intestine could explain female larger exposure a: CTT = Colon Transit Time 28

29 Case study #4 Felodipine ER Development of a biowaiver in support of site manufacturing change (Astra-Zeneca, Sweden to Zentiva, Turkey) 29

30 Felodipine Biopharmaceutical properties High permeability Permeability 1 Caco2 : cm/s No polarity of transport Scaled to human jejunal Peff = 1, cm/s Precipitation from super-saturated solutions 2 In the presence of HPMC or HPMC-AS drug stays super-saturated for 3 hours Tp = 140 to 2000 seconds 1: DMD 38: , : European Journal of Pharmaceutics and Biopharmaceutics 70 (2008)

31 Felodipine Biopharmaceutical properties Phys-chem & biopharm properties 1 Clinical dose : 2.5 & 5 mg Log P = 5.58, MP = 146 celcius No pka in physiological range Fu,p = 0.4%, B:P = 0.7 Low aqueous solubility (0,9-1,2µg/mL) Impact of surfactants on solubility Low solubility (BCS II) Medium chosen for in vitro drug product dissolution (CTAB 0,4%) SDS discarded due to interaction with matrix Physiological surfactants European Journal of Pharmaceutics and Biopharmaceutics 64 (2), 2006, DMD 38: , 2010 International Journal of Pharmaceutics 405 (2011) Pharmaceutical Research 11 (8)

32 Felodipine GastroPlus model building Full PBPK model Human American male of 32y/o + 73 kg 32

33 Felodipine GastroPlus model building ACAT model Amount of fluid reduced to 7,5% and 2% in SI and colon match the free liquid volume measured by Schiller 1 (MRI) 1 : Aliment. Pharmacol. Ther 2005, 22,

34 Felodipine GastroPlus model building Estimation of clearance Liver & gut tissue Use of Km and Vmax values + intrinsinc human liver clearance measured in vitro for felodipine isomers 1,2 Model verification on IV and oral solutions 3 1: Drug metabolism and disposition 19(5) : Current Drug Metabolism 8(7) 2007, : BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 8, (1987) 34

35 Goodness of fit oral solutions Model considered adequate for IR products Acceptable anticipation of Cmax and AUC 35

36 In vitro In vivo extrapolation for MR formulations Use of literature data from Wingstrand K.et al. 1 and Abrahamson B. et al. 2 In vitro and in vivo data for extended release products Use of in vitro release data (using dossier method) USP2, 500 ml 0.1M phosphate medium ph6.5 with 0.4% CTAB, 37 C, 100 rpm 3 batches with different release rates (tablet A, B and C) Level B correlation already demonstrated by Astra Zeneca (part of the dossier) In GastroPlus : Switch formulation as controlled release integral tablet Use of in vitro as direct input for IVIVe 1 : International Journal of Pharmaceutics, 60 (1990) : Pharmaceutical research 11(8)

37 Felodipine tablet A Direct IVIVe Use of the Weibull 2 phase function to fit in vitro data In vitro in vivo 37

38 Felodipine tablet B Direct IVIVe Use of the Weibull 2 phase function to fit in vitro data In vitro in vivo 38

39 Felodipine tablet C Direct IVIVe Use of the Weibull 2 phase function to fit in vitro data In vitro in vivo Almost complete metabolism of fraction absorbed upper GI 39

40 Felodipine tablet A Use of PK profile to fit in vivo dissolution In vivo in vitro In vivo release more complete than in vitro? Nice match of the first 2,5 hours release 40

41 Felodipine tablet B Use of PK profile to fit in vivo dissolution In vivo in vitro In vivo release more complete than in vitro? Nice match of the first 4 hours release 41

42 Felodipine tablet C Use of PK profile to fit in vivo dissolution In vivo in vitro In vivo release more complete than in vitro? 42

43 Felodipine tablet C Use of PK profile to fit in vivo dissolution Hump in the PK profile ASF model Optimal Log G SA/V 6.1 boost lipophilic drug absorption from lower segments of GI tract 1 Effect could also be related to mechanical stress on the hydrophilic matrix upon large colon arrival & food intake 1:Advanced Drug delivery reviews , S41-S67 43

44 Level A IVIVc 3 types of formulations Good correlation with release from 2-5H Later time points In vivo > In vitro Higher permeability or higher disintegration? Overall Level A correlation considered adequate to waive manufacturing site change (same formulation, same dissolution) 44

45 Case study #5 Darifenacin 15 mg ER Generic formulation development Impact of physiology on model construction 45

46 Darifenacin.HBr Biopharmaceutical properties 1 BCS class I MR product C 28 H 30 N 2 O 2. HBr pka = 9.2 (base) MW = (base ) Log P = f u,p = 2% B:P = 0.68 CYP2D6 & CYP3A4 hepatic and intestinal metabolism Fa ~ 97% Caco2 data P app A2B = cm/s P app B2A = cm/s Medium ph Solubility, Cs [mg/ml] 0.1M HCl M HCl Acetate buffer Phosphate buffer Water Clinical dose = 15 mg, extended release product (hydrophilic matrix) 1 : Clin Pharmacokinet 2006; 45 (4):

47 Generic formulation development Reference = Emselex 15mg Prolonged release matrix tablet (20-24H) Dissolution Parameters: Apparatus Apparatus I (Basket) Temperature 37 ± 0.5 C Rotation Speed 100 Volume 900 ml Good profile similarity but ph 6.8 t 50% = 2.2h 47

48 Darifenacin 15 mg vs. Emselex 15 mg BE study Fed state, cross over, healtly volunteers Randomized and dosed 56 (23 females and 33 males), completed 53 Darifenacin 15 mg (Test) vs Emselex 15 mg (Ref) BE successful 48

49 Building the GastroPlus model Compartmental approach Use of literature IV data calculate 3 compartment model Direct application of this model for oral Fixed liver FPE of 63% 49

50 Direct IVIVe with Darifenacin ph 6.8 data Use of the Weibull single phase function as input Overestimation of PK from 10 hours 50

51 Direct IVIVe with Darifenacin ph 6.8 data Dissolution of the tablet in the lower segments of the GI tract Majority of the drug absorbed from the lower segments 51

52 Direct IVIVe with Darifenacin ph 6.8 data Reduction of ASF factors in the colon to 0.2 Incomplete dissolution Let weibull fit to max 92% released? Metabolic degradation due to microflora? Better data match 52

53 Direct IVIVe with Emselex ph 6.8 data Using adjustment of ASF as for the Test product Dissolution complete for this drug product Under-estimation What s wrong? 53

54 Use of average profiles? Large variability observed for both test and reference products In vitro dissolution compatible with observed PK? Large variability in the human PK with both ref and test Meaning of average Cp(t) profile? 54

55 Cp time profiles for individual subjects Peaks and troughs in the PK profiles 55

56 Cp time profiles for individual subjects Peaks and troughs in the PK profiles 56

57 Darifenacin : Peaks in the PK profiles Potential causes multiple peaks 1 Enterohepatic recirculation Only in case of food administration (not before 4 hours in fasted clinical trials) Salivary Enteric recirculation Site specific absorption Gastric motility Highly permeable and soluble drugs, i.e. markers of gastric emptying Other causes Colon peristalsis matrix degradation Presence of microflora matrix degradation? Darifenacin ER peaks in the fed state PK profiles Most frequent 4 hours (emptying), 8-10 hours (food), 20 hours post administration (following morning) Not systematic for Test and Ref, not formulation related Not seen by IV route Except for 4-6 hour time peak (gastric emptying) 1: Clin Pharmacokinet 2010; 49 (6):

58 Impact of free water volume, hydrodynamics, hydrostatic pressure on release? Meals and waking increase peristalsis and intraluminal pressure in the colon From S. Rao et al rpm 86 min Basket 1:S.S.C. Rao et al., Am. J. Gastroenterology, 99 (2004)

59 Analysis of individual profiles for 20 subjects Modeling of individual PK data 2 compartment disposition model Fractional doses (up to 4) Fit of V/F, k, k 12, k 21, D i, t Di, k ai Keeping V/F, k, k 12, k 21 constant for Ref and Test 59

60 Analysis of individual profiles for 20 subjects Calculation of in vivo absorption %Abs = 100 Using previous parameters Comparison of in vivo absorption to in vitro dissolution n i=1 D i 1 e k ai t t Di D 60

61 Analysis of individual profiles for 20 subjects Calculation of in vivo absorption %Abs = 100 Using previous parameters Comparison of in vivo absorption to in vitro dissolution n i=1 D i 1 e k ai t t Di D +/- marked phases in the in vivo absorption 61

62 In vitro vs in vivo (average +/- SD) Emselex y=x Overall agreement between in vitro (n=12) and in vivo (n=20) for both formulations Darifenacin y=x 62

63 In vitro vs in vivo (average +/- SD) y=x Stomach not emptied Large Tmax range owing to multiple peaks Darifenacin dissolves more rapidly than Emselex which shows in vivo after stomach emptying No appreciable impact on Cmax (T/R=1.1 or AUC (T/R=1) Current limitation of PBPK tools 63

64 Conclusions - Perspectives IVIVc/IVIVe are useful in LCM, generic and NCE commercial formulation development Material screening (prototypical dosage forms, due diligence) Material definition (type of DP, target DP release rate or location) to maximize efficacy or minimize side effects Acceptable dissolution limits to ensure bioequivalence Risk assessment (Test to Reference exposure ratio for bioequivalence or justification for new specifications) Biowaivers (Avoid bioequivalence testing whenever possible to allow filing of new products LCM + generics without running human testing) 64

65 Conclusions - Perspectives IVIVe for BCS I modified release formulations Works well for short release (0-4h) in fasted state including hydrophilic matrixes (Paracetamol, Zolpidem) Cardizem MR pellets (0-24H) works well in fasted state Darifenacin hydrophilic matrixes (5-20h) in fed state : IVIVc obtained using deconvoluted absorption profile (multiple peaks) IVIVe not possible (modeling of multiple peaks) IVIVe for BCS II modified release Worked for Felodipine in fasted state if vitro ensures sufficient sink Felodipine (5-20h) correlation in vivo abs more rapid than in vitro dissolution? Need more examples of IVIVc/IVIVe to draw conclusions One of the objectives of OrBiTo project (extend biowaivers) 65

66 Conclusions - Perspectives Perspective for improvements of IVIVe More physiological PBPK models Transit patterns (partial gastric emptying, different transit rates with impact of excipients and drugs) Mechanical forces (random + relation to food and nyctemeral cycle) Viscosity and diffusion in the lumen Free vs bound water (UWL) Link between in vitro performance and in vivo performance Dissolution methodology Viscosity, hydrodynamics, mechanical forces Selection of excipients for media (cf. Felodipine and Cardizem) Integration of dissolution/disintegration data in PBPK models Allow a better estimation of within and between subject variability Improve the in vitro-in vivo correlations 66

67 Acknowledgements Céline Ollier Amandine Mathieu Jun Chen Vanaja Kanamaluru Sylvie Fabre-Decourt Valérie Faillat Proux Véronique Hubert Catherine Marianne-dit-cassou Inga Gwose Catherine Janus Evelyne Chassagneux Nadine Quetand Anne Lanotte Çiğdem Bayka Stéphane Beilles Louis Henrion Mathieu Faliph Jean-Pierre Collaveri Philippe Longuemard Victor Ariel Amithkumar Devgan Kum Prasad Priscilla Brun Shirishbhai Patel Yashwant Phadke Philippe Longuemard Dominique Beau Yuko Harada Olivier Rougeot Hervé Maze Jack Thomas 67

68 Back up slides 68