PK-UK Challenges and benefits of using PBPK to evaluate an IVIVC for drugs with nonideal solubility and/or permeability. Bath, November 2014

Transcription

1 PK-UK 2014 Challenges and benefits of using PBPK to evaluate an IVIVC for drugs with nonideal solubility and/or permeability Bath, November 2014 Prof. Dr. Jennifer Dressman Dressman Bath 2014

2 Why IVIVC and what are the challenges to establishing an IVIV relationship? IVIVCs Support bridging studies during clinical studies Support formulation and manufacturing changes after registration BUT, So far, most IVIVCs have been for MR dosage forms Even for these, the in vitro results are usually generated with tests that resemble QC tests, so the IVIVC may not be very robust IVIV relationships for IR dosage forms have been difficult to attain with classical methods Dressman

3 Recommendation: pay attention to the in vitro test design! Part I: biorelevant dissolution tests what are these? Dressman

4 Conc (ng/ml) General approach to dissolution testing Hypothesis: the closer the dissolution test conditions to the physiology, the better the chances of predicting product performance Simulation (fasted) Simulation (fed) Fasted Fed Dressman Time (hour)

5 Finding the right dissolution test.. THREE important considerations: WHERE in the GI tract is drug released from the dosage form? HOW LONG does the dosage form have to release the drug? COMPOSITION of the fluids into which the drug is released?

6 Finding the right dissolution test.. WHERE in the GI tract is drug released from the dosage form? This will vary with the drug product e.g. Immediate release dosage forms Enteric coated dosage forms Extended release dosage forms Pulsatile delivery. The site(s) of release and/or % released at each site of release are often also dependent on whether the dosage form is given before or after a meal, so the dissolution test should also reflect the dosing conditions

7 Finding the right dissolution test.. HOW LONG does the dosage form have to release the drug? The drug must be released before or at its site(s) of absorption, otherwise release will not result in absorption. So it is important to understand the permeability of the drug at various points in the gut. The passage of the dosage form through the stomach depends on unit size and prandial state.

8 Finding the right dissolution test.. COMPOSITION of the fluids into which drug is released The foods and drinks we consume, gastric juices, bile, pancreatic juices, bacterial fermentation as well as water re-uptake all combine to influence the composition of the GI fluids at various points in the gut.

9 GI-appropriate media composition and volume: biorelevant dissolution media 1. Fasted state Stomach: FaSSGF: simulates reduced surface tension in the stomach Small intestine: FaSSIF to simulate basal bile secretion in upper SI Colon: FaSSCOF to simulate conditions in a fasted state PK study Vertzoni et al. EJPB 2005, Dressman et al. Pharm.Res. 1998, Vertzoni et al. Pharm. Res. 2010

10 GI-appropriate media composition and volume: biorelevant dissolution media 2. Fed State Stomach: FeSSGF: Milk/buffer ph 5 combination to simulate gastric conditions after a standard breakfast Small intestine: FeSSIF-V2 to simulate postprandial bile secretion, lipolysis products, increased buffer capacity and osmolality in upper SI after food intake Colon: FeSSCOF to simulate the ascending colon in the fed state Jantratid et al., Pharm. Res. 2008, Vertzoni et al., 2010

11 Biorelevant dissolution media Using instant powders to make the biorelevant media: Study of a Standardized Taurocholate Lecithin Powder for Preparing the Biorelevant Media FeSSIF and FaSSIF Dissolution Technologies source:

12 Dressman Case example 1: Relationship between dissolution and PK of Danazol (a poorly soluble but highly permeable drug)

13 Case example 1. danazol Aqueous solubility: Dose: 200 mg pka: neutral log P: µg/ml D:S 200 liters H 2 O 20 liters FaSSIF 6 liters FeSSIF

14 Danatrol dissolution profiles in various media at 100 rpm x 3 SIF

15 Danazol s food effect reflects its dissolution characteristics x 3 Plasma profiles of danazol after administration in the fasted ( ) and fed ( ) state (from Charman et al.)

16 Part II: Combining biorelevant dissolution testing with PBPK modeling to achieve IVIV relationships for poorly soluble drugs Dressman

17 Biorelevant dissolution tests alone: Qualitative forecast of food effects and formulation trends possible But, how can we arrive at a more quantitative prediction?? Coupling with PBPK models (IV-IS-IV-R): Quantitative forecast of food effects and formulation trends possible, since contributions of all steps affecting bioavailability can be addressed Dressman

18 PBPK Modeling and PK Simulation Stomach Small intestine Drug Solid drug Gastric emptying Solid drug Excretion water/meal Dissolution in gastric media Dissolution in intestinal media Precipitation Dissolved drug Gastric emptying Dissolved drug Calculation of PK profile Distribution and elimination Permeation (Drug in Plasma) x BA Initial Assumptions in the model - Negligible absorption from the stomach - Simultaneous solid and liquid emptying from the stomach (disintegrating dosage form) - No intestinal permeability restrictions (for high permeable drugs)

19 Dissolved % Conc (ng/ml) IV-IS-IV Strategy to predict oral absorption Set up in vitro dissolution testing Biorelevant media: fasted/fed, gastric/intestinal Test parameters: apparatus, volume, hydrodynamics Linkage Understand in vivo performance Further investigation to understand absorption mechanism and indentify key factor which affect on the in vivo performance Development of a desired formulation (no food effect, less variability, high BA) Control strategy with a key attribute (design space, quality by design) Predict in vivo drug release Qualitative prediction based on the extent in dissolution, comparing with the in vivo data (AUC, ranking order) Predict PK profile with in silico PBPK modeling Quantitative prediction based on the extent in dissolution, comparing with the in vivo data (AUC, C max, T max ) Time Time

20 Dressman Case example 2: Coupling biorelevant dissolution with PBPK to understand the effect of particle size on PK of aprepitant (poorly soluble, highly permeable)

21 Case example: Aprepitant BCS Class 2 (low solubility and high permeability) pk a : 9.7 (basic) Cs : 0.02 mg/ml in SGF sp (ph1.2), mg/ml in SIF sp (ph 6.8) Log P : 4.8 : 7.8 x 10-6 cm/sec (Caco-2) P app Micronized, nanosized formulations Indication: Emesis Dressman

22 Dissolved % % dissolved Dissolution of aprepitant 125mg in biorelevant media Micronized Nanoformulation : FaSSIF-V2 : FeSSIF-V2 : SIFsp FaSSIF-V2 FeSSIF-V2 SIFsp Time (minute) Time (min) Dressman

23 Conc (ng/ml) Simulated profiles of aprepitant in the fasted and fed state 1400 Micronized 1400 Nanoformulation Simulation (fasted) Simulation (fed) Fasted Fed Simulation (fasted) Simulation (fed) Fasted Fed Dressman Time (hour) Y. Shono et al. EJPB 76: (2010) Value added: prediction of z value (=> particle size) at which food effect is eliminated

24 Value added of IVISIVC: mechanistic insight 1. Effects of dissolution rate (z) on PK profile Fasted Fed Plasma celecoxib concentration (ng/ml) z fasted 2 z fasted z fasted 0.5 z fasted 0.2 z fasted Plasma celecoxib concentration (ng/ml) , z fed z fed z fed ~ Time (h) Time (h) Fasted: highly dependent on dissolution rate in addition to solubility Fed: no significant effect of dissolution rate ===> depends on gastric emptying

25 2. Effects of gastric emptying rate on PK profile in the fed state Plasma celecoxib concentration (ng/ml) 1600 GER = 6 kcal/min 1400 GER = 5 kcal/min 1200 GER = 4 kcal/min 1000 GER = 3 kcal/min 800 GER = 2 kcal/min Time (h)

26 Dressman Case example 3: prediction of PK of a Merck & Co. development compound, which is neither highly soluble nor highly permeable and, being a weak base, might precipitate upon entry into the small intestine

27 Case example: Compound A BCS Class 4 (neither solubility or permeability is high) pk a : 4.2, 7.6, 9.1 (basic) Cs : 0.02 mg/ml in SGF sp (ph1.2), mg/ml in SIF sp (ph 6.8) Log D : ph 1.5, ph 7.4 P app : 0.8 x 10-6 cm/sec (Caco-2) OH H N N O 2 S NH N S CF 3 Dressman

28 Compound A pharmacokinetic model A precipitation step for the fasted state and a limitation to permeability were introduced into the Stella Model Dose Solid drug in stomach Dissolution in stomach Dissolved drug in stomach Plasma concentration Distribution and elimination Gastric solid emptying Dissolution in small intestine Solid drug in small intestine Gastric liquid emptying Absorption through SI mucosa Dissolved drug in small intestine Absorbed drug in plasma Precipitaton Dressman

29 Compound A transfer model data Transfer model data revealed transfer rate depedent precipitation in the fasted state, but no precipitation in the fed state fed Dressman

30 Concentration [ng/ml] Concentration [ng/ml] Compound A PBPK simulation A B Time [h] in vivo, fasted simulation, fasted (FaSSGF/FaSSIF v2) simulation, fasted (FaSSGF/FaSSIF "old") simulation, fasted (FaSSGF/SIF) simulation, fasted, no permeability restriction in vivo, fed simulation, fed (FeSSGF/FeSSIF v2) simulation, fed (FeSSGF/SIF) simulation, fed, no permeability restriction Only when biorelevant media are used and precipitation in the fasted state as well as a permeability restriction is invoked, is it possible to simulate the in vivo profiles accurately Dressman Time [h]

31 Dressman Case example 4: prediction of nifedipine (poorly soluble, highly permeable, first pass substrate) PK after administration of the Adalat osmotic pump formulation

32 nifedipine pharmacokinetic model Peroral dose Dissolution stomach Intravenous dose Small intestine Drug in venous blood pool Drug in arterial blood pool Absorption First pass metabolism in SI and liver Distribution of drug into organs Metabolism and elimination Step 1: in silico description of nifedipine PK to account for first pass (using PK-SIM) Dressman

33 % Dissolved, % Released nifedipine release and dissolution in vitro Step 2: release and dissolution in the Type 3 tester (BioDis) using a biorelevant media profile % released, Adalat OROS 60mg % dissolved, Adalat OROS 60mg Time [h] Dressman

34 Plasma concentration [ng/ml] Plasma concentration [ng/ml] Plasma concentration [ng/ml] Plasma concentration [ng/ml] Nifedipine PK Time [h] Step 3: prediction of PK profile based on PK-SIM model for first pass AND biorelevant dissolution testing Time [h] Conclusion: drug dissolution after release from the MR dosage form is rate-limiting to absorption Time [h] Time [h] Dressman

35 Strategy to understand and forecast oral drug absorption Combine results from biorelevant dissolution tests with physiologically based pharmacokinetic modeling to create in vitro in silico in vivo relationships Dressman

36 IVIVC Challenges ahead Integration of appropriately biorelevant dissolution data (i.e. use the right level of biorelevant media) Appropriate integration of dissolution data into the commercial PBPK models (especially for MR dosage forms that do not have robust, zero-order release kinetics) Appropriate integration of precipitation data into commercial PBPK models Dressman

37 Acknowledgments Prof. Dr. Christos Reppas & Dr. Maria Vertzoni (U-Athens) Dr. Yasushi Shono (U-Frankfurt, now Takeda) Dr.s Filippos Kesisoglou & Henry Wu (Merck & Co., Inc.) Dr. Christian Wagner (U-Frankfurt, now FDA) Dressman

38 and Many Thanks for your attention!