Slide 1: Using In Silico PK Simulations for Early Formulation Development of Amorphous Solid Dispersions
Enabling a Healthier World Using In Silic o PK Sim ulations for Early Form ulation De ve lop m e nt of Am orp hous Solid Disp e rsions De anna Mud ie Fe b ruary 15, 20 23 Business Use Only 1
Slide 2: Outline
Outline Ke y de sign ASD b iope rform anc e Case stud y: Sum m ary: In silic o PK c onside rations for asse ssm e nt ac alab rutinib ASD sim ulations c an d e - Am orp hous Solid tab le ts ove rc om e risk ASD form ulation Dispe rsions p H e ffe c t d e ve lop m e nt Fe bruary 15, 20 23 Business Use
Slide 3: Key Design Considerations for Amorphous Solid Dispersions
Ke y De sign Consid e rations for Am orp hous Solid Disp e rsions February 15, 2023 3
Slide 4: Amorphous Solid Dispersions (ASDs) Can Enhance Bioavailability of Poorly Soluble Drugs
Am orp hous Solid Disp e rsions (ASDs) Can Enhanc e Bioavailab ility of Poorly Solub le Drugs Am orp hous Drug BCS 1 Increasing Solubility BCS 4 10% 25% High Ene rgy Polym orp h Low Ene rgy Polym orp h BCS 3 BCS 2 Increasing Free Energy 15% 50% Amorphous form provides solubility enhancement over cry
Slide 5: ASD Dosage Forms Can Be Designed to Maximize Unit Dosage Strength and Achieve Key Attributes
ASD Dosage Form s Can b e De signe d to Maxim ize Unit Dosage Stre ngth and Ac hie ve Ke y Attrib ute s ASDs dosage forms Key formulation factors Tab le ts Drug & polym e r p rope rtie s ASD partic le prope rtie s Cap sule s Exc ipie nt type s & c om position Suspe nsions Proc e ssing param e te rs
Slide 6: Amorphous Solid Dispersion Bioperformance Assessment
Am orp hous Solid Disp e rsion Biop e rform anc e Asse ssm e nt February 15, 2023 6
Slide 7: To Perform Well In Vivo ASDs Must Dissolve Adequately and Maintain Supersaturation
To Pe rform We ll in Vivo ASDs Must Dissolve Ad e q uate ly and Maintain Sup e rsaturation Micelle -bound Good sustainm e nt and dissolution rate drug Inade quate sustainm e nt Unbound Inade quate dissolution rate drug Drug/polymer colloids Crystalline form Brewster, ME et al. Pharmazie. 2008 Mar;63
Slide 8: In Vivo Performance Depends Upon Physiological, Drug Substance, and Formulation Properties
In Vivo Pe rform anc e De p e nd s Up on Physiologic al, Drug Sub stanc e , and Form ulation Prop e rtie s Gastrointestinal fluid Drug substance Particle & dosage form Polymer (ASDs) • pH • Intrinsic solubility • Size distribution • Solubility vs. pH • Buffe r c ap ac ity & spe c ie s • Crystalline
Slide 9: Traditional Methods may be Limited For Predicting Bioperformance of Some ASD Drug Products
Trad itional Me thod s m ay b e Lim ite d For Pre d ic ting Biop e rform anc e of Som e ASD Drug Prod uc ts ≠ sourc e : d avid d arling.info How c an we use traditional m e thods and ne w Use in vitro – in silic o toolkit and m e c hanistic m e thods to unde rstand biope rform anc e of oral drug app
Slide 10: In Vitro Performance Toolkit for Assessing ASD Bioperformance
In Vitro Pe rform anc e Toolkit for Asse ssing ASD Biop e rform anc e Controlled transfer Solvent -shift polymer screen ASD dissolution Tablet dissolution - USP dissolution • Am orp hous “solubility” • Pre c ipitation rate • Pre c ip itation rate of tab le t – static • Pre c ip itation rate vs. e m
Slide 11: Assembling All the Pieces Using in Silico Tools
Asse m b ling All the Pie c e s Using in Silic o Tools In silico absorption Inputs Hypothesis/”What if” Questions predictions Calculated & measured Outputs drug properties Param e te r se nsitivity asse ssm e nt Ide ntifie d physiologic al barrie rs In vitro data to ab sorp tion Te c hnology and for
Slide 12: Case study: Acalabrutinib ASD Tablets Overcome pH Effect
Case stud y: Ac alab rutinib ASD Tab le ts Ove rc om e p H Effe c t February 15, 2023 12
Slide 13: Calquence (Crystalline Acalabrutinib) Shows Reduced Performance with ARAs
Calq ue nc e ® (Crystalline Ac alab rutinib ) Shows Re d uc e d Pe rform anc e with ARAs Gastric pH - Gastric pH – fasting on ARAs 10 1 Solubility (mg/ml) Bruton tyrosine kinase inhibitor indic ate d for onc ology 0.1 Plasm a AUC re duc e d by 4 3% whe n take n with PPI* Crystalline ac alabrutinib*
Slide 14: Amorphous Solid Dispersion (ASD) Tablets to Overcome pH Effect
Am orp hous Solid Disp e rsion (ASD) Tab le ts to Ove rc om e p H Effe c t 1.7 BCS 2 S+ P e ff : 5.4 X 10 -4 c m / s* 1.6 Crystallization Te nde nc y → pKa : 3.5, 5.8 (basic )* Me lting point: 214 °C Ϯ 1.5 Crystallization Challe nge Tm / Tg (K/ K) 1.4 Intrinsic sol.: 4 8 µg/ m l* Glass transition: 1
Slide 15: In Vitro – in Silico ASD Development Strategy
In Vitro – in Silic o ASD De ve lop m e nt Strate gy Polymer screen ASD manufacture ASD dissolution Stre am line d ap p roac h b ase d up on d rug, p olym e r, & p hysiologic al p rop e rtie s Tablet dissolution In silico prediction In vivo study Mud ie e t al. Pharmaceutics 20 21, 13, 1257 Fe bruar
Slide 16: ASD Tablet Design and Performance Goals
ASD Tab le t De sign and Pe rform anc e Goals ASD tablet design In vivo study goals 50 / 50 ac alabrutinib/ HPMCAS-H ASD in IR table t Mitigate pH e ffe c t using ASD table t Good stability Matc h plasm a e xposure of faste d Calque nc e using ASD table t 60 % sm alle r than Calque nc e c apsule s S
Slide 17: ASD Tablets Achieve Performance Goals In Vitro
ASD Tab le ts Ac hie ve Pe rform anc e Goals In Vitro 10 0 mg d ose 17 (1 mg/ ml d ose c onc .) Gastric Compartment, pH 2 Intestinal Compartment 1000 600 Calque nc e c apsule Calque nc e c apsule Concentration (µg/mL) Concentration (µg/mL) 800 400 600 15-m in t 1/ 2 p H 2 or 6 ASD 400 ASD table t 20
Slide 18: In Silico Predictions – Gain Confidence in Formulation Identified From in Vitro Testing
In Silic o Pre d ic tions – Gain Confid e nc e in Form ulation Id e ntifie d From in Vitro Te sting GastroPlus® v9.8 (Simulations Plus, Inc.) Faste d be agle dog physiology Gastric pH adjusted to re fle c t pe ntagastrin (bulk pH ~2) or fam otidine pre tre atm e nts (bulk pH ~6) and adjuste d for su
Slide 19: In Silico Input - Solubility vs. pH and Surface vs. Bulk pH
In Silic o Inp ut - Solub ility vs. p H and Surfac e vs. b ulk p H Adjusted Adjusted 𝒅𝒅𝑴𝑴 𝑫𝑫𝒆𝒆𝒆𝒆𝒆𝒆 Surface pH vs. bulk pH Sim ulate d (surface) (surface) = � 𝑨𝑨𝒔𝒔 (𝒕𝒕) � 𝑪𝑪𝒔𝒔 − 𝑪𝑪𝒃𝒃 𝒕𝒕 bulk pH pH ASD pH 𝒅𝒅𝒅𝒅 𝑹𝑹 Calquence Tablet capsule 8 Cs = ʄ(pH s) 7 ASD (Me…
Slide 20: In Silico Input - in vitro Dissolution Rates
In Silic o Inp ut - in vitro Dissolution Rate s 𝟐𝟐/𝟑𝟑 𝒅𝒅𝒅𝒅 𝑴𝑴𝒖𝒖,𝒕𝒕 𝟑𝟑 � 𝑫𝑫 USP 2 transfer test = 𝒛𝒛 � 𝑴𝑴𝒖𝒖,𝒐𝒐 𝑪𝑪𝒔𝒔 − 𝑪𝑪𝒃𝒃 𝒛𝒛 = 𝝆𝝆 � 𝒓𝒓𝟐𝟐 𝒅𝒅𝒅𝒅 𝑴𝑴𝒖𝒖,𝒐𝒐 pH 2 gastric test pH 6 gastric test 400 z = 0 .0 11 Ac alab rutinib (µg/ m L) Ac alab rutinib…
Slide 21: In Silico Predictions Suggest ASD Tablets Will Overcome pH Effect in Dogs
In Silic o Pre d ic tions Sugge st ASD Tab le ts Will Ove rc om e p H Effe c t in Dogs 100 mg dose Mitigate p H e ffe c t (AUCs within 2%) 5,000 Acalabrutinib concentration (ng/ml) 4,000 ASD tablet, low pH Matc h e xp osure of Calq ue nc e at low p H (AUCs within ~10 %) 3,000 ASD tablet, high pH Cal
Slide 22: In Vivo Outcome Matches Bottom-up in Silico Predictions
In Vivo Outc om e Matc he s Bottom – up in Silic o Pre d ic tions Ove rnight fast, n = 6, c rossove r study, Absolute average fold 100 mg dose AUC0-inf (ng h/mL) error (AAFE) 1 – wk washout Obs Sim AUC0-inf Cp vs. time 5,000 ASD tablet, low Acalabrutinib concentration (ng/ml) 4,000 8161 9766 1.2 1.3
Slide 23: Summary
Sum m ary ASD tab le ts ove rc am e ac alab rutinib p H e ffe c t on the first try using in vitro – in silic o d e ve lop m e nt ap p roac h In silic o PK sim ulations suc c e ssfully p re d ic te d in vivo stud y re sults using ‘b ottom up ’ ap p roac h In silic o PK sim ulations c an ac c e le rat
Slide 24: References
Re fe re nc e s Mudie DM, Ste wart AM, Rosale s JA, Biswas N, Adam MS, Sm ith A, Craig CD, Morge n MM, Vodak DT. Am orphous Solid Dispe rsion Table ts Ove rc om e Ac alabrutinib pH Effe ct in Dogs. Pharmaceutics . 20 21 Apr 15;13(4 ):557. https:/ / doi.org/ 10 .3390 / pharm ac e utic s130 4 0 557 Mu
Slide 25: Acknowledgments
Ac knowle d gm e nts Aaron Stewart Molly Adam David Vodak Jesus Rosales Adam Smith Henny Zijlstra Michael Morgen Christopher Craig David Lyon Kimberly Shepard Nishant Biswas Fe bruary 15, 20 23 Business Use Only 25
Slide 26: Questions
Que stions Email: de anna.m udie @lonza.c om February 15, 2023 26