Deprtment of Phrmceuticl Technology nd Cosmetology Fculty of Phrmcy University of Belgrde An investigtion into the possibilities nd limittions of in silico bsorption modeling: GstroPlus TM simultion of nimesulide orl bsorption Sndr Grbić Vldimir Lukić Ivn Kovčević Jelen Projčić Zoric Đurić ECPS2012
In Silico Absorption Simultion Implementtion: Formultion development Assessment of the influence of drug properties on orl drug bsorption Prediction of food effects Prediction of drug-drug interctions Estblishment of in vitro-in in vivo correltion (IVIVC) Justifiction of biowivers ECPS2012 2
Gstrointestinl Simultion Technology (GstroPlus TM softwre pckge, Simultion Plus Inc., Lncster, CA, USA) Physiologiclly bsed bsorption model Mthemticl model Predictive model - Physiologicl prmeters of nimls or humns - Drug physicochemicl nd phrmcokinetic properties - Formultion properties of drug products prediction plsm concentrtion ECPS2012 3 time
ACAT Advnced Comprtmentl Absorption nd Trnsit Model GstroPlus Mnul, 2008. Simultion Plus Inc., Lncster, USA 4
Generl Modeling nd Simultion Strtegy Model construction Dt collection Prmeters optimiztion Model vlidtion The ccurte prediction is often limited by the lck nd/or inpproprite selection of relible input dt ECPS2012 5
Model Drug: Nimesulide (NIM) BCS Clss II drug Highly permeble Wek cid; pk 6.4 b ph-surfctnt-dependent solubility Tblet strength 100 mg; recommended dosge: twice dily After orl dministrtion, NIM is rpidly nd extensively bsorbed c Merini F et l. J Phrm Sci. 2004;93(3):540-52. b Dellis D et l. J Phrm Biomed Anl. 2007;44:57 62; c Bernreggi A. Clin Phrmcokinet. 1998;35:247-74. ECPS2012 6
Model Presumptions Model 1 influx trnsporters in the intestine influence NIM bsorption djustment of the bsorption scle fctors (ASFs) ph-surfctnt induced increse in NIM solubility in vivo Model 2 optimiztion of solubility nd permebility vlues ECPS2012 7
Summry of NIM Input Prmeters Prmeter Model 1 Model 2 Moleculr weight (g/mol) 308.31 logd (ph 7.4) 1.8 1.48 b pk Humn jejunl permebility (cm/s) 6.4 b 2.225 x 10-4 c 1.116 x 10-4 2.002 x 10-4 d Dose (mg) 100 Dose volume (ml) Solubility t ph 4.5 (mg/ml) Men precipittion time (s) Diffusion coefficient (cm 2 /s) Drug prticle density (g/ml) Effective prticle rdius (µm) 200 e 0.007 f 0.017 b 0.030 d 900 g 0.757 x 10-5 c 1.2 g 25 g 5 d 25 g Prmeter Model 1 Model 2 Body weight (kg) First pss extrction in liver (%) Blood/plsm conc. rtio Unbound percent in plsm (%) 0.1 h / 88 e 0.668 c 1 g 4.513 c 3 Clernce (L/h/kg) 0.039 h 0.028 Volume of distribution (L/kg) 0.226 h 0.14 Elimintion hlf-life (h) 4.02 3.42 Simultion time (h) 15 Dosge form IR tblet IR suspension/ IR tblet Rinsford KD, ed. Nimesulide: ctions nd uses. Birkhäuser Verlg; 2005; b Dellis D et l. J Phrm Biomed Anl. 2007;44:57 62; c in silico predicted (ADMETPredictor module); d optimized vlues; e Jovnovic D et l. Vojnosnit Pregl. 2005;62(12):887 93; f Grbic S et l. Drug Dev Ind Phrm. 2009;35(7):852 6; g defult GstroPlus TM vlues; h Bernreggi A. Clin Phrmcokinet. 1998;35:247-74.
ASF Vlues Employed Comprtment Model 1 Model 2 (GstroPlus TM defult) Stomch 0 0 Duodenum 1000 2.687 Jejunum 1 500 2.668 Jejunum 2 2.600 2.633 Ileum 1 0.500 2.588 Ileum 2 0.500 2.551 Ileum 3 5.547 2.460 Cecum 6.098 1.328 Asc colon 12.240 1.995 ECPS2012 9
Model 1: Initil Simultion Results... IR tblet 3.5 3 2.5 Cp (µg/ml ml) 2 1.5 1 0.5 0 predicted with initil input vlues observed 0 2 4 6 8 10 12 14 t (h) Jovnovic D et l. Vojnosnit Pregl. 2005;62(12):887 93.
Model 1: Optimiztion... IR tblet 3.5 3 2.5 Cp (µg/ /ml) 2 1.5 1 0.5 predicted with djusted prticle rdius nd ASF vlues reported t mx : 1-4 h,b 0 observed Prmeter Observed Simulted PE (%) C mx (µg/ml) 3.19 3.21-0.63 0 2 4 6 8 10 12 14 t (h) Jovnovic D et l. Vojnosnit Pregl. 2005;62(12):887 93. b Rinsford KD et l. Curr Med Res Opin. 2006;22(6):1161 70. t mx (h) 4.00 3.15 21.25 AUC 0 t (µg h/ml) 25.78 25.96-0.70 AUC 0 (µg h/ml) 30.96 29.10 6.01
Model 1: Predicted NIM Dissolution nd Absorption Profiles IR tblet 100 % dissolved/bsorbed 80 60 40 20 0 totl dissolved totl bsorbed 0 2 4 6 8 10 12 14 t (h) ECPS2012 12
Model 1: Comprtmentl Absorption of NIM IR tblet 100.00 99.9 80.00 60.00 40.00 Amount bsor rbed (%) 20.00 0.00 0 20.4 36.7 9.9 2.5 2.6 13.4 12.8 1.7 Stomch Duodenum Jejunum 1 Jejunum 2 Ileum 1 Ileum 2 Ileum 3 Cecum Asc Colon Totl ECPS2012 13
Model 2: Initil Simultion Results... IR suspension Cp (µg/m ml) 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 predicted with initil input vlues observed 0 2 4 6 8 10 12 14 t (h) Jovnovic D et l. Vojnosnit Pregl. 2005;62(12):887 93. 14
Model 2: Optimiztion... 4.5 PSA IR suspension 4 3.5 Solubility = 0.03 mg/ml Permebility = 2.023 x 10-4 cm/s Cp (µg/m ml) 3 2.5 2 1.5 1 0.5 0 predicted with optimized solubility nd permebility vlues observed Prmeter Observed Simulted PE (%) C mx (µg/ml) 3.98 4.27-7.18 0 2 4 6 8 10 12 14 t (h) individul t mx : 1.5-6 h t mx (h) 3.00 4.10-36.67 Jovnovic D et l. Vojnosnit Pregl. 2005;62(12):887 93. AUC 0 t (µg h/ml) 35.23 35.68-1.30 ECPS2012 15 AUC 0 (µg h/ml) 36.61 39.60-8.17
Model 2: Vlidtion... IR tblet 3.5 3 predicted observed 2.5 Cp (µg/ /ml) 2 1.5 1 0.5 reported t mx : 1-4 h,b 0 Prmeter Observed Simulted PE (%) C mx (µg/ml) 3.19 3.39-6.16 0 2 4 6 8 10 12 14 t (h) Jovnovic D et l. Vojnosnit Pregl. 2005;62(12):887 93. b Rinsford KD et l. Curr Med Res Opin. 2006;22(6):1161 70. t mx (h) 4.00 3.40 15.00 AUC 0 t (µg h/ml) 25.78 25.69 0.35 ECPS2012 16 AUC 0 (µg h/ml) 30.96 27.92 9.82
Model 2: Predicted NIM Dissolution nd Absorption Profiles IR tblet 100 % dissolved/bsorbed 80 60 40 20 0 totl dissolved totl bsorbed 0 2 4 6 8 10 12 14 t (h) ECPS2012 17
Model 2: Comprtmentl Absorption of NIM IR tblet 100.00 80.00 60.00 40.00 69.8 Amount bsor rbed (%) 20.00 0.00 0 6.3 26.0 17.8 8.0 6.1 3.5 1.7 0.3 Stomch Duodenum Jejunum 1 Jejunum 2 Ileum 1 Ileum 2 Ileum 3 Cecum Asc Colon Totl ECPS2012 18
Model Considertions Model 1 Model 2 Influx trnsporters re involved in nimesulide bsorption Accurte prediction of nimesulide verge plsm profile fter orl dministrtion High drug permebility is predominting fctor for nimesulide bsorption Incomplete NIM dissolution/bsorption from IR tblet ECPS2012 19
Conclusions Gstrointestinl simultion technology cn be used for evlution nd prediction of orl drug bsorption In order to obtin meningful in silico modeling, the necessry input dt hve to be crefully selected nd/or experimentlly verified PSA is vluble tool for identifiction of criticl prmeters ffecting the rte nd extent of drug bsorption ECPS2012 20