Metformin: Mechanistic Absorption Modeling and IVIVC Development Maziar Kakhi*, Ph.D. FDA Silver Spring, MD 20993 Viera Lukacova, Ph.D. Simulations Plus Lancaster, CA 93534 [email protected] [email protected] AAPS Annual Meeting and Exposition Orlando FL, October 25-29, 2015 * Disclaimer: The views expressed in this presentation are those of the author and do not reflect the opinion nor the policy of the FDA. 1 Presentation Overview • Metformin – general considerations • Validation study database • Metformin absorption model • IVIVC development/validation • Conclusions 2 Metformin – General Considerations • Used in the treatment of type 2 diabetes mellitus. • Highly soluble. • Incompletely absorbed with an oral bioavailability ranging from 40 to 60%. • Undergoes site-dependent absorption primarily in the upper part of the intestine. • Carrier-mediated transport known to play active role in drug absorption and disposition. • Poses a challenge for classical level A in vitro – in vivo correlation (IVIVC) approaches. 3 Validation Study Database Data were only considered for pharmacokinetics of metformin administered in healthy human subjects. Study Tucker et al. Br. J. Clin. Pharmac (1981), 12, 235-246 Pentikäinen et al. Eur. J. Clin. Pharmacol. (1979), 16, 195-202 Formulation Route of Administration Dose Fed / Fasted Avg / Ind Cp-t Data infusion (15 min) Intravenous 250 mg - Average (N=4) IR tablet (Glucophage) Oral 500 &1500 mg Fed Average (N=4) Infusion (5 min) Intravenous IR tablet Oral 4.4 μCi/500 mg Fasted Individual (N=3) 500 mg Fasted Bolus, solution BMS clinical data study 1 (April-July 1996) Proximal SI Distal SI Proximal SI Infusion (4 hrs) Distal SI Average (N=8) Average (N=4) Average (N=10) 500 mg Fasted Colon Average (N=6) N= 1 or 2 Crossover IR tablet ('minitabs') Oral 8x50 mg / 30 min Fasted Average (N=16) BMS clinical data study 2 (November 1996) IR tablet (Glucophage) ER capsule (fast, medium, slow) Oral 1000 mg Fed & Fasted Individual (N=8) BMS clinical data study 3 (March-April 2010) IR tablet Oral 500 mg 1000 mg Fed Individual (N=27) Individual (N=26) 4 Metformin absorption model • Metformin in solution behaves as an hydrophilic cation. Limited passive transcellular absorption. • Passive paracellular absorption mainly in upper GI tract: molecule size vs. decreasing paracellular pore radius. • Paracellular absorption is not assumed to be saturable. • Metformin is primarily a substrate for organic cation transporters OCT1 and OCT3 along basolateral and apical membrane of intestinal epithelia. • OCT1 influxes metformin from portal vein into enteroctye; OCT3 influxes metformin from gut lumen into enterocyte. 5 Metformin absorption model – contd. • Carrier-mediated transport modeled using Michealis-Menten kinetics. • Disposition of metformin modeled using compartmental mammillary PK model. • Major route of elimination is secretion in urine. 6 Sponge Effect Hypothesis1 ∆𝒕 • Metformin dose undergoes predominantly paracellular absorption. • Uptake across apical (AP) membrane occurs by means of OCT3-transporter. 1 Assumed OCT-like transporter effluxes metformin into lumen for further paracellular absorption or re-uptake into enterocytes downstream. Proctor WR, Bourdet DL, Thakker DR. 2008. Drug Metabolism and Disposition 36(8):1650-1658. 7 Modeling Strategy Investigation of the effect of: • Dosing locations for site administration studies. Labeled site Intestinal compartment where the drug was administered in the simulation Proximal SI Model 1 Middle of Duodenum Distal SI Jejunum2 Colon Ascending colon Model 2 Model 3A Model 3B Model 4 Jejunum1 Jejunum1 Jejunum1 Jejunum1 Beginning of Ileum1 Ascending colon Middle of Ileum1 Ascending colon Middle of Ileum1 Ascending colon End of Ileum1 Ascending colon • ASF models of Gastro Plus v6.8 (Opt logD 6.1 SA/V, Theoretical SA/V, and Theoretical). • Inclusion/exclusion of colonic OCT expression level. • Intestinal electrical potential gradient: 58,102 (default) mV. 8 Modeling Strategy - cont. • Fit CLr, Total Peff, and Vmax values for intestinal transporters for each set of model options (administration sites, ASF model, EPG, presence of OCT in colon). • Models screened for: • Fitted ratio Peff,Trans/Peff,Para across site administration studies. • Quality of prediction of Cp-t observations from PO-administration studies. 9 Absorption Model Validation – Tucker IV/PO • Higher STT means initially less drug available for absorption, but the absorption will continue for longer. • Tucker et al. Br. J Clin Pharmac. (1981) 12:235-246 report Cmax of 3.1 µg/ml for 1500 mg. 10 Absorption Model Validation – Pentikäinen IV/PO • Little observed variability clearance between 3 subjects. in renal • Simulations based on default STT of 0.25h. 11 Absorption Model Validation – BMS Study 3 • STT fixed at 1h for both simulations. • CLr and Vmax scaling factors fitted against both IR doses. 12 ER Formulation – BMS Study 3 / In Vitro Data f2 Analysis Fast-Medium 22 Fast-Slow 17 Medium-Slow 35 Apparatus USP 2 Medium Phosphate buffer, pH 6.8 Volume 1000 ml Paddle speed 100 rpm Average (N=6) • Tmax,Fed < Tmax,Fasted • Cmax,Fasted-Fast > Cmax,Fasted-IR • Fasted IR & Fast formulation Cp-t curves exhibit similar initial rate of increase. • Balan et al. 2001. JPS. 90(8):1176-1185: use of numerical deconvolution failed for fasted data set. • ‘Extended’ convolution method required to achieve (internally) predictive level A correlation. 13 Procedure for Mechanistic Deconvolution • Mechanistic deconvolution performed for fed and fasted arm of BMS clinical data study 2. • In vivo dissolution profile assumed to behave as double Weibull function. • Initial estimate for in vivo dissolution profile obtained from in vitro data. • STT, Vmax scaling factors and CLr fitted to average and individual Cp-t profiles for IR formulation. • STT additionally fitted to individual Cp-t profiles for ER formulations to study effect on resulting IVIVC. 14 IVIVC – Levy Plot for Fasted State STT rate limiting step for absorption of fast formulation? Correlation function defined to be ≥ 0 • • • STT fitted to individual Cp-t profiles for ER formulations. IVIVC constructed using Medium and Slow formulations. Quadratic function had lowest AIC. 15 IVIVC – Validation Fasted State Individual deconvolution, STT fitted to Ind ER profiles Study STT=1.69 h STT=1.63 h Fasted STT=2.58 h Average deconvolution, STT fitted to Avg ER profiles Study Fasted Formulation Parameter AUC(0-t) ng h/ml Slow Int Cmax ng/ml AUC(0-t) ng h/ml Medium Int Cmax ng/ml AUC(0-t) ng h/ml Avg Abs %PE Int Cmax ng/ml AUC(0-t) ng h/ml Fast Ext Cmax ng/ml %PE 3.9 -23.0 -10.1 -22.6 7.0 22.8 -9.1 -16.9 Formulation Parameter AUC(0-t) ng h/ml Slow Int Cmax ng/ml AUC(0-t) ng h/ml Medium Int Cmax ng/ml AUC(0-t) ng h/ml Avg Abs %PE Int Cmax ng/ml AUC(0-t) ng h/ml Fast Ext Cmax ng/ml %PE 19.2 4.5 12.4 -10.3 15.8 7.4 5.7 -14.0 Individual deconvolution, STT fitted to IR profile Study Fasted Formulation Parameter AUC(0-t) ng h/ml Slow Int Cmax ng/ml AUC(0-t) ng h/ml Medium Int Cmax ng/ml AUC(0-t) ng h/ml Avg Abs %PE Int Cmax ng/ml AUC(0-t) ng h/ml Fast Ext Cmax ng/ml %PE 10.5 7.0 16.0 -7.9 13.2 7.4 1.7 -19.6 16 IVIVC – Levy Plot for Fed State • • • STT fitted to individual Cp-t profiles for ER formulations. IVIVC constructed using all formulations. Power law function had lowest AIC. 17 IVIVC – Validation Fed State Individual deconvolution, STT fitted to Ind ER profiles STT=1.18 h Study STT=0.95 h Fed STT=1.05 h Average deconvolution, STT fitted to Avg ER profiles Study Fed Formulation Parameter AUC(0-t) ng h/ml Slow Int Cmax ng/ml AUC(0-t) ng h/ml Medium Int Cmax ng/ml AUC(0-t) ng h/ml Fast Int Cmax ng/ml AUC(0-t) ng h/ml Avg Abs %PE Int Cmax ng/ml %PE -2.3 -23.2 -0.6 -11.0 -8.5 -12.9 3.8 15.7 Formulation Parameter AUC(0-t) ng h/ml Slow Int Cmax ng/ml AUC(0-t) ng h/ml Medium Int Cmax ng/ml AUC(0-t) ng h/ml Fast Int Cmax ng/ml AUC(0-t) ng h/ml Avg Abs %PE Int Cmax ng/ml %PE 1.0 -30.3 7.2 -7.6 -6.1 -10.5 4.8 16.1 Individual deconvolution, STT fitted to IR profile Study Fed Formulation Parameter AUC(0-t) ng h/ml Slow Int Cmax ng/ml AUC(0-t) ng h/ml Medium Int Cmax ng/ml AUC(0-t) ng h/ml Fast Int Cmax ng/ml AUC(0-t) ng h/ml Avg Abs %PE Int Cmax ng/ml %PE -16.3 -44.0 -3.2 -17.8 -9.2 -6.5 9.6 22.8 18 IVIVC – Validation Comparison Study: Fasted State Formulation Slow Int Balan et al. Basic Convolution Medium Int Fast Int Slow Int Balan et al. Extended Convolution Medium Int Fast Int Slow Int Phoenix WinNonlin Numerical Deconvolution Medium Int Fast Int Parameter AUC(0-22) ng h/ml Cmax ng/ml AUC(0-22) ng h/ml Cmax ng/ml AUC(0-22) ng h/ml Cmax ng/ml %PE 102.7 50.4 56.1 9.9 17.1 3.9 AUC(0-22) ng h/ml Cmax ng/ml AUC(0-22) ng h/ml Cmax ng/ml AUC(0-22) ng h/ml Cmax ng/ml -1.6 -7.3 1.4 -10.8 -2.4 -11.0 AUC(0-24) ng h/ml Cmax ng/ml AUC(0-24) ng h/ml Cmax ng/ml AUC(0-24) ng h/ml Cmax ng/ml 46.8 -22.9 26.9 -41.5 -0.3 -35.8 19 IVIVC – Validation Comparison • Mechanistic model predicted the changes in % of drug entering portal vein across the three formulations • Similar trends were previously fitted using the extended convolution based approach 20 Conclusions • Developed level A IVIVC is currently not adequately predictive but even the preliminary IVIVC based on mechanistic model: • performs better than numerical deconvolution and basic one- stage direct convolution methods. • does not require adjustment of bioavailable fraction to dose, as required in extended convolution. • Model predictions show that stomach transition time plays a critical role in absorption behavior of metformin. • Mechanistic absorption model predicts Cmax roughly proportional to dose. 21 Acknowledgments • Peter Timmins Ph.D., Drug Product Science and Technology, Bristol-Myers Squibb, Moreton, United Kingdom • Jonathan Brown, Ph.D., Drug Product Science and Technology, Bristol-Myers Squibb, Moreton, United Kingdom • John Crison, Ph.D., formerly Drug Product Science and Technology, Bristol-Myers Squibb, New Brunswick, NJ, USA 22 Back Up slides 23 Fraction(s) of Drug Absorbed Fa F FDp Absorption Dose Portal vein D A Liver SC Bioavailability PV Gut wall To faeces Metabolism Metabolism * Modified from van de Waterbeemd, H, and Gifford, E. ADMET In Silico Modelling: Towards Prediction Paradise? Nat. Rev. Drug Disc. 2003, 2:192-204 24 ACAT Model – Gastro Plus v8.6 25 Permeability Efflux Transporter Influx Transporter Passive Diffusion Blood Paracellular Transport Tight Junction 26 Physicochemical Properties Parameter Value Source LogP -1.26 (-1.432) ADMET Predictor LogD -2.27 (-3.37@pH 4.03) ADMET Predictor pKa 2.67 & 12.04 (2.8 &11.52) ADMET Predictor Molar mass 129.17 g/mol4 Solubility ≥ 165 mg/ml (300 mg/ml5, 500 mg/ml6) Total Peff (jejunem) Diffusion coefficient 1.18 x10-5 cm/s (3.26x10-5 cm/s in rat 1.20 x10-5 cm/s in human7) 1.14 x10-5 cm2/s ADMET Predictor Optimized8 ADMET Predictor 2 Graham et al. 2011. Clin Pharmacokinet. 50(2):81-98. BMS internal data. 4 Dose set to metformin free base in all simulation studies 5 Desai et al. 2014. J. Pharm. Sci. 103:920-926 6 Bretnall, Clarke. 1998. Brittain HG, ed. Analytical Profiles of Drug Substances and Excipients, Vol. 25. Academic Press, pp. 243-293. 7 Song et al. 2006. World J Gastroenterol. 12(25): 4064-4070 8 Optimized based on BMS site administration/absorption data. ADMET Predictor calculates 0.66 x 10 -4 cm/s. 3 27 PK and Physiological Properties Parameter Value Source % drug unbound in protein 100 % Tucker et al. 1981 Blood/plasma conc. ratio 0.559 Tucker et al. 1981 Central compt. VC Fitted to IV data Tucker et al. 1981 Pentikäinen et al. 1979 Renal Clearance Fitted to IV/IR data Multiple studies Efflux/Influx Vmax Fitted to IR data Multiple studies Influx Km (Basolateral, OCT1) 292 mg/l UCSF-FDA TransPortal10 Influx Km (Apical, OCT3) 202 mg/l UCSF-FDA TransPortal Efflux Km (Apical) 1655 mg/l Optimized 9 From data of Tucker et al. B/P ratio was calculated and determined to be very low. Therefore, no RBC binding assumed within first few hours suggesting that for normal hematocrit B/P ratio is 0.55. 10 http://dbts.ucsf.edu/fdatransportal/compounds/metformin/ 28 Transporter (Initial) Estimates 29 Tucker et al. Br. J Clin Pharmac. (1981) 12:235-246 30 Tucker et al. Br. J Clin Pharmac. (1981) 12:235-246 31 Mechanistic Deconvolution: In Vivo Release Fasted Fed 32
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