Semi-Mechanistic Pharmacokinetic/ Pharmacodynamic Model of Exenatide - PowerPoint PPT Presentation

Semi-Mechanistic Pharmacokinetic/ Pharmacodynamic Model of Exenatide Long-Action Microspheres in Diabetic Rats Wei Lu Peking University, China WCOP 2012, Seoul

Background  Exenatide, a glucagon-like peptide 1 receptor agonist as novel therapy for type 2 diabetes  Commercialized preparations: Two injectable suspensions

Background Drawback of commercialized preparation  Is prepared through a rather complicated process  In vivo release isn’t constant Exenatide Conc. (pg/ml) Time (day)

Background Double-walled microspheres (DWMS)  An improved drug delivery system that can increase encapsulation efficiency, reduce burst effect, make drug release constantly and persistently

Objective 1. To improve the release property of exenatide preparation 2. To assess the IVIVC of exenatide DWMS using model-based method 3. To establish a semi-mechanistic PK/PD model for exenatide double-walled microspheres (DWMS)

Outlines Preparation and Characterization of DWMS Pharmacokinetics of DWMS Pharmacokinetics/Pharmacodynamics of DWMS

Outlines Preparation and Characterization of DWMS Pharmacokinetics of DWMS Pharmacokinetics/Pharmacodynamics of DWMS

Preparation and Characterization of DWMS

Preparation and Characterization of DWMS Preparation and Characterization of DWMS  In vitro release and degradation

Preparation and Characterization of DWMS Pharmacokinetics of DWMS Pharmacokinetics/Pharmacodynamics of DWMS

Preparation and Characterization of DWMS Pharmacokinetics of DWMS Pharmacokinetics/Pharmacodynamics of DWMS

Pharmacokinetics of exenatide in solution and in DWMS DWMS k a ∙F , , Solution

Pharmacokinetics of exenatide in solution The pharmacokinetic parameters of exenatide solution Parameter Definition Estimate Inter-individual (RSE %) variability (CV %) k a (h -1 ) Absorption rate constant 4.45 (12.3) 38.3 Cl/F (L/h) Central clearance 0.198 (6.46) 27.7 V c /F(L) Central volume of distribution 0.397 (8.82) 30.1 Q/F (L/h) Inter-compartmental clearance 0.086 (18.6) 64.9 V p /F(L) Peripheral volume of distribution 1.180 (27.0) 82.2 Residual error σ 1 (Proportional) CV% 0 (Fixed) σ 2 (Additive) 0.179 μg/L SD

Pharmacokinetics of exenatide in DWMS The pharmacokinetic parameters of exenatide DWMS Parameter Definition Estimate Inter-individual (RSE %) variability (CV %) F ra1 Fraction of drug in transit Comp 1 0.113 (20.4) - F ra2 Fraction of drug in transit Comp 2 0.0301 (31.1) 130 F ra3 Fraction of drug in transit Comp 3 0.00554 (28.6) 28.8 F ra4 Fraction of drug in absorption Comp 0.00326 (22.4) - k tr1 (h -1 ) Transit rate constant 1 0.00398 (26.4) 4.0 k tr2 (h -1 ) Transit rate constant 2 0.113 (16.4) 18.9 Residual error σ 1 (Proportional) CV% 23.7 σ 2 (Additive) SD ( μ g/L) 0 (Fixed) - Refers to the values were fixed as 0

Pharmacokinetics of exenatide 210 μ g 5 mg Exenatide Conc. (ng/ml) 21 μ g 2.5 mg 4.2 μ g 1.25 mg Time (h) Exenatide solution Exenatide DWMS

IVIVC of exenatide in DWMS

Summary 1. Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type II diabetes 2. The pharmacokinetics of exenatide in solution and in DWMS were investigated 3. Transit compartment model was used to characterize the in vivo release behavior of exenatide DWMS, and a model-based simulation was conducted for IVIVC

Preparation and Characterization of DWMS Pharmacokinetics of DWMS Pharmacokinetics/Pharmacodynamics of DWMS

Preparation and Characterization of DWMS Pharmacokinetics of DWMS Pharmacokinetics/Pharmacodynamics of DWMS

PK/PD of exenatide - Exenatide and insulin S C dINSP      m 1 k k (1 ) INSP  0 p dt SC C 50  dINS S C       1 m k (1 ) INSP k INS  p outI dt SC C 50

PK/PD of exenatide - Exenatide and insulin Parameters of insulinotropic effects Parameter Definition Estimate IIV (RSE %) (CV %) S m1 Maximum insulin tropic response factor 0.866 (8.95) 28.5 SC 50 (μg/L) Conc. for 50% of insulin tropic effect 3.68 (22.4) 29.5 k 0 (mU/L/h) Zero-order precursor input rate constant 24.0 (15.5) - k p (h -1 ) 5.68·E -4 Insulin precursor release rate constant (9.82) - k outI (h -1 ) Insulin output rate constant 2.38 (14.4) 10.8 Residual error  1 (Proportional) CV% 18.1 ε 2 (Additive) SD (mU/L) 0.602 - Refers to the values were fixed as 0

Pharmacokinetics/Pharmacodynamics of DWMS PK/PD of exenatide - Exenatide and insulin 210 μ g 5 mg Insulin Conc. (mM/L) 21 μ g 2.5 mg 4.2 μ g 1.25 mg Time (h) Exenatide solution Exenatide DWMS

PK/PD of exenatide - Insulin and blood glucose dINS    e k 0 ( INS INS ) e e dt dGLU                k 1 I ( INS INS ) k 1 S ( INS INS ) GLU inG m 0 outG m 2 e e 0 dt

PK/PD of exenatide - Exenatide and insulin Parameters of blood glucose-lowering effects Parameter Definition Estimate IIV (RSE %) (CV %) k outG (h -1 ) * Glucose output rate constant 2.28 (29.5) 81.6 S m2 (L/mU) Stimulation factor of insulin 0.0472 (21.4) 53.1 I m (L/mU) Inhibition factor of insulin 0.00832 (22.7) 78.2 k e0 (h -1 ) First-order elimination rate constant 1.33 (11.1) 39.2 from the effect compartment Residual error σ 1 (Proportional) CV% 0 (Fixed) σ 2 (Additive) SD 0.0871 * k outG = k inG

PK/PD of exenatide - Exenatide and insulin 210 μ g 5 mg Blood glucose 42 μ g 2.5 mg 4.2 μ g 1.25 mg Time (h) Exenatide solution Exenatide DWMS

Pharmacokinetics/Pharmacodynamics of DWMS PK/PD model prediction/validation Dose=20 μ g/rat

Summary 1. An indirect response model was developed to characterize the insulin behavior after injection of exenatide solution and DWMS 2. Combined effect compartment/indirect response model described the blood glucose lowering effects of insulin nicely 3. The model predication showed good agreement with the experimental results

Conclusions  A simple method was developed to prepare exenatide DWMS and its physicochemical characteristics, in vitro release and degradation were investigated  A series of transit-compartment was applied to describe the long-term in vivo release of exenatide from DWMS. On the basis of the transit-compartment model, simulation was conducted to predict the in vivo release and absorption of exenatide from DWMS, and the IVIVC was compared by deconvolution  On the basis of exenatide insulinotropic effects and the relationship between insulin and blood glucose, an integrative PK/PD model was constructed to characterize the insulin concentration-time profiles, and the turnover of blood glucose after drug administration

Acknowledgement Pfizer China Peking University/Pfizer Pharmacometrics Education Center Dr. Xingang Li Dr. Xipei Wang Dr. Tianyan Zhou Xiaoliang Cheng Dr. Zaiquan Li Chenhui Deng Dr. Dewei Shang Xuan Zhou Dr. Liang Li Yupeng Ren Dr. Shanshan Bi Ye Chen Dr. Hanqing Li Xiangfei Jiu

The 4 th International Symposium in Quantitative Pharmacology (ISQP) 2013 November 1-3 Beijing, China