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

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

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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

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Semi-Mechanistic Pharmacokinetic/ Pharmacodynamic Model of Exenatide Long-Action Microspheres in Diabetic Rats

Wei Lu Peking University, China WCOP 2012, Seoul

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Background

  • Exenatide, a glucagon-like peptide 1 receptor

agonist as novel therapy for type 2 diabetes

  • Commercialized preparations: Two injectable

suspensions

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Drawback of commercialized preparation

  • Is prepared through a rather complicated process
  • In vivo release isn’t constant

Exenatide Conc. (pg/ml) Time (day)

Background

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Background

Double-walled microspheres (DWMS)

  • An improved drug delivery system that can increase

encapsulation efficiency, reduce burst effect, make drug release constantly and persistently

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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)

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

Outlines

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

Outlines

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Preparation and Characterization of DWMS

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  • In vitro release and degradation

Preparation and Characterization of DWMS

Preparation and Characterization of DWMS

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

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

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ka∙F

, ,

Solution DWMS

Pharmacokinetics of exenatide in solution and in DWMS

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Parameter Definition Estimate (RSE %) Inter-individual variability (CV %) ka (h-1) Absorption rate constant 4.45 (12.3) 38.3 Cl/F (L/h) Central clearance 0.198 (6.46) 27.7 Vc/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 Vp/F(L) Peripheral volume of distribution 1.180 (27.0) 82.2 Residual error σ1 (Proportional) CV% 0 (Fixed) σ2 (Additive) SD 0.179 μg/L

The pharmacokinetic parameters of exenatide solution

Pharmacokinetics of exenatide in solution

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Parameter Definition Estimate (RSE %) Inter-individual variability (CV %) Fra1 Fraction of drug in transit Comp 1 0.113 (20.4)

  • Fra2

Fraction of drug in transit Comp 2 0.0301 (31.1) 130 Fra3 Fraction of drug in transit Comp 3 0.00554 (28.6) 28.8 Fra4 Fraction of drug in absorption Comp 0.00326 (22.4)

  • ktr1 (h-1)

Transit rate constant 1 0.00398 (26.4) 4.0 ktr2 (h-1) Transit rate constant 2 0.113 (16.4) 18.9 Residual error σ1 (Proportional) CV% 23.7 σ2 (Additive) SD (μg/L) 0 (Fixed)

  • Refers to the values were fixed as 0

The pharmacokinetic parameters of exenatide DWMS

Pharmacokinetics of exenatide in DWMS

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Time (h)

Exenatide Conc. (ng/ml)

210 μg 21 μg 4.2 μg 5 mg 2.5 mg 1.25 mg

Exenatide solution Exenatide DWMS

Pharmacokinetics of exenatide

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IVIVC of exenatide in DWMS

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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

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

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

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1 50

(1 )

m p

S C dINSP k k INSP dt SC C      

1 50

(1 )

m p

  • utI

S C dINS k INSP k INS dt SC C        

PK/PD of exenatide

  • Exenatide and insulin
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Parameter Definition Estimate (RSE %) IIV (CV %) Sm1 Maximum insulin tropic response factor 0.866 (8.95) 28.5 SC50 (μg/L)

  • Conc. for 50% of insulin tropic effect

3.68 (22.4) 29.5 k0 (mU/L/h) Zero-order precursor input rate constant 24.0 (15.5)

  • kp (h-1)

Insulin precursor release rate constant 5.68·E-4 (9.82)

  • koutI (h-1)

Insulin output rate constant 2.38 (14.4) 10.8 Residual error 1 (Proportional) CV% 18.1 ε2 (Additive) SD (mU/L) 0.602

  • Refers to the values were fixed as 0

Parameters of insulinotropic effects

PK/PD of exenatide

  • Exenatide and insulin
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Exenatide solution Exenatide DWMS

5 mg 2.5 mg 1.25 mg

Time (h)

210 μg 21 μg 4.2 μg

Insulin Conc. (mM/L)

Pharmacokinetics/Pharmacodynamics of DWMS

PK/PD of exenatide

  • Exenatide and insulin
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0 (

)

e e e

dINS k INS INS dt   

   

2

1 ( ) 1 ( )

inG m

  • utG

m e e

dGLU k I INS INS k S INS INS GLU dt           

PK/PD of exenatide

  • Insulin and blood glucose
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Parameter Definition Estimate (RSE %) IIV (CV %) koutG (h-1)* Glucose output rate constant 2.28 (29.5) 81.6 Sm2 (L/mU) Stimulation factor of insulin 0.0472 (21.4) 53.1 Im (L/mU) Inhibition factor of insulin 0.00832 (22.7) 78.2 ke0 (h-1) First-order elimination rate constant from the effect compartment 1.33 (11.1) 39.2 Residual error σ1 (Proportional) CV% 0 (Fixed) σ2 (Additive) SD 0.0871

* koutG= kinG

Parameters of blood glucose-lowering effects

PK/PD of exenatide

  • Exenatide and insulin
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Exenatide solution Exenatide DWMS

5 mg 2.5 mg 1.25 mg

Time (h)

42 μg 4.2 μg 210 μg

Blood glucose

PK/PD of exenatide

  • Exenatide and insulin
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Dose=20 μg/rat

Pharmacokinetics/Pharmacodynamics of DWMS

PK/PD model prediction/validation

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Summary

  • 1. An indirect response model was developed to

characterize the insulin behavior after injection

  • f 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

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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

  • f 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

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Acknowledgement

  • Dr. Xingang Li
  • Dr. Tianyan Zhou
  • Dr. Zaiquan Li
  • Dr. Dewei Shang
  • Dr. Liang Li
  • Dr. Shanshan Bi
  • Dr. Hanqing Li
  • Dr. Xipei Wang

Xiaoliang Cheng Chenhui Deng Xuan Zhou Yupeng Ren Ye Chen Xiangfei Jiu Pfizer China Peking University/Pfizer Pharmacometrics Education Center

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