Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys: Development of a Predictive Model for Amyloid Precursor Protein Processings

Xingrong Liu, Harvey Wong, Kimberly Scearce-Levie, Ryan J. Watts, Melis Coraggio, Young G. Shin, Kun Peng, Kristin R. Wildsmith, Jasvinder K. Atwal, Jason Mango, Stephen P. Schauer, Kelly Regal, Kevin W. Hunt, Allen A. Thomas, Michael Siu, Joseph Lyssikatos, Gauri Deshmukh, Cornelis E.C.A. Hop

Research output: Contribution to journalArticle

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Abstract

This study was conducted to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of two novel inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1), GNE-629 [(4S,4a9S,10a9S)-2-amino-89-(2- fluoropyridin-3-yl)-1-methyl-39,49,4a9,10a9- tetrahydro-19H-spiro[imidazole-4, 109-pyrano[4,3-b]chromen]- 5(1H)-one] and GNE-892 [(R)-2-amino-1,39,39- trimethyl-79-(pyrimidin- 5-yl)-39,49-dihydro-29H-spiro[imidazole-4,19- naphthalen]-5(1H)-one], and to develop a PK-PD model to predict in vivo effects based solely on in vitro activity and PK. GNE-629 and GNE-892 concentrations and PD biomarkers including amyloid b (Ab) in the plasma and cerebrospinal fluid (CSF), and secreted APPb (sAPPb) and secreted APPa (sAPPa) in the CSF were measured after a single oral administration of GNE-629 (100 mg/kg) or GNE-892 (30 or 100 mg/kg) in cynomolgus monkeys. A mechanistic PK-PD model was developed to simultaneously characterize the plasma Ab and CSF Ab, sAPPa, and sAPPb using GNE-629 in vivo data. This model was used to predict the in vivo effects of GNE-892 after adjustments based on differences in in vitro cellular activity and PK. The PK-PD model estimated GNE-629 CSF and free plasma IC50 of 0.0033 mM and 0.065 mM, respectively. These differences in CSF and free plasma IC50 suggest that different mechanisms are involved in Ab formation in these two compartments. The predicted in vivo effects for GNE-892 using the PK-PD model were consistent with the observed data. In conclusion, a PK-PD model was developed to mechanistically describe the effects of BACE1 inhibition on Ab, sAPPb, and sAPPa in the CSF, and Ab in the plasma. This model can be used to prospectively predict in vivo effects of new BACE1 inhibitors using just their in vitro activity and PK data.

Original languageEnglish (US)
Pages (from-to)1319-1328
Number of pages10
JournalDrug Metabolism and Disposition
Volume41
Issue number7
DOIs
StatePublished - Jul 1 2013

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Amyloid beta-Protein Precursor
Haplorhini
Pharmacokinetics
Amyloid
Cerebrospinal Fluid
Inhibitory Concentration 50
Macaca fascicularis
Oral Administration
Biomarkers
GNE-629
2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro(imidazole-4,1'-naphthalen)-5(1H)-one
Enzymes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys : Development of a Predictive Model for Amyloid Precursor Protein Processings. / Liu, Xingrong; Wong, Harvey; Scearce-Levie, Kimberly; Watts, Ryan J.; Coraggio, Melis; Shin, Young G.; Peng, Kun; Wildsmith, Kristin R.; Atwal, Jasvinder K.; Mango, Jason; Schauer, Stephen P.; Regal, Kelly; Hunt, Kevin W.; Thomas, Allen A.; Siu, Michael; Lyssikatos, Joseph; Deshmukh, Gauri; Hop, Cornelis E.C.A.

In: Drug Metabolism and Disposition, Vol. 41, No. 7, 01.07.2013, p. 1319-1328.

Research output: Contribution to journalArticle

Liu, X, Wong, H, Scearce-Levie, K, Watts, RJ, Coraggio, M, Shin, YG, Peng, K, Wildsmith, KR, Atwal, JK, Mango, J, Schauer, SP, Regal, K, Hunt, KW, Thomas, AA, Siu, M, Lyssikatos, J, Deshmukh, G & Hop, CECA 2013, 'Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys: Development of a Predictive Model for Amyloid Precursor Protein Processings', Drug Metabolism and Disposition, vol. 41, no. 7, pp. 1319-1328. https://doi.org/10.1124/dmd.112.050864
Liu, Xingrong ; Wong, Harvey ; Scearce-Levie, Kimberly ; Watts, Ryan J. ; Coraggio, Melis ; Shin, Young G. ; Peng, Kun ; Wildsmith, Kristin R. ; Atwal, Jasvinder K. ; Mango, Jason ; Schauer, Stephen P. ; Regal, Kelly ; Hunt, Kevin W. ; Thomas, Allen A. ; Siu, Michael ; Lyssikatos, Joseph ; Deshmukh, Gauri ; Hop, Cornelis E.C.A. / Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys : Development of a Predictive Model for Amyloid Precursor Protein Processings. In: Drug Metabolism and Disposition. 2013 ; Vol. 41, No. 7. pp. 1319-1328.
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AU - Watts, Ryan J.

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AU - Shin, Young G.

AU - Peng, Kun

AU - Wildsmith, Kristin R.

AU - Atwal, Jasvinder K.

AU - Mango, Jason

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AU - Deshmukh, Gauri

AU - Hop, Cornelis E.C.A.

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N2 - This study was conducted to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of two novel inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1), GNE-629 [(4S,4a9S,10a9S)-2-amino-89-(2- fluoropyridin-3-yl)-1-methyl-39,49,4a9,10a9- tetrahydro-19H-spiro[imidazole-4, 109-pyrano[4,3-b]chromen]- 5(1H)-one] and GNE-892 [(R)-2-amino-1,39,39- trimethyl-79-(pyrimidin- 5-yl)-39,49-dihydro-29H-spiro[imidazole-4,19- naphthalen]-5(1H)-one], and to develop a PK-PD model to predict in vivo effects based solely on in vitro activity and PK. GNE-629 and GNE-892 concentrations and PD biomarkers including amyloid b (Ab) in the plasma and cerebrospinal fluid (CSF), and secreted APPb (sAPPb) and secreted APPa (sAPPa) in the CSF were measured after a single oral administration of GNE-629 (100 mg/kg) or GNE-892 (30 or 100 mg/kg) in cynomolgus monkeys. A mechanistic PK-PD model was developed to simultaneously characterize the plasma Ab and CSF Ab, sAPPa, and sAPPb using GNE-629 in vivo data. This model was used to predict the in vivo effects of GNE-892 after adjustments based on differences in in vitro cellular activity and PK. The PK-PD model estimated GNE-629 CSF and free plasma IC50 of 0.0033 mM and 0.065 mM, respectively. These differences in CSF and free plasma IC50 suggest that different mechanisms are involved in Ab formation in these two compartments. The predicted in vivo effects for GNE-892 using the PK-PD model were consistent with the observed data. In conclusion, a PK-PD model was developed to mechanistically describe the effects of BACE1 inhibition on Ab, sAPPb, and sAPPa in the CSF, and Ab in the plasma. This model can be used to prospectively predict in vivo effects of new BACE1 inhibitors using just their in vitro activity and PK data.

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