Limits...
Population PK-PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197.

De Buck S, Hueber W, Vitaliti A, Straube F, Emotte C, Bruin G, Woessner R - CPT Pharmacometrics Syst Pharmacol (2015)

Bottom Line: PK was characterized using a two-compartment model with mixed-order absorption and limited-capacity tissue binding.This may indicate a mechanism by which the inflammatory response acquires the ability to bypass p38.Simulations of posology dependence in drug effect suggest that an intermittent regimen may offer clinical benefit over continuous dosing and limit the impact of tolerance development.

View Article: PubMed Central - PubMed

Affiliation: Novartis Institute for Biomedical Research, DMPK, Clinical PK-PD Basel Switzerland.

ABSTRACT
The p38 mitogen-activated protein kinase (p38) is a key signaling pathway involved in regulation of inflammatory cytokines. Unexpectedly, several clinical studies using p38 inhibitors found no convincing clinical efficacy in the treatment of chronic inflammation. It was the objective of this study to characterize the population pharmacokinetics (PK) of BCT197 in healthy volunteers and to examine the relationship between BCT197 exposure and pharmacodynamics (PD) measured as inhibition of ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFα), a downstream marker of p38 activity. PK was characterized using a two-compartment model with mixed-order absorption and limited-capacity tissue binding. The PK-PD relationship revealed that suppression of TNFα was partly offset over time, despite continuous drug exposure. This may indicate a mechanism by which the inflammatory response acquires the ability to bypass p38. Simulations of posology dependence in drug effect suggest that an intermittent regimen may offer clinical benefit over continuous dosing and limit the impact of tolerance development.

No MeSH data available.


Related in: MedlinePlus

Goodness‐of‐fit plots for the final population (a–d) PK model and (e‐f) PD model. The lines of identity and local polynomial regression are represented by the solid black line and blue dashed line, respectively.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4759708&req=5

psp412037-fig-0003: Goodness‐of‐fit plots for the final population (a–d) PK model and (e‐f) PD model. The lines of identity and local polynomial regression are represented by the solid black line and blue dashed line, respectively.

Mentions: A summary of subject demographics and data used for model building is presented in Supplementary Table S1 online. Demographic and baseline characteristics were well balanced across the single and multiple dose groups. Median plasma concentration of BCT197 after single‐dose administration and once‐daily dosing for 2 weeks are depicted in Figure1. A summary of the model building is presented in Supplementary Table S2. The final PK model is depicted in Figure2a. Basic goodness‐of‐fit plots of the final model did not show any relevant trends of model misspecification (Figure3a–d). Simulation‐based diagnostics also indicated good performance of the model (Supplementary Figures S1 and S2). η‐Shrinkage was low‐to‐moderate (<30%) for all parameters, indicating post‐hoc estimates could be obtained with confidence.


Population PK-PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197.

De Buck S, Hueber W, Vitaliti A, Straube F, Emotte C, Bruin G, Woessner R - CPT Pharmacometrics Syst Pharmacol (2015)

Goodness‐of‐fit plots for the final population (a–d) PK model and (e‐f) PD model. The lines of identity and local polynomial regression are represented by the solid black line and blue dashed line, respectively.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4759708&req=5

psp412037-fig-0003: Goodness‐of‐fit plots for the final population (a–d) PK model and (e‐f) PD model. The lines of identity and local polynomial regression are represented by the solid black line and blue dashed line, respectively.
Mentions: A summary of subject demographics and data used for model building is presented in Supplementary Table S1 online. Demographic and baseline characteristics were well balanced across the single and multiple dose groups. Median plasma concentration of BCT197 after single‐dose administration and once‐daily dosing for 2 weeks are depicted in Figure1. A summary of the model building is presented in Supplementary Table S2. The final PK model is depicted in Figure2a. Basic goodness‐of‐fit plots of the final model did not show any relevant trends of model misspecification (Figure3a–d). Simulation‐based diagnostics also indicated good performance of the model (Supplementary Figures S1 and S2). η‐Shrinkage was low‐to‐moderate (<30%) for all parameters, indicating post‐hoc estimates could be obtained with confidence.

Bottom Line: PK was characterized using a two-compartment model with mixed-order absorption and limited-capacity tissue binding.This may indicate a mechanism by which the inflammatory response acquires the ability to bypass p38.Simulations of posology dependence in drug effect suggest that an intermittent regimen may offer clinical benefit over continuous dosing and limit the impact of tolerance development.

View Article: PubMed Central - PubMed

Affiliation: Novartis Institute for Biomedical Research, DMPK, Clinical PK-PD Basel Switzerland.

ABSTRACT
The p38 mitogen-activated protein kinase (p38) is a key signaling pathway involved in regulation of inflammatory cytokines. Unexpectedly, several clinical studies using p38 inhibitors found no convincing clinical efficacy in the treatment of chronic inflammation. It was the objective of this study to characterize the population pharmacokinetics (PK) of BCT197 in healthy volunteers and to examine the relationship between BCT197 exposure and pharmacodynamics (PD) measured as inhibition of ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFα), a downstream marker of p38 activity. PK was characterized using a two-compartment model with mixed-order absorption and limited-capacity tissue binding. The PK-PD relationship revealed that suppression of TNFα was partly offset over time, despite continuous drug exposure. This may indicate a mechanism by which the inflammatory response acquires the ability to bypass p38. Simulations of posology dependence in drug effect suggest that an intermittent regimen may offer clinical benefit over continuous dosing and limit the impact of tolerance development.

No MeSH data available.


Related in: MedlinePlus