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Ozanezumab dose selection for amyotrophic lateral sclerosis by pharmacokinetic-pharmacodynamic modelling of immunohistochemistry data from patient muscle biopsies.

Berges A, Bullman J, Bates S, Krull D, Williams N, Chen C - PLoS ONE (2015)

Bottom Line: The rich plasma concentration data and the sparse IHC data after one or two intravenous doses of ozanezumab were modelled simultaneously using a non-linear mixed-effect approach.The final PKPD model was a two-compartment PK model combined with an effect compartment PD model that accounted for the delay in ozanezumab concentrations to reach the site of action which is skeletal muscle.The model was used as a simulation tool to design a dose regimen for sustained drug-target co-localization in a phase II study.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, London, United Kingdom.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease with a high unmet medical need. In this context, a potential therapy should be brought to patients in the most expeditious way and early exploration of pharmacology is highly beneficial. Ozanezumab, a humanised IgG monoclonal antibody against Nogo-A protein which is an inhibitor of neurite outgrowth, is currently under development for the treatment of ALS and has been recently assessed in 76 patients in a first-in-human study. Inadequate target engagement has been recognised as a major contributing reason for drug trial failures. In this work, we describe the development of a pharmacokinetic-pharmacodynamic (PKPD) model using immunohistochemistry (IHC) data of co-localization of ozanezumab with Nogo-A in skeletal muscle as a surrogate measure of target engagement. The rich plasma concentration data and the sparse IHC data after one or two intravenous doses of ozanezumab were modelled simultaneously using a non-linear mixed-effect approach. The final PKPD model was a two-compartment PK model combined with an effect compartment PD model that accounted for the delay in ozanezumab concentrations to reach the site of action which is skeletal muscle. Diagnostic plots showed a satisfactory fit of both PK and IHC data. The model was used as a simulation tool to design a dose regimen for sustained drug-target co-localization in a phase II study.

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Model simulations of percentages of membrane Nogo-A co-localized with ozanezumab following one-hour infusion at 5, 10 and 20 mg/kg/h every 28 days (dashed lines); and at 2.5, 5 and 10 mg/kg/h every 14 days (solid lines).
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pone.0117355.g004: Model simulations of percentages of membrane Nogo-A co-localized with ozanezumab following one-hour infusion at 5, 10 and 20 mg/kg/h every 28 days (dashed lines); and at 2.5, 5 and 10 mg/kg/h every 14 days (solid lines).

Mentions: The PKPD model was used to help understand the impact of dose and dosing frequency on the extent and sustainability of PD response in term of Nogo-A and ozanezumab co-localization on muscle membrane. For example, the model-simulated time course of co-localization is shown in Fig. 4 for the same total monthly doses of 5, 10 and 20mg/kg, administered as one-hour intravenous infusions, given either as full doses every four weeks or as half doses every two weeks.


Ozanezumab dose selection for amyotrophic lateral sclerosis by pharmacokinetic-pharmacodynamic modelling of immunohistochemistry data from patient muscle biopsies.

Berges A, Bullman J, Bates S, Krull D, Williams N, Chen C - PLoS ONE (2015)

Model simulations of percentages of membrane Nogo-A co-localized with ozanezumab following one-hour infusion at 5, 10 and 20 mg/kg/h every 28 days (dashed lines); and at 2.5, 5 and 10 mg/kg/h every 14 days (solid lines).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4338135&req=5

pone.0117355.g004: Model simulations of percentages of membrane Nogo-A co-localized with ozanezumab following one-hour infusion at 5, 10 and 20 mg/kg/h every 28 days (dashed lines); and at 2.5, 5 and 10 mg/kg/h every 14 days (solid lines).
Mentions: The PKPD model was used to help understand the impact of dose and dosing frequency on the extent and sustainability of PD response in term of Nogo-A and ozanezumab co-localization on muscle membrane. For example, the model-simulated time course of co-localization is shown in Fig. 4 for the same total monthly doses of 5, 10 and 20mg/kg, administered as one-hour intravenous infusions, given either as full doses every four weeks or as half doses every two weeks.

Bottom Line: The rich plasma concentration data and the sparse IHC data after one or two intravenous doses of ozanezumab were modelled simultaneously using a non-linear mixed-effect approach.The final PKPD model was a two-compartment PK model combined with an effect compartment PD model that accounted for the delay in ozanezumab concentrations to reach the site of action which is skeletal muscle.The model was used as a simulation tool to design a dose regimen for sustained drug-target co-localization in a phase II study.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, London, United Kingdom.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease with a high unmet medical need. In this context, a potential therapy should be brought to patients in the most expeditious way and early exploration of pharmacology is highly beneficial. Ozanezumab, a humanised IgG monoclonal antibody against Nogo-A protein which is an inhibitor of neurite outgrowth, is currently under development for the treatment of ALS and has been recently assessed in 76 patients in a first-in-human study. Inadequate target engagement has been recognised as a major contributing reason for drug trial failures. In this work, we describe the development of a pharmacokinetic-pharmacodynamic (PKPD) model using immunohistochemistry (IHC) data of co-localization of ozanezumab with Nogo-A in skeletal muscle as a surrogate measure of target engagement. The rich plasma concentration data and the sparse IHC data after one or two intravenous doses of ozanezumab were modelled simultaneously using a non-linear mixed-effect approach. The final PKPD model was a two-compartment PK model combined with an effect compartment PD model that accounted for the delay in ozanezumab concentrations to reach the site of action which is skeletal muscle. Diagnostic plots showed a satisfactory fit of both PK and IHC data. The model was used as a simulation tool to design a dose regimen for sustained drug-target co-localization in a phase II study.

Show MeSH
Related in: MedlinePlus