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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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Related in: MedlinePlus

Plasma drug concentration (top), muscle drug concentration (middle) and co-localization of Nogo-A with drug (bottom).In the top and bottom panels: visual predictive check for final model is shown (the points are the observations, the black line is the median of the simulations and the ribbon delimits the 5th and 95th percentiles of the simulations). In the middle panel: points are the observations, black line and dark ribbon represent model-simulated median and 5th—95th percentile of effect compartment concentration, blue line and light ribbon represent model-simulated median and 5th—95th percentile of peripheral compartment concentration.
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pone.0117355.g001: Plasma drug concentration (top), muscle drug concentration (middle) and co-localization of Nogo-A with drug (bottom).In the top and bottom panels: visual predictive check for final model is shown (the points are the observations, the black line is the median of the simulations and the ribbon delimits the 5th and 95th percentiles of the simulations). In the middle panel: points are the observations, black line and dark ribbon represent model-simulated median and 5th—95th percentile of effect compartment concentration, blue line and light ribbon represent model-simulated median and 5th—95th percentile of peripheral compartment concentration.

Mentions: Plasma ozanezumab concentration-time profiles were available for all subjects in Part 1 and in Part 2. Muscle ozanezumab concentrations were limited to the patients with muscle biopsies. Fig. 1 illustrates the PK profiles from Part 2, which was repeat dosing, both in plasma (upper panel) and in muscles lysates (middle panel). The plasma ozanezumab PK profiles showed a peak concentration proportional to the dose at the end of infusion, followed by a bi-exponential decline with a terminal half-life of approximately 20 days. Muscle ozanezumab concentrations, quantifiable only in a subset of subjects, increased with increasing dose. A similar trend was seen in the detection of ozanezumab in tissue samples by IHC (Fig. 2, bottom panel).


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)

Plasma drug concentration (top), muscle drug concentration (middle) and co-localization of Nogo-A with drug (bottom).In the top and bottom panels: visual predictive check for final model is shown (the points are the observations, the black line is the median of the simulations and the ribbon delimits the 5th and 95th percentiles of the simulations). In the middle panel: points are the observations, black line and dark ribbon represent model-simulated median and 5th—95th percentile of effect compartment concentration, blue line and light ribbon represent model-simulated median and 5th—95th percentile of peripheral compartment concentration.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0117355.g001: Plasma drug concentration (top), muscle drug concentration (middle) and co-localization of Nogo-A with drug (bottom).In the top and bottom panels: visual predictive check for final model is shown (the points are the observations, the black line is the median of the simulations and the ribbon delimits the 5th and 95th percentiles of the simulations). In the middle panel: points are the observations, black line and dark ribbon represent model-simulated median and 5th—95th percentile of effect compartment concentration, blue line and light ribbon represent model-simulated median and 5th—95th percentile of peripheral compartment concentration.
Mentions: Plasma ozanezumab concentration-time profiles were available for all subjects in Part 1 and in Part 2. Muscle ozanezumab concentrations were limited to the patients with muscle biopsies. Fig. 1 illustrates the PK profiles from Part 2, which was repeat dosing, both in plasma (upper panel) and in muscles lysates (middle panel). The plasma ozanezumab PK profiles showed a peak concentration proportional to the dose at the end of infusion, followed by a bi-exponential decline with a terminal half-life of approximately 20 days. Muscle ozanezumab concentrations, quantifiable only in a subset of subjects, increased with increasing dose. A similar trend was seen in the detection of ozanezumab in tissue samples by IHC (Fig. 2, bottom panel).

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