USING BIOMARKERS FOR EARLY PHASE DOSE SELECTION WITH PROTEIN ANTAGONIST DRUGS Ivan Nestorov

Slides:



Advertisements
Similar presentations
Introduction to Pharmacology
Advertisements

LAKSHMAN KARALLIEDDE OCTOBER 2011
Pharmacology for Anesthesia I Introduction. What is a Drug?
1 PK/PD modeling within regulatory submissions Is it used? Can it be used and if yes, where? Views from industry 24 September 2008.
Drug ? RESPONSE altering their biochemical &/or biophysical activity  Depress  Activate  Replace  Irritate  Destroy PHARMACODYNAMICS  Absorb 
Pharmacotherapy in the Elderly Paola S. Timiras May, 2007.
Pharmacotherapy in the Elderly Judy Wong
Definitions Pharmacokinetics –The process by which a drug is administered, absorbed, distributed, bound, inactivated, metabolized and eliminated by the.
Clinical Pharmacology Overview From the Antiviral Perspective Kellie Schoolar Reynolds, Pharm.D. Pharmacokinetics Team Leader Office of Clinical Pharmacology.
Comparability of a human IgG1 after cell line switching: A retrospective view Peter Lloyd Head of PK-PD, Novartis Biologics.
LymphoStat-BTM A Case Study for Endpoints and Trial Design in SLE
Practical Pharmacokinetics
The General Concepts of Pharmacokinetics and Pharmacodynamics Hartmut Derendorf, PhD University of Florida.
PHARMACOKINETICS 1. Fate of drugs in the body 1.1 absorption
PK/PD Modeling in Support of Drug Development Alan Hartford, Ph.D. Associate Director Scientific Staff Clinical Pharmacology Statistics Merck Research.
Nonlinear Pharmacokinetics
Pharmacokinetics Introduction
Concepts and Applications of Pharmacokinetics
Animal Studies and Human Health Consequences Sorell L. Schwartz, Ph.D. Department of Pharmacology Georgetown University Medical Center.
1 Applied Pharmacokinetics of Antiepileptic Drugs (AEDs) B. Gitanjali Gitanjali-21:
1 Axcan Public Presentation for the FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting July 23, 2008.
PLASMA HALF LIFE ( t 1/2 ).  Minimum Effective Concentration (MEC): The plasma drug concentration below which a patient’s response is too small for clinical.
Pharmacokinetic and Pharmacodynamic Studies for Systemic Exposure of Locally Acting Drugs Hartmut Derendorf, Ph.D. Günther Hochhaus, Ph.D. University of.
EMEA London Pharmacokinetic- pharmacodynamic integration in veterinary drug development: an overview P.L. Toutain National Veterinary School ;Toulouse.
Basic Pharmacokinetics The time course of drug action Collected and Prepared By S.Bohlooli, PhD.
D EPARTMENT OF I MMUNOLOGY & H ISTOCOMPATIBILITY – U NIVERSITY OF T HESSALY TNFRSF13B/TACI and TNFRSF13C/BAFFR in B cell chronic lymphocytic leukemia.
Model structure  Law of mass action applied to describe the reversible solifenacin-AGP, solifenacin-albumin and solifenacin-VBC binding  VBC positioned.
BASIC PHARMACOLOGY 2 SAMUEL AGUAZIM(MD).
Core Concepts in Pharmacology Chapter 5 Pharmacokinetics.
CHEE 4401 Definitions drug - any substance that affects the structure or functioning of an organism pharmaceutics - the area of study concerned with the.
The General Concepts of Pharmacokinetics and Pharmacodynamics
TNF-a.
1. Fate of drugs in the body 1.1 absorption 1.2 distribution - volume of distribution 1.3 elimination - clearance 2. The half-life and its uses 3. Repeated.
INTRODUCTION CLINICAL PHARMACOKINETICS
BIOPHARMACEUTICS.
1 Pharmacokinetics: Introduction Dr Mohammad Issa.
Principles of pharmacokinetics Prof. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague Cycle II, Subject: General.
BY PROF. AZZA EL-MEDANY DR. OSAMA YOUSIF General Features & Conditions to use antirheumatic Low doses are commonly used early in the course of the disease.
© Paradigm Publishing, Inc.1 Chapter 2 Basic Concepts of Pharmacology.
European Patients’ Academy on Therapeutic Innovation The key principles of pharmacology.
PHARMACODYNAMICS M.T. Piascik PHA 824 November 11, 2008.
Disease modified Anti-rheumatic drugs ( DMARD)
PHT 415 BASIC PHARMACOKINETICS
The General Concepts of Pharmacokinetics and Pharmacodynamics
Dr. Laila M. Matalqah Ph.D. Pharmacology Pharmacodynamics 2 General Pharmacology M212.
1 C-MOA- Efalizumab Mechanism of Action and Dose Determination Charles Johnson, MB, ChB Senior Director Head of Specialty Biotherapeutics Genentech, Inc.
1 Biopharmaceutics Dr Mohammad Issa Saleh. 2 Biopharmaceutics Biopharmaceutics is the science that examines this interrelationship of the physicochemical.
Clinical Pharmacokinetics. Time course Duration Onset Absorptive phase Elimination phase.
Carla Chieffo, David Cook, Qinfang Xiang, and Lawrence A. Frohman Efficacy and Safety of an Octreotide Implant in the Treatment of Patients With Acromegaly.
B Cell Activation Abul K. Abbas UCSF FOCiS.
Basic Concepts of Pharmacology © Paradigm Publishing, Inc.
By : Dr. Roshini Murugupillai
DRUG RECEPTORS AND PHARMACODYNAMICS
Understanding the Basics of Pharmacology
Pharmacokinetics.
Biopharmaceutics Dr Mohammad Issa Saleh.
Pharmacokinetics & pharmacodynamcs
Introduction; Scope of Pharmacology Routes of Drug Administration
INTRODUCTION to Pharmacology
Clinical Pharmacokinetics
1 Concentration-time curve
Therapeutic Drug Monitoring chapter 1 part 1
Introduction to Pharmacology
Introduction to Pharmacology
Selvadurai Muralidharan, Kalaimani Jaya Raja Kumar
Introduction to Pharmacology
Vaccines for Lung Cancer
Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti–IL-6 receptor.
Monoclonal antibodies and fusion proteins and their complications: Targeting B cells in autoimmune diseases  Susan Lee, MD, Mark Ballow, MD  Journal of.
Presentation transcript:

USING BIOMARKERS FOR EARLY PHASE DOSE SELECTION WITH PROTEIN ANTAGONIST DRUGS Ivan Nestorov

TALK FRAMEWORK Setting the stage: introductions and definitions PK and binding as major early markers Biological activity as validation for binding Walk-through example Regulatory implications

THERAPEUTIC PROTEINS after B.M. Rao, D.A. Laufenburger, K.D. Wittrup. Integrating cell-level kinetic modeling into the design of engineered protein therapeutics. Nature Biotechnology. 23: , Antagonists (e.g. antibodies, soluble receptors) - block native protein interactions by binding to target protein(s) –Examples – anti-TNF, anti-VEGF, anti-BLyS/APRIL Agonists (e.g. cytokines, growth factors) - stimulate cell surface receptors –Examples – erythropoietin, rhGH, G-CSF, IL-2 Targeting agents (e.g. antibodies, immunotoxins) – target specific cell surface antigens or deliver therapeutic agents –Examples – anti-CD20

BAFF-R BCMA TACI B-Cell APRIL BLyS (BAFF) Heterotrimer B cell differentiation B cell survival Antibody production Ig class switch EXAMPLES: BLYS/APRIL antagonist (atacicept)

THE RESPONSE CASCADE M Danhof, G Alvan, SG Dahl, J Kuhlmann, G Paintaud. Mechanism-based pharmacokinetic- pharmacodynamic modeling-a new classification of biomarkers. Pharm Res. 2005; 22: PHASE 1 DATA HOW TO USE THIS INFORMATION FOR DOSAGE REGIMEN DESIGN IN PHASE 2/3?

Atacicept exposure–response cascade (RA) BLyS/APRIL Inhibition DOSE & Freq. MoA Biomarkers Disease Biomarkers Clinical Markers Clinical Endpoints FREE DRUG FREE TARGET COMPLEX Binding & Inhibition Biological activity Disease related activity Clinical activity Clinical efficacy IgX FACS IgX RF ACPA ESR, CRP JOINT CNTS ACRXX% DAS28

THERAPEUTIC PROTEINS Large molecules, slow PK and PD Specific binding to targets dominant (by engineering) Target load often: –Significant (in molar concentration terms) –Distributed across various tissues –Constantly renewed by endogenous production of targets –Endogenous production may be boosted by depletion Nonspecific binding sometimes negligible (!!! check) No P450 metabolism, but Ab’s to drug possible Protein drug metabolism often capacity limited

PK & TARGET BINDING: MAJOR EARLY MARKERS Free drug PK is expected to be nonlinear –Unless nonlinearity is overwhelmed –Or unless total drug is measured –PK Assays are critical Dosing should be targeted at the saturation –Below saturation – sub-therapeutic regimen –Above saturation – waste of drug and/or potential over-inhibition –Saturation – both in blood and tissues –Saturation is a dynamic process – at all times

FREE DRUG PK TISSUES, SoA ABSORPTION SITE BLOOD L1 KINETICS BINDING TO L1 & L2 TISSUES, SoA BLOOD L2 KINETICS TISSUES, SoA BLOOD endogenous production BINDING EQUILIBRIUM: Binding affinity Drug & ligand concentrations –Systemically –In tissues Dosing schedule Endogenous ligand production –Systemically –In tissues PK & BINDING

FREE DRUG PK TISSUES, SoA ABSORPTION SITE BLOOD L1 KINETICS BINDING TO L1 & L2 TISSUES, SoA BLOOD L2 KINETICS TISSUES, SoA BLOOD endogenous production PK, BINDING & DOSING OBJECTIVE: Adequate binding –Process in time –At Sites of Action –Not necessarily complete binding of ligand Markers of PK/binding –Free drug –Total drug –Complex concentration –Free ligand concentration Means to achieve goal: –Type of dosing regimen –Dosing levels –Dosing frequency –Mode of administration

ACCUMULATION OF COMPLEX P.P. Tak, et al. Atacicept in patients with rheumatoid arthritis: an exploratory, multicenter, double-blind, placebo-controlled, dose – escalating, single and repeat dose phase 1b study. Accepted Arthr. & Rheum. ar , 2007.

BLyS Concentration after Rituximab in RA G. Cambridge et al. Circulating Levels of B Lymphocyte Stimulator in Patients With Rheumatoid Arthritis Following Rituximab Treatment. Arthritis and Rheumatism 54: (2006). BLyS accummulation rate in serum: ~0.08 ng/mL/day

DESIGN SO FAR: Type of dosage: Loading - Maintenance –Eliminate initial target ligand load –Boost the redistribution of target ligand –Compensate endogenous ligand production Dose levels and dosing frequency ??? Mode of administration: ???

RECEPTOR MEDIATED PK A. Munafo, A. Priestley, I. Nestorov, J. Visich, M. Rogge. Safety, pharmacokinetics and pharmacodynamics of atacicept in healthy volunteers. Eur. J. Clin. Pharm. 63: (2007). Atacicept/BLyS Complex Free Atacicept

QUIZ: DOSING FREQUENCY? Terminal Halflife: days

30-40% incomplete inhibition Next dose? QUIZ: DOSING FREQUENCY?

Biological activity tracks target ligand binding More frequent dosing at smaller doses yields better effect Biological Activity Drug-Ligand Complex

DESIGN SO FAR: Biological activity tracks binding Type of dosage: Loading - Maintenance –Eliminate initial ligand load –Boost the redistribution of ligand –Compensate endogenous ligand production Dose levels and dosing frequency –More frequent smaller doses yield higher biological activity compared to less frequent higher doses –Single dose saturation – between 75 and 210 mg –Dosing interval to maximize inhibition – 7 – 14 days –What doses / dosing intervals??? Mode of administration: ???

S.C. ADMINISTRATION of PROTEIN DRUGS Uptake by lymphatic system Poorly quantified Dependent on MW Lymphatic & blood circulation closely interwined Consider kinetic vs dynamic rates Lymph can be SoA S.C. injection

… but biological activity is the same … S.c. Atacicept systemic bioavailability is ~ % … COMPARING S.C. & I.V. ADMINISTRATION

… because target binding is the same! COMPARING S.C. & I.V. ADMINISTRATION

DESIGN SO FAR: Biological activity tracks binding Type of dosage: Loading - Maintenance –Eliminate initial ligand load –Boost the redistribution of ligand –Compensate endogenous ligand production Dose levels and dosing frequency –More frequent smaller doses yield higher biological activity compared to less frequent higher doses –Single dose saturation – between 75 and 210 mg –Dosing interval to maximize inhibition – 7 – 14 days –What doses / dosing intervals??? Mode of administration: SC

TIME TO BECOME QUANTITATIVE… ATACICEPT Pop PK/PD MODEL I. Nestorov et al. Population modeling of the relationship between TACI ‑ Ig exposure and biomarker response in patients with rheumatoid arthritis (RA). Population Analysis Group in Europe meeting PAGE 2006, June 14-16, Abs. Site CentralPeripheral IgM, IgG, IgA CL QKa VcVp DOSE

Varying doses, same dosing frequency (QW) Simulations: Dose saturation of effect Going beyond 150 mg for QW not justified IgM [% of baseline]

DESIGN COMPLETE Biological activity tracks binding Type of dosage: Loading - Maintenance –Eliminate initial ligand load –Boost the redistribution of ligand –Compensate endogenous ligand production Dose levels and dosing frequency –More frequent smaller doses yield higher biological activity compared to less frequent higher doses –Single dose saturation – between 75 and 210 mg –Dosing interval to maximize inhibition – 7 – 14 days –Dosing frequency – once weekly (QW) –Dose levels for Phase 2/3 study: 25, 75 and 150 mg Mode of administration: SC

REGULATORY ACTION PHASE 1

CONCLUSIONS PK and target binding are major early biomarkers for protein antagonists Saturation of binding can be used for early phase dosage regimen design Population PK/PD modeling helps quantify saturation Mechanistic validation should be implemented as much as possible