PK/PD Study Strategies for PK/PD Study Strategies for Biopharmaceuticals: Is Bigger Better? Biopharmaceuticals: Is Bigger Better? Sharon A. Baughman, Ph.D. Sharon A. Baughman, Ph.D. Presented to the New Jersey Presented to the New Jersey American Chemical Society American Chemical Society Drug Metabolism Discussion Group Drug Metabolism Discussion Group October 14th, 2009 October 14th, 2009
New Drug Approvals and R&D Spending New Drug Approvals and R&D Spending
Trends in Total Cost per Drug Trends in Total Cost per Drug 900 900 802 802 800 800 700 700 Cost Per Drug (MM of 2000 $) Cost Per Drug (MM of 2000 $) 600 600 500 500 400 400 318 318 300 300 200 200 138 138 100 100 0 0 Yr 1975 Yr 1987 Yr 2000 Yr 1975 Yr 1987 Yr 2000 Di Masi et al (2003) J Health Econ 22:151
Industry Duration Industry Duration 10.4 8.6 6.6 6.5 5.8 5.1 1.8 1.4 0.8 Clinical Development FDA Total NCEs mAbs Proteins Source: NCE (Dimasi, Parexel 2002); mAbs and Proteins (Reichert, Parexel 2002)
Development Cost Per Phase Development Cost Per Phase Late 115.2 115.2 120 120 NO GO Decision Early Cost Per Phase (MM of 2000 $) 100 Cost Per Phase (MM of 2000 $) 100 NO GO 80 80 Decision 60 60 41.7 41.7 40 40 15.2 15.2 20 20 0 0 Phase 1 Phase 2 Phase 3 Phase 1 Phase 2 Phase 3 Di Masi et al (2003) J Health Econ 22:151
Monoclonal Antibodies in Development Monoclonal Antibodies in Development
Future of Monoclonal Antibodies Future of Monoclonal Antibodies
Why Large Molecules? Why Large Molecules? � Around 60% of revenue growth forecast to come from biologic � Around 60% of revenue growth forecast to come from biologic products (therapeutic proteins and monoclonal antibodies): products (therapeutic proteins and monoclonal antibodies): – By 2010, annual sales of biologics will have increased by – By 2010, annual sales of biologics will have increased by $26bn, compared to a $13bn increase for small molecules. $26bn, compared to a $13bn increase for small molecules. � Within the Big Pharma peer set, the revenue growth rate to � Within the Big Pharma peer set, the revenue growth rate to 2010 forecast for biologics is a robust CAGR of 13.0%, 2010 forecast for biologics is a robust CAGR of 13.0%, outstripping the near-static CAGR of 0.9% predicted for small outstripping the near-static CAGR of 0.9% predicted for small molecules. The small molecule growth rate is depressed by molecules. The small molecule growth rate is depressed by continued exposure to intense generic competition. continued exposure to intense generic competition. � Big Pharma has assumed a strong position within the antibody � Big Pharma has assumed a strong position within the antibody market, a major attraction of this product type being the total market, a major attraction of this product type being the total absence of generic risk. absence of generic risk.
Definition of Biopharmaceuticals Definition of Biopharmaceuticals � FDA – Biologics: Any virus, therapeutic serum, toxin, antitoxin or � FDA – Biologics: Any virus, therapeutic serum, toxin, antitoxin or analogous product applicable to the prevention, treatment or cure of analogous product applicable to the prevention, treatment or cure of diseases or injuries of man diseases or injuries of man – Includes proteins, peptides, their derivatives or products of which – Includes proteins, peptides, their derivatives or products of which they are components they are components (Section 351 of PHS Act, 21 CFR 600.3(h)) (Section 351 of PHS Act, 21 CFR 600.3(h)) � European Union – Biological Medicinal Product: a protein or nucleic � European Union – Biological Medicinal Product: a protein or nucleic acid–based pharmaceutical substance used for therapeutic or in vivo acid–based pharmaceutical substance used for therapeutic or in vivo diagnostic purposes, which is produced by means other than direct diagnostic purposes, which is produced by means other than direct extraction from a native (nonengineered) biological source extraction from a native (nonengineered) biological source
What is a Drug? What is a Drug? Section 201(g)(1): Section 201(g)(1): � Recognized in USP or other compendia � Recognized in USP or other compendia � Intended to diagnose, cure, mitigate, treat or prevent � Intended to diagnose, cure, mitigate, treat or prevent disease disease � Intended to affect structure or function � Intended to affect structure or function � Intended as component of these � Intended as component of these � Exceptions for foods and supplements � Exceptions for foods and supplements
Historical Perspective of Historical Perspective of Biological Regulations Biological Regulations � 1902 Biologic Control Act/1906 Pure Food Drug Act � 1902 Biologic Control Act/1906 Pure Food Drug Act � 1972-Transfer of Biologics Regulation to FDA’s Bureau of � 1972-Transfer of Biologics Regulation to FDA’s Bureau of Biologics (prior regulated by NIH) Biologics (prior regulated by NIH) � 1982-Bureau of Drug and Biologics Merged � 1982-Bureau of Drug and Biologics Merged � 1987-Center for Biologics Separated from Center for Drugs � 1987-Center for Biologics Separated from Center for Drugs � 1993 Center for Biologics Re-organization into Review � 1993 Center for Biologics Re-organization into Review Divisions oriented toward product type Divisions oriented toward product type � 1995 REGO-Biologics Regulations Brought into Line with Drug � 1995 REGO-Biologics Regulations Brought into Line with Drug Regulations Regulations � 2003 CBER’s incorporation of therapeutic proteins into CDER � 2003 CBER’s incorporation of therapeutic proteins into CDER � 2005 full integration within CDER review divisions � 2005 full integration within CDER review divisions
Relative Size of Small Molecules and Relative Size of Small Molecules and Proteins Proteins www.gene.com
Comparison of Small Molecules and Comparison of Small Molecules and Biologics Biologics Small Molecules Biologics Low MW Large MW Mostly well defined physicochemical properties Complex physicochemical properties (e.g. tertiary structure, glycosylation) Chemically synthesized Biotechnology produced from host cell lines and isolated from culture media Generally stable Both heat and shear sensitive (aggregation) Single entity, high chemical purity, purity standards Often heterogeneous mixture, broad specifications well established that may change during development, difficult to synthesize Rapidly enters systemic circulation through blood Larger molecules (>15-20 kDa) primarily reach capillaries circulation via lymphatics, subject to proteolysis Oral administration often possible Usually parenterally administered Distributes to multiple organs/tissues Distribution often limited to plasma and/or extracellular fluids Metabolized to active and non-active metabolites Catabolized to endogenous amino acids Specific toxicities (Not associated with Mostly receptor mediated toxicity, including pharmacological effect) exaggerated pharmacological effects Non-antigenic Usually antigenic (MW> 10 kDa) One bioanalytical method for PK studies Several bioanalytical methods( drug, antibody) for PK studies Baumann, Current Drug Metabolism, 2006
Utility of PK and PD in Drug Utility of PK and PD in Drug Utility of PK and PD in Drug Research and Development Research and Development Research and Development Research Preclinical Clinical • Minimize unnecessary • Optimize dose regimen • Provide pivotal decision studies in animal models making information • Optimize dose for tox • Select Lead Molecule (eg, dose regimen) studies • Support Go/No Go • Predict safe/efficacious decisions clinical doses • Reduce risks in clinical (therapeutic window) trials • Understand ADME and impact on PK/PD These are the same for small molecules and large molecules. However….
PK of Biologics PK of Biologics � Absorption � Absorption � Distribution � Distribution � Metabolism � Metabolism � Elimination � Elimination � Analytical Assays � Analytical Assays
Absorption of Biologics Absorption of Biologics � Molecular Weight (MW): ↑ MW = ↑ T max � Molecular Weight (MW): ↑ MW = ↑ T max – Absorption via capillaries MW < 1,000 Da – Absorption via capillaries MW < 1,000 Da – Via lymphatic MW > 16,000 Da – Via lymphatic MW > 16,000 Da � Route of Administration (IV, SC, IM) � Route of Administration (IV, SC, IM) � Absorption kinetics may be non-linear � Absorption kinetics may be non-linear – May produce different C p – May produce different C p � Immunogenicity may differ based on route � Immunogenicity may differ based on route – SC > IM > IV – SC > IM > IV
Absorption of Biologics Absorption of Biologics Supersaxo, 1990
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