Table Of ContentProteins and Peptides
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DRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs
Executive Editor
James Swarbrick
PharmaceuTech, Inc.
Pinehurst,NorthCarolina
Advisory Board
Larry L. Augsburger Harry G. Brittain
University ofMaryland Center forPharmaceuticalPhysics
Baltimore,Maryland Milford, NewJersey
Jennifer B. Dressman Robert Gurny
University ofFrankfurt Institute Universite deGeneve
ofPharmaceuticalTechnology Geneve,Switzerland
Frankfurt, Germany
Jeffrey A. Hughes
Anthony J. Hickey University ofFloridaCollege
University ofNorthCarolina of Pharmacy
Schoolof Pharmacy Gainesville,Florida
ChapelHill,NorthCarolina
Vincent H. L. Lee
Ajaz Hussain USFDA Center forDrug
Sandoz Evaluationand Research
Princeton,NewJersey LosAngeles, California
Joseph W. Polli Kinam Park
GlaxoSmithKline Purdue University
ResearchTrianglePark WestLafayette,Indiana
NorthCarolina
Jerome P. Skelly
Stephen G. Schulman Alexandria,Virginia
Universityof Florida
Gainesville,Florida Elizabeth M. Topp
University ofKansas
Yuichi Sugiyama Lawrence,Kansas
University of Tokyo,Tokyo,Japan
Peter York
Geoffrey T. Tucker University ofBradford
University of Sheffield Schoolof Pharmacy
Royal Hallamshire Hospital Bradford,United Kingdom
Sheffield, United Kingdom
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For information on volumes 1–152 in the Drugs and Pharmaceutical Science
Series, please visit www.informahealthcare.com
153. Pharmaceutical Stress Testing: Predicting Drug Degradation, edited by
Steven W. Baertschi
154. Handbook of Pharmaceutical Granulation Technology: Second Edition,
edited by Dilip M. Parikh
155. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Fourth Edition, edited by Robert L. Bronaugh and Howard I. Maibach
156. Pharmacogenomics: Second Edition, edited by Werner Kalow, Urs A.
Meyer and Rachel F. Tyndale
157. Pharmaceutical Process Scale-Up, Second Edition, edited by Michael
Levin
158. Microencapsulation: Methods and Industrial Applications, Second Edition,
edited by Simon Benita
159. Nanoparticle Technology for Drug Delivery, edited by Ram B. Gupta and
Uday B. Kompella
160. Spectroscopy of Pharmaceutical Solids, edited by Harry G. Brittain
161. Dose Optimization in Drug Development, edited by Rajesh Krishna
162. HerbalSupplements-DrugInteractions:ScientificandRegulatoryPerspec-
tives,editedbyY.W.FrancisLam,Shiew-MeiHuang,andStephenD.Hall
163. Pharmaceutical Photostability and Stabilization Technology, edited by
Joseph T. Piechocki and Karl Thoma
164. Environmental Monitoring for Cleanrooms and Controlled Environments,
edited by Anne Marie Dixon
165. Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited
by Dakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young
166. NanoparticulateDrugDeliverySystems,editedbyDeepakThassu,Michel
Deleers, and Yashwant Pathak
167. Endotoxins: Pyrogens, LAL Testing and Depyrogenation, Third Edition,
edited by Kevin L. Williams
168. Good Laboratory Practice Regulations, Fourth Edition, edited by
Anne Sandy Weinberg
169. Good Manufacturing Practices for Pharmaceuticals, Sixth Edition, edited
by Joseph D. Nally
170. Oral-Lipid Based Formulations: Enhancing the Bioavailability of Poorly
Water-soluble Drugs, edited by David J. Hauss
171. Handbook of Bioequivalence Testing, edited by Sarfaraz K. Niazi
172. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes,
edited by Robert O. Williams III, David R. Taft, and Jason T. McConville
173. Clean-in-Place for Biopharmaceutical Processes, edited by Dale A.
Seiberling
174. Filtration and Purification in the Biopharmaceutical Industry, Second
Edition, edited by Maik W. Jornitz and Theodore H. Meltzer
175. Protein Formulation and Delivery, Second Edition, edited by Eugene J.
McNally and Jayne E. Hastedt
176. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Third
Edition, edited by James McGinity and Linda A. Felton
177. Dermal Absorption and Toxicity Assessment, Second Edition, edited by
Michael S. Roberts and Kenneth A. Walters
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duction/z_3B2_3D_files/978-1-4200-7806-2_seriespage_O.3d][18/9/09/
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178. Preformulation Solid Dosage Form Development, edited by Moji C.
Adeyeye and Harry G. Brittain
179. Drug-Drug Interactions, Second Edition, edited by A. David Rodrigues
180. Generic Drug Product Development: Bioequivalence Issues, edited by
Isadore Kanfer and Leon Shargel
181. PharmaceuticalPre-ApprovalInspections:AGuidetoRegulatorySuccess,
Second Edition, edited by Martin D. Hynes III
182. Pharmaceutical Project Management, Second Edition, edited by Anthony
Kennedy
183. Modified Release Drug Delivery Technology, Second Edition, Volume 1,
edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts,
and Majella E. Lane
184. Modified-Release Drug Delivery Technology, Second Edition, Volume 2,
edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts,
and Majella E. Lane
185. ThePharmaceuticalRegulatoryProcess,SecondEdition,editedbyIraR.
Berry and Robert P. Martin
186. HandbookofDrugMetabolism,SecondEdition,editedbyPaulG.Pearson
and Larry C. Wienkers
187. PreclinicalDrugDevelopment,SecondEdition,editedbyMarkRoggeand
David R. Taft
188. Modern Pharmaceutics, Fifth Edition, Volume 1: Basic Principles and
Systems, edited by Alexander T. Florence and Juergen Siepmann
189. Modern Pharmaceutics, Fifth Edition, Volume 2: Applications and
Advances, edited by Alexander T. Florence and Juergen Siepmann
190. New Drug Approval Process, Fifth Edition, edited by Richard A.Guarino
191. DrugDeliveryNanoparticulateFormulationandCharacterization,editedby
Yashwant Pathak and Deepak Thassu
192. Polymorphism of Pharmaceutical Solids, Second Edition, edited by Harry
G. Brittain
193. OralDrugAbsorption:PredictionandAssessment,SecondEdition,edited
by Jennifer J. Dressman, hans Lennernas, and Christos Reppas
194. Biodrug Delivery Systems: Fundamentals, Applications, and Clinical
Development, edited by Mariko Morista and Kinam Park
195. Pharmaceutical Process Engineering, Second Edition, edited by Anthony
J. Hickey and David Ganderton
196. Handbook of Drug Screening, Second Edition, edited by Ramakrishna
Seethala and Litao Zhang
197. Pharmaceutical Powder Compaction Technology, Second Edition, edited
by Metin Celik
198. Handbook of Pharmaceutical Granulation Technology, Dilip M. Parikh
199. Pharmaceutical Preformulation and Formulation: A Practical Guide from
Candidate Drug Selection to Commercial Dosage Form, Second Edition,
edited by Mark Gibson
200. International Pharmaceutical Product Registration, SecondEdition, edited
by Anthony C. Cartwright and Brian R. Matthews
201. Generic Drug Product Development: Bioequivalence-International
Regulatory Requirements, edited by Leon Shargel and Isadore Kanfer
202. Proteins and Peptides: Pharmacokinetic, Pharmacodynamic, and
Metabolic Outcomes, edited by Randall J. Mrsny and Ann Daugherty
Proteins and Peptides
Pharmacokinetic, Pharmacodynamic,
and Metabolic Outcomes
edited by
Randall J. Mrsny
University of Bath
Bath, UK
Ann Daugherty
Genentech
South San Francisco, California, USA
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Proteinsandpeptides:pharmacokinetic,pharmacodynamic,andmetabolicoutcomes
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ISBN-13:978-1-4200-7806-0(hardcover:alk.paper)
ISBN-10:1-4200-7806-2(hardcover:alk.paper) 1. Proteins—Therapeuticuse.
2. Proteins—Metabolism.3. Peptidedrugs. I.Mrsny,RandallJ.,1955-II.
Daugherty,AnnL.,1954-III.Series:Drugsandthepharmaceuticalsciences,202.
[DNLM:1. Peptides—pharmacokinetics.2. Proteins—pharmacokinetics.3. Drug
DeliverySystems—methods.4. DrugDiscovery—methods.5. Peptides—therapeutic
use.6. Proteins—therapeuticuse. W1DR893Bv.2022009/QU55P96452009]
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Preface
The promise of biotechnology and an increased understanding of the human
genome have resulted in an explosion of protein and peptide therapeutics
entering research and development pipelines in biopharmaceutical as well as
traditional pharmaceutical companies. Increasingly, these protein and peptide
candidates are being designed to address previously untreatable diseases and
conditions. To advance these molecules into clinical trials, however, an under-
standing of their pharmacokinetic, pharmacodynamic, and metabolic fate is
required.Thestudyoftheseeventsrepresentsemergingdisciplineswithissues
and challenges distinct from those of small molecules, on which many of the
principles of these fields were initially developed.
That many of the protein and peptide therapeutics being evaluated are
endogenous or emulate an endogenous material potentially defines preestab-
lishedpharmacokinetic,pharmacodynamic,andmetabolicparametersforthese
moleculesinthehumanmodel.Unfortunately,orfortunately,initialpreclinical
testing of potential protein and peptide therapeutics requires obtaining infor-
mationonsafetyandpreclinicalefficacyin(typically)severalnonhumananimal
models. Such studies are complicated, or rather compromised, by the fact that
nonhumanmodelsmaynotexpresscriticalelementssuchasreceptors,binding
proteins, and enzyme activities that function to define pharmacokinetic, phar-
macodynamic, and metabolic parameters in humans. Additionally, human
disease states being emulated, but never fully recapitulated, in nonhuman ani-
mal models may or may not faithfully describe conditions that will be con-
fronted in the clinic. All of these issues are further complicated by the fact that
these peptide and protein therapeutic candidates must be formulated for long-
term storage stability and delivered at concentrations and in locations that are
likely very different from endogenous events.
Most protein and peptide therapeutics are administered by injection,
usually being formulated with a strategy to minimize the frequency of these
injections.Inthisregard,recentstudieshaveidentifiedseveralalternativeroutes
ofadministrationforproteinsandpeptidesthatwerepreviouslynotconsidered
a viable option for delivery. Although the size and labile nature of protein and
peptide therapeutic candidates typically impede their passage across most
biological barriers, intranasal and pulmonary delivery for therapeutic proteins
and peptides is now a commercial reality. Additionally, tremendous progress
has been made for the delivery of proteins and peptides via transdermal and
oral routes as well as delivery to the eye and brain. All of these routes pose
unique pharmacokinetic, pharmacodynamic, and metabolic challenges for the
proteinorpeptidebeingdelivered,eachofwhichmightbealteredinthehuman
model of disease relative to the nonhuman models initially examined.
The chapter topics that follow were selected to provide an overall road-
mapforunderstandingourcurrentunderstandingofparametersthatdefinethe
pharmacokinetic, pharmacodynamic, and metabolic challenges for the delivery
vii
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viii Preface
of protein or peptide therapeutics. In general, these chapters recite lessons
learnedforthemajorareasofproteinsandpeptidetherapeuticsthathavebeen
successfully taken to market, for example, antibodies, interleukins, interferons,
growth factors, and peptide hormones. Additionally, chapters have been
includedthatexploreinnovationsforproteinandpeptidedeliverythatinclude
needle-lessdeliveryandstrategiestodeliverthesemoleculestolocationssuchas
the eye and brain. Although all of the chapters were written with a forward-
lookingperspective,withthegoalofidentifyingissuesthatarelikelytobecome
increasingly important in the future. It is hoped that the information shared in
thesechapterswillprovidethereaderwithanincreasedunderstandingofissues
critical for successfully guiding a protein or peptide therapeutic candidate
through the maze of issues that define the pharmacokinetics, pharmacody-
namics, and metabolism of these molecules.
We would like to take this opportunity to again thank our authors, who
representkeycontributorsintheseareas,fortheexpertisethattheyhaveshared.
Itisoursincerewishthattheknowledgeputforthinthefollowingchapterswill
have a positive impact on the development of new drugs that will improve
health and alleviate suffering.
RandallJ.Mrsny
AnnDaugherty
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Contents
Preface . . . . vii
Contributors . . . . xi
1. In Vitro/In Vivo Correlations of Pharmacokinetics, Pharmacodynamics,
and Metabolism for Hematologic Growth Factors and Cytokines 1
Graham Molineux and Stephen J. Szilvassy
2. In Vitro–In Vivo Correlations of Pharmacokinetics, Pharmacodynamics,
and Metabolism for Antibody Therapeutics 15
C. Andrew Boswell, Rong Deng, Kedan Lin, Wendy S. Putnam, Cherry Lei,
Frank-Peter Theil, Amita Joshi, Paul J. Fielder, and Leslie A. Khawli
3. In Vitro/In Vivo Correlations of Pharmacokinetics, Pharmacodynamics,
and Metabolism for Extracellular Matrix–Binding Growth Factors 53
Matthew A. Nugent, Maria Mitsi, and Jean L. Spencer
4. Metabolic Processes at Injection Sites Affecting Pharmacokinetics,
Pharmacodynamics, and Metabolism of Protein and Peptide
Therapeutics 80
Randall J. Mrsny
5. Local Tissue Responses to Polymer Implants Affecting
Pharmacokinetics, Pharmacodynamics, and Metabolism
of Proteins and Peptides 106
James M. Anderson and William G. Brodbeck
6. Engineering as a Means to Improve the Pharmacokinetics
of Injected Therapeutic Proteins 129
Mark S. Dennis, Yik A. Yeung, Henry B. Lowman, and Robert F. Kelley
7. Ophthalmic Delivery of Protein and Peptide Therapeutics;
Pharmacokinetics, Pharmacodynamics, and Metabolism
Considerations 163
Arto Urtti
8. Pharmacokinetic and Pharmacodynamic Aspects of Intranasal
Delivery 173
Henry R. Costantino, Anthony P. Sileno, Mike Templin, Chingyuan Li,
Diane Frank, Gordon C. Brandt, and Steven C. Quay
ix
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x Contents
9. Oral Delivery of Protein and Peptide Therapeutics: PK/PD and
Metabolism Considerations 192
Puchun Liu and Steven Dinh
10. Drug Interaction Studies of Therapeutic Biologics: Protein and Peptide
Actions and Interactions That Alter Their Pharmacokinetics,
Pharmacodynamics, and Metabolism 207
Iftekhar Mahmood
11. Intersection of Pharmacogenomics with Pharmacokinetics and
Pharmacodynamics 225
Cecile M. Krejsa, Emmanuel Monnet, and David Cregut
Index . . . . 251
