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1949stone

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[资源] Biopharmaceutics Modeling and Simulations

The aim of this book is to provide a systematic understanding of biopharmaceutical
modeling. Probably, this is the first book challenging this difficult task.
Biopharmaceutical modeling demands a wide range of knowledge. We need
to understand the physical theories, the physiology of the gastrointestinal tract,
and the meaning of drug parameters. This book covers the wide range of scientific
topics required to appropriately perform and evaluate biopharmaceutical
modeling. In this book, oral absorption of a drug is mainly discussed. However,
the same scientific framework is applicable for other administration routes such
as nasal and pulmonary administrations.
Oral absorption of a drug is a complex process that consists of dissolution,
precipitation, intestinal wall permeation, and gastrointestinal transit. In addition,
drug metabolism can also occur in the intestinal wall and the liver before drug
molecules enter into systemic circulation.
Historically, a reductionist approach has been taken to understand the oral
absorption of a drug. Each process of oral absorption was reduced to its subprocesses
up to the molecular level. However, understanding each piece of the puzzle
is insufficient in understanding the whole picture of oral absorption. It is critically
important to reconstruct the whole process of oral absorption and understand the
interrelationship between each piece that comprises oral absorption of a drug.
In the field of biology, computational systems biology has been emerging
since the millennium [1]. In systems biology, the interactions between biological
molecules are investigated in both reductionist and constitutive approaches
tunderstand the quantitative relationship between a disease state and each molecular
process. In this book, a similar approach is applied for the oral absorption
of a drug.
In the first section of this book, the whole picture of oral absorption is discussed.
As the central dogma of oral drug absorption, the interplay of dissolution
rate, solubility, and permeability of a drug is discussed in a comprehensive manner
without using mathematics. Even though the discussion in the first section
is only a conceptual and qualitative outline, correct understanding of this central
dogma will be of great benefit for drug discovery and development. The central
dogma of oral drug absorption is the basis of the biopharmaceutical classification
system (BCS), which is widely used in drug discovery and development [2].
We then move forward to each theory that comprises the entire oral absorption
model. In this book, the entire mathematical framework is called the “gastrointestinal
unified theoretical framework (GUT framework).” The concept of
“concentration” is first discussed in detail, as it is critically important for understanding
biopharmaceutical modeling. Then, theories of solubility, dissolution,
precipitation, membrane permeation, and drug metabolisms are discussed. Each
theory is described based on the unified definition of drug concentration and then
incorporated into the GUT framework.
We then move forward to the physiological and drug property data that is
used for biopharmaceutical modeling. The quality of biopharmaceutical modeling
heavily relies on the quality of input data. The input data are roughly categorized
into drug property and physiological parameters. These data are reviewed from
the viewpoint of their use in biopharmaceutical modeling.
Before moving on to the discussions about practical applications of biopharmaceutical
modeling in drug research, the validity of biopharmaceutical modeling
is critically reviewed. A step-by-step approach has been taken to validate the
biopharmaceutical modeling employing Occam’s razor as a leading principle.
As the applications of biopharmaceutical modeling in drug research, biopharmaceutical
classification system, dose/particle size dependency prediction,
selection of solid form and enabling formulation, food effect prediction, etc. are
then discussed.
Next, the strategy to use biopharmaceutical modeling in drug research and
regulatory application is discussed. Introduction of good simulation practice for
biopharmaceutical modeling would be an emergent issue for regulatory application.
Many figures and tables are provided to make it easy to understand biopharmaceutical
modeling. In addition, more than 900 references are cited. I hope that
readers will enjoy reading this book and that this book will be a helpful reference
for biopharmaceutical modeling.
I would like to thank Mr. Jonathan Rose of John Wiley & Sons, Inc. for giving
me this opportunity to write a book about biopharmaceutical modeling.
I would like to thank Dr. Takashi Mano and Dr. Ravi Shanker for carefully
reading my manuscript and giving me valuable advice. They also supported the
investigation of biopharmaceutical modeling at Pfizer. I also thank Dr. Brian
Henry, Dr. Mark McAllister, and Ms. Nicola Clear for their kind support at
Pfizer. The scientific discussion with the Pfizer biopharmaceutics group members
improved my understanding of this subject. The suggestions from Prof.
Steve Sutton, Dr. Kazuko Sagawa, and Ms. Kelly Jones about in vivo physiology
are greatly appreciated. Ms. Joanne Bennett kindly lectured me about the cell
culture models. I would like to thank Dr. Claudia da Costa Mathews, Dr. Hannah
Pearce, Dr. Sue Mei Wong, Mr. Simon Pegg, Mr. Neil Flanagan, Mr. Mike
Cram, Mr. Unai Vivanco, Ms. Sonia Patel, and Mr. Richard Manley for investigating
the enabling formulations and physchem screening. I would like to thank
the Pfizer Pharmaceutical Science members for supporting and inspiring me to
pursue the sciences and practical drug research work. I would like to thank Dr.
Tomomi Mastuura for her instructions about pharmacokinetics. I would like to
thank Dr. Stefan Steyn for implementation of biopharmaceutical modeling in
early drug discovery.
Thanks also goes to the Pfizer Nagoya Pharm R&D members. Mr. Shohei Sugimoto,
Dr. Toshiyuki Niwa, Dr. Naofumi Hashimoto, Mr. Akinori Ito, Dr. Takashi
Kojima, Mr. Omura Atsushi, and Mr. Morimichi Sato kindly taught me solid-state
chemistry and enabling formulations. I would like to thank Mr Arimich Okazaki,
Mr. Yohei Kawabata, Ms. Keiko Kako, Dr. Sumitra Tavornvipas, Ms. Akiko
Suzuki, Ms. Tomoko Matsuda, and Ms. Shiho Torii for kindly working together
toward progress of the science at the Nagoya site.
I would like to thank Dr. Ryusuke Takano of Chugai Pharm. for his excellent
works on biopharmaceutical sciences. I also would like to thank the Chugai
physicochemical and pharmacokinetics group members, especially Mr. Hirokazu
Hamada, Dr. Noriyuki Takata, Dr. Akiko Koga, Mr. Ken Goshi, Dr. Kazuya
Nakagomi, Mr. Ro Irisawa, Ms. Harumi Onoda, Dr. Hidetoshi Ushio, Dr. Yoshiki
Hayashi, Dr. Yoshiaki Nabuchi, Dr. Minoru Machida, and Dr. Ryoichi Saito. They
brought me up as an industrial scientist. I would like to thank Dr. Ken-ichi Sakai
and Mr. Kouki Obata for working with me toward progress of the sciences at
Chugai.
I would like to thank Dr. Alex Avdeef for finding a young scientist at a
rural countryside in Japan and introducing him to the world. I greatly appreciate
the kind support from the UK physicochemical scientist community, especially,
Dr. John Comer, Dr. Karl Box, Dr. Alan Hill, Dr. Nicola Colclough, Dr. Toni
Llinas, Dr. Darren Edwards, and other scientists. Their kind support made my
UK life enjoyable and fruitful. I would also like to thank Prof. Amin Rostamihochaghan,
Dr. David Turner, Dr. Sibylle Neuhoff, and Dr. Jamai Masoud of
SimCYP. I would like to thank Prof. Per Artursson, Dr. Manfred Kansy, Dr.
Bernard Faller, Dr. Edward Kerns, and Dr. Li Di for discussions about PAMPA.
I would like to thank Dr. Lennart Lindfors for constructive discussions.
I greatly appreciate the mentorship of Prof. Katsuhide Terada and Prof. Shinji
Yamashita. I also would like to thank Dr. Makoto Kataoka and Dr. Yoshie
Masaoka for the collaboration works.
Finally, I would like to express my greatest thanks to my wife, Hitomi.Without
her dedicated support, I could not have gone through the tough task of writing a
book like this. I sincerely dedicate this book to her.
Kiyo Sugano

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