Translational ADMET for Drug Therapy

Principles, Methods, and Pharmaceutical Applications

Souzan B. Yanni

• Publisher: Wiley-Interscience
• Year: 2015
• Print ISBN:
  9781118838273
• eBook ISBN:
  9781118838327
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Serving as a practical handbook about ADMET for drug therapy, this book presents effective technologies, methods, applications, data interpretation, and decision-making tactics for pharmaceutical and preclinical scientists. Chapters cover case studies and in vivo, in vitro, and computational tools for drug discovery and development, with new translational approaches to clinical drug investigations in various human populations.

• Illustrates ADME properties, from bedside to bench and bench to bedside, for the design of safe and effective medicine in human populations
• Provides examples that demonstrate the integration of in vitro, in vivo, and in silico data to address human PKPD and TKTD and help determine the proper therapeutic dosage
• Presents successful tools for evaluating drugs and covers current translational ADMET with regulatory guidelines
• Offers a hands-on manual for researchers and scientists to design and execute in vitro, in silico, preclinical, and clinical studies
• Includes discussion of IND / NDA filing and drug labeling to support drug registration and approval

Chapter 1
Translational Concept and Determination of Drug Absorption

1.1 Drug Absorption, Mechanism, and Its Impact on Drug Bioavailability, Drug Disposition, and Drug Safety

Discovery, development, and approval of a new drug is a long process that takes on average 12–14 years and costs an average of about $1.8 billion [1]. The financial burden and time for bringing to the market a new medicine are considered as major challenges in the pharmaceutical industry. In addition, the decrease in the number of truly innovative therapeutic areas that have been approved by the regulatory authorities around the globe was a reflection of higher attrition in late-stage drug development (Phase 2 and 3), despite the advancement of new technologies. However, the high-throughput screening; structure activity relationship (SAR) using absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties; and target efficacy-based molecular and cell biology in collaboration with advanced medicinal and combinatory chemistry have increased the number of drug candidates successfully reaching Phase 1 due to better preclinical characterization and improved ADMET properties. For example, the Phase 2 success rates for drug candidates have fallen from 28% in 2006 to 18% in 2009, with ∼50% of success to progressing through Phase 2. The decrease in Phase 2 is mainly due to insufficient efficacy, undesired side effects, and/or poor pharmacokinetics (PK) of the newly developed drug, which account for 51% of the drug failures [2–4]. Therefore, correct prediction of the efficacy of novel drug candidates especially in the early stage preclinical phases is crucial.

The accurate assessment of absorbed drug dose, exposure, and disposition in in vitro and in preclinical animal models that translate to human clinical data may improve the success rate of bringing a needed medicine to the stage of reaching human patients.

For the drug to be absorbed in the intestine, several processes are involved. First, the physicochemical properties of drugs such as solubility, dissolution rate, lipophilicity, and molecular weight (MW) are major driving parameters for the drug absorption in the gastrointestinal (GI) tract, as a molecule should be in a solution to permeate the intestinal membranes, and the rate at which the molecule gets into the solution impacts its ability to get absorbed. Second, the drug has to cross several physiological parameters before it reaches the bloodstream, such as effect of pH, stomach emptying, intestinal transient time, disease state, age, diet, various GI fluids, and so forth. The sum of physiochemical and physiological parameters can either hinder or facilitate the permeability of a drug in the intestinal sections.

It is important to emphasize here, as the drug absorption will be discussed in detail, that the drug's permeability is indeed the major determinant of its ability to be absorbed in the intestine. The permeability of drugs can be either by a passive diffusion mechanism, following the “rule of 5,” or by an active process driven by the intestinal transporters. Drug transporters can either promote the absorption (by uptake transporters such as OCT, OAT, PepT1, OATP) or hinder the absorption (efflux transporters such as P-gp, MRP2, BCRP).

Last, the drug absorption can be influenced by other significant factors, such as the metabolism by drug-metabolizing enzymes that are expressed mostly in the duodenal section of the small intestine. Thus, the intestinal metabolism, which may also cause drug–drug interactions (DDIs), changes the extent of oral drug absorption. As will be discussed later, effective orally absorbed drug will ensure systemic exposure. Absorption through membranes of the GI tract and metabolism by gut and hepatic metabolism are key players for drug exposure in systemic circulation—that is, oral bioavailability—before it reaches the other body organs.

1.1.1 Drug Absorption and Oral Bioavailability

In ADME processes that exert the pharmacokinetic properties of a new drug, absorption is a process by which a given extravascular dose (EV), that is, an oral dose (PO), reaches the systemic circulation. The absorption of a drug can be described by any drug dose that is administered orally, subcutaneously, intramuscularly, or any other way different from a direct injection into the vascular system. The term oral “bioavailability” (F) is a parameter that is used in pharmacokinetics to quantify the ability of a compound dosed orally to reach the systemic circulation, after surviving any first-pass extraction in the gut and liver. The systemic F can be determined from Equation (1.1):

1.1

where

refers to the area under the curve (AUC) from an oral administration and

refers to the AUC from intravenous (iv) administration. Accordingly, the drug becomes bioavailable when it overcomes the potential barriers to reach the systemic circulation. A compound with

(or 100%) indicates that a given oral dose produces an identical systemic exposure to that observed in the corresponding iv dose, indicating that it is fully absorbed and fully escaped any potential of metabolism in both the gut and liver.

(50%) indicates that in transit from the oral administration site to the systemic circulation, half of the compound is lost; in this case, the oral dose to systemic concentration relationship indicates that the oral dose must be twice that of an equivalent iv dose to achieve a similar systemic exposure.

Although there are several approaches for a drug to become bioavailable, the oral dosing route is the most convenient, well-tolerated, patient-compliant, and cost-effective route of drug administration; however, it is still a complex route of administration, as the absorption from the gut into the systemic circulation may requires consideration to avoid inter- and intrapatient variability in a compound's pharmacokinetic profile [5].

Oral administration,

, can be described as shown in Equation (1.2):

1.2

where

is the fraction of the dose absorbed from the gut, and

,

, and

are the bioavailability of the compound in the intestine, liver, and lung (t...

Table of contents

• Cover
• Title Page
• Copyright
• Table of Contents
• Contributors
• Preface
• Acknowledgement
• Chapter 1: Translational Concept and Determination of Drug Absorption
• Chapter 2: Distribution: Principle, Methods, and Applications
• Chapter 3: Metabolism: Principle, Methods, and Applications
• Chapter 4: Excretion: Principle, Methods, and Applications for Better Therapy
• Chapter 5: Drug–Drug Interaction: From Bench to Drug Label
• Chapter 6: General Toxicology: Principle, Methods, and Applications1
• Chapter 7: Toxicokinetics and Toxicity Testing in Drug Development1
• Chapter 8: PBPK Modeling and In Silico Prediction for ADME and Drug–Drug Interaction
• Chapter 9: Translational Tools toward Better Drug Therapy in Human Populations
• Chapter 10: Phase 1–Phase 3 Clinical Studies, Procedures, Responsibilities, and Documentation
• Chapter 11: Regulatory Submission: MIST and Drug Safety Assessment
• Index
• End User License Agreement