**1. Introduction**

The intention of this chapter is to provide an overview of how pharmacokinetics, also termed PK, is applied in early drug development. Since, PK is defined as the study of the effects of

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

a living organism on an administered drug, the majority of pharmacokinetic studies involve the measurement of a specific compound in an easily sampled physiological fluid, like blood, plasma, serum and on occasion, in saliva. Excreted substances are also measured in urine or feces. In some rarer situations, measurements are made with more invasive sampling methods, such as a tissue biopsy, cerebral spinal fluid, bronchoalveolar lavage fluid, or middle ear effusion fluid. Regardless of the sample type, the measured concentrations are regarded as indicative of the concentrations at the specific site of action for the drug. Even excreted drug data can be used to describe the PK within the body; drug excretion rates into urine are recognized as proportional to plasma concentrations at midpoints of the collection interval, and amounts of drug in urine and feces can give some idea of excretion pathways. Series of drug concentrations measured in biological fluids over an adequate amount of time give the pharmacokinetic scientist a 'window' into the body, and by analyzing the time course of concentrations, information on the unseen drug in the various body compartments can be inferred. Thus, applied pharmacokinetics are useful in various types of pharmacological evaluations, be it for academic purposes, clinical research (inside and outside of drug development), or in clinical medicine (individualized dosing and therapeutic drug monitoring) [1–3].

**Figure 1**) [9, 10]. However these three phases do not encompass the entirety of the research for any given new drug: nonclinical research starts prior to Phase 1, and post-marketing studies (sometimes referred to as Phase 4) continue after Phase 3 and medicines regulatory agency's approval. Once a new chemical entity (NCE), a new molecular entity (NME), a new biological entity (NBE), a new active substance (NAS) or a new therapeutic entity (NTE) [11], also called investigational product (IP), or in general for this chapter, a new drug, is identified and the minimum *in vitro* and animal data are gathered, and after filing an application with the appropriate regulatory agency, a promising substance can start clinical research [12]. For sake of clarity, an overview of the three phases of studies is given below and the roles of PK data are highlighted. Phase 1 studies (some exploratory studies are also called Phase 0) in clinical drug development are described as the initial introduction of the drug into humans, in small numbers of healthy subjects (if appropriate), starting at lower doses and escalating as safe to therapeutic ranges and super therapeutic ranges if possible. The reasons for studying higher doses, if deemed safe to do so, can be multi-faceted. Confirming safety at higher doses helps determine a margin of safety around the efficacious doses, and aids in determining the clinical relevance of any drug–drug- and drug-disease-interactions, or special population differences that may be elucidated later. Pharmacokinetics over a wider range leads to the ability to correlate drug effects (therapeutic or adverse) with drug exposure, and to characterize these relationships [13]. The aforementioned safety margin also allows the drug sponsor some flexibility in determination of the final marketed dose if necessary. Phase 1 also includes specific studies designed to study special populations, such as the elderly, children, in people

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**Figure 1.** Phases of drug development built on pharmacokinetics.

While there are readily available printed and online materials on pharmacokinetic topics such as its technical terms, model definitions and calculation methods [4–5]; there are some gaps when it comes to how the science of pharmacokinetics is used in drug development. Several authors however, have touched on various aspects and a reader of this chapter may gain additional knowledge by consulting them [6–8]. Most healthcare workers and scientists are relatively familiar with the clinical pharmacology and medicine package inserts which include a pharmacokinetic section of an approved drug's labeling. This section of the package insert gives the general information that has been gleaned from large amounts of research and helps the practitioner or scientist understand the general absorption, distribution, metabolism, and elimination of a given therapeutic agent. In essence, this is only a short summary of what is known about this drug. Not readily apparent from the short summary is the role that pharmacokinetics had from the start of a drug's development through its approval journey. Through the application of pharmacokinetics, the maximum information can be extracted from data when only a few subjects are available as in a first in human (FIH) clinical study and then this information is applied to the design and interpretation of the next study during the drug's development phase. Furthermore, even before the first clinical human study is conducted, pharmacokinetic and toxicological data from animals can be used to predict human pharmacokinetics and to assist in the determination of a safe starting dose and the optimal study design. In fact, the reader will note that the continual theme in this chapter is that pharmacokinetic data and their interpretation in the first study is important in obtaining additional pharmacokinetic, safety, and efficacy information a subsequent study, and so on, throughout the drug development process. In the following pages, various types of PK evaluations and/or studies are described.

### **2. Pharmacokinetics and early drug development**

Clinical drug development, meaning drug research in human subjects, is generally described in three phases, each comprised of a number of different clinical studies, Phases 1, 2, and 3, (see **Figure 1**) [9, 10]. However these three phases do not encompass the entirety of the research for any given new drug: nonclinical research starts prior to Phase 1, and post-marketing studies (sometimes referred to as Phase 4) continue after Phase 3 and medicines regulatory agency's approval. Once a new chemical entity (NCE), a new molecular entity (NME), a new biological entity (NBE), a new active substance (NAS) or a new therapeutic entity (NTE) [11], also called investigational product (IP), or in general for this chapter, a new drug, is identified and the minimum *in vitro* and animal data are gathered, and after filing an application with the appropriate regulatory agency, a promising substance can start clinical research [12]. For sake of clarity, an overview of the three phases of studies is given below and the roles of PK data are highlighted.

a living organism on an administered drug, the majority of pharmacokinetic studies involve the measurement of a specific compound in an easily sampled physiological fluid, like blood, plasma, serum and on occasion, in saliva. Excreted substances are also measured in urine or feces. In some rarer situations, measurements are made with more invasive sampling methods, such as a tissue biopsy, cerebral spinal fluid, bronchoalveolar lavage fluid, or middle ear effusion fluid. Regardless of the sample type, the measured concentrations are regarded as indicative of the concentrations at the specific site of action for the drug. Even excreted drug data can be used to describe the PK within the body; drug excretion rates into urine are recognized as proportional to plasma concentrations at midpoints of the collection interval, and amounts of drug in urine and feces can give some idea of excretion pathways. Series of drug concentrations measured in biological fluids over an adequate amount of time give the pharmacokinetic scientist a 'window' into the body, and by analyzing the time course of concentrations, information on the unseen drug in the various body compartments can be inferred. Thus, applied pharmacokinetics are useful in various types of pharmacological evaluations, be it for academic purposes, clinical research (inside and outside of drug development), or in

58 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

clinical medicine (individualized dosing and therapeutic drug monitoring) [1–3].

**2. Pharmacokinetics and early drug development**

While there are readily available printed and online materials on pharmacokinetic topics such as its technical terms, model definitions and calculation methods [4–5]; there are some gaps when it comes to how the science of pharmacokinetics is used in drug development. Several authors however, have touched on various aspects and a reader of this chapter may gain additional knowledge by consulting them [6–8]. Most healthcare workers and scientists are relatively familiar with the clinical pharmacology and medicine package inserts which include a pharmacokinetic section of an approved drug's labeling. This section of the package insert gives the general information that has been gleaned from large amounts of research and helps the practitioner or scientist understand the general absorption, distribution, metabolism, and elimination of a given therapeutic agent. In essence, this is only a short summary of what is known about this drug. Not readily apparent from the short summary is the role that pharmacokinetics had from the start of a drug's development through its approval journey. Through the application of pharmacokinetics, the maximum information can be extracted from data when only a few subjects are available as in a first in human (FIH) clinical study and then this information is applied to the design and interpretation of the next study during the drug's development phase. Furthermore, even before the first clinical human study is conducted, pharmacokinetic and toxicological data from animals can be used to predict human pharmacokinetics and to assist in the determination of a safe starting dose and the optimal study design. In fact, the reader will note that the continual theme in this chapter is that pharmacokinetic data and their interpretation in the first study is important in obtaining additional pharmacokinetic, safety, and efficacy information a subsequent study, and so on, throughout the drug development process. In the following pages, various types of PK evaluations and/or studies are described.

Clinical drug development, meaning drug research in human subjects, is generally described in three phases, each comprised of a number of different clinical studies, Phases 1, 2, and 3, (see Phase 1 studies (some exploratory studies are also called Phase 0) in clinical drug development are described as the initial introduction of the drug into humans, in small numbers of healthy subjects (if appropriate), starting at lower doses and escalating as safe to therapeutic ranges and super therapeutic ranges if possible. The reasons for studying higher doses, if deemed safe to do so, can be multi-faceted. Confirming safety at higher doses helps determine a margin of safety around the efficacious doses, and aids in determining the clinical relevance of any drug–drug- and drug-disease-interactions, or special population differences that may be elucidated later. Pharmacokinetics over a wider range leads to the ability to correlate drug effects (therapeutic or adverse) with drug exposure, and to characterize these relationships [13]. The aforementioned safety margin also allows the drug sponsor some flexibility in determination of the final marketed dose if necessary. Phase 1 also includes specific studies designed to study special populations, such as the elderly, children, in people

**Figure 1.** Phases of drug development built on pharmacokinetics.

with hepatic or renal impairment. In these studies, pharmacokinetic endpoints are the primary goal, allowing relatively small studies (low numbers of subjects) to inform the future Phase 2 and 3 studies and marketing after approval. The results of these studies are reflected in the approved drug's labeling, where warnings about the use in certain disease-states or dosage adjustments are communicated.

[14]. A thorough Phase I study to determine QTc prolongation and potential for cardiac arrhythmias (if not characterized already in earlier studies) should not be run until some idea of the clinical doses and exposures are determined and after a few studies have shown some

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Pharmacokinetic analyses types can be broken into two general approaches: compartmental and non-compartmental. Non-compartmental analyses are a series of calculations that estimate the exposures and elimination properties of a drug with very few assumptions about the particular mechanisms involved. Non-compartmental exposure parameters (such as area under the concentration-time curve (AUC) and the maximum exposure (Cmax) can be calculated and are interpretable when no other PK information is available; these parameters indicate the amount of drug in the body and for how long it is there, and the peak concentra-

Compartmental methods can be described as the determination of a mathematical expression, or model, which adequately describes the PK of a given drug. On the most basic level, these models consist of the mathematical description representing the body as one or a series of hypothetical volume compartments which drug distributes into and out of, or from which it is eliminated. These models not only describe the PK properties of a drug, but can be predictive of PK at different dose levels or administration conditions. Complex models aid in the elucidation of smaller processes which make up the PK in its entirety, such as the rate and capacity

The process of fitting PK data to a given mathematical description, or model, is known as compartmental modeling. This modeling is carried out with specialized software applications and [15, 16] **Figure 2** shows the simplest one-compartment PK model where drug is introduced by an intravenous bolus injection into a representative volume compartment and the differential and integrated equations that can be fitted to actual data to determine the values of the constants as defined. Multiple-compartment PK models, such as a 2-compartment model, or a 3-compartmental model, commonly describe a concentration-time course adequately, but more complex models may contain more compartments. The mathematical models are based on the processes which move drug into or out of the compartments; these may be a constant rate of infusion or elimination (a zero-order kinetic process) or concentration-driven diffusion processes (first-order kinetics) or by saturable active transport or metabolic processes (Michaelis–Menten kinetics), or combinations thereof [17–19]. The intention of a compartmental model can be as straightforward as to find the simplest model which describes the PK and predicts drug exposures under new conditions, like a higher dose, or when administered in multiple doses over time, or when administered under a different route

of the different metabolism pathways involved in a drug's elimination.

promise for the drug's future approval.

**3. Pharmacokinetic analyses**

**3.1. Compartmental pharmacokinetics**

tion that is achieved.

In Phase 2 studies of clinical drug development, the objective is not only to determine that a drug continues to be safe but that it remains to be safe when used in patients with the disease it is intended for to treat. The information gathered in Phase 2 serves the dual purpose of studying safety and efficacy while providing proof to the sponsor that the drug is worthy of further development. The pivotal Phase 2 study for continuation of Phase 2 and/ or starting Phase 3 is often called 'Proof of Concept (POC).' The value of PK measurements in Phase 2 adds another layer of understanding how the body processes the drug; these studies determine differences in PK data between categories of patients, namely those with the targeted disease and normal healthy volunteers. Sometimes patients will have higher or lower exposures of a drug due to the difference in ability to absorb a drug, or the drug may be eliminated differently due to the disease state. In general, the more the patient is affected/ weakened by the disease, the more PK will differ from healthy subjects. Knowledge of the PK in the patient population forms a bridge to knowledge of safety and perhaps efficacy gathered in Phase 1. Phase 2 PK facilitates any need for dose adjustments to achieve safety or efficacy. PK correlations with efficacy can begin in earnest once patient data is available; this data along with the Phase 1 data is modeled and simulations using those models assist in choosing the Phase 3 dose ranges.

Phase 3 in clinical drug development consists of several large studies in patient populations designed to collect further safety data, to observe possible adverse events which occur only rarely, to continue to evaluate efficacy and compare with current therapies for the indication, and to guide its use once approved and on the market. However, clinical research does not necessarily come to a halt at the end of Phase 3. After approval and marketing, additional studies may be run by the sponsor to establish marketing claims and to seek new indications. Adverse event data are continually collected to identify even rarer adverse events not uncovered in Phase 3. Phase 3 PK data is usually performed only as a few samples in many subjects or complete profiles in a subset of subjects; this data is for confirmatory purposes, used in correlation with efficacy or adverse events. This data is added to the ongoing modeling (discussed later in Section 3.1) to discern sources of variability in the PK data from the patient population.

The above descriptions of each phase of drug development may seem as though each phase precedes sequentially, one starting after the end of the other; however this may not always be the case. While typically the end of Phase 2 commences the beginning of Phase 3, the other phases may overlap in time. This is mainly to conserve research and development resources. For instance, the longer animal studies and reproductive toxicity studies may not run until the results are needed to support the Phase I and II studies for drugs that may require longer treatment durations or research in women of child-bearing potential (WOCBP), respectively [14]. A thorough Phase I study to determine QTc prolongation and potential for cardiac arrhythmias (if not characterized already in earlier studies) should not be run until some idea of the clinical doses and exposures are determined and after a few studies have shown some promise for the drug's future approval.
