CHAPTER 1
DRUG PHARMACOKINETICS AND TOXICOKINETICS

1.1 INTRODUCTION

Pharmacokinetics (PK) is the science that describes the time-course of drug concentration in the body resulting from administration of a certain drug dose. Similarly, toxicokinetics (TK) is the science that investigates how the body handles toxicants as illustrated by its plasma profile at various time points. In comparison, pharmacodynamics (PD) is the science that describes the relationship of the time-course of drug concentration and its effects in the body [1, 2].

PK is considered a biomarker of drug exposure as well as marker of efficacy and safety. Key determinants of the pharmacokinetics of a drug include absorption, distribution, metabolism, and elimination (ADME) [3]. Discovering novel therapeutic agents is an increasingly time-consuming and costly process. Most estimates indicate that it takes approximately 10-15 years and more than $1.2 billion to discover and develop a successful drug product [4]. It is well established that poor drug PK is one of the leading causes of compounds failure in preclinical and clinical drug development [5]. For example, attrition due to poor pharmacokinetics contributed to 10% of the attrition reported for compounds developed by the pharmaceutical industry in 2001 (Figure 1.1) [6].

Figure 1.1 The contribution of various factors to the overall attrition of NCEs in year 2001.

Kola and Landis 2004 [6]. Reproduced with permission of Nature Publishing Group.

Compounds with poor PK profile tend to have low oral systemic plasma exposure and high interindividual variability, which limits their therapeutic utility (Figure 1.2) [7]. Therefore, a better understanding of the PK profile early on enables the discovery of compounds with drug-like properties [8]. In drug discovery settings, the main outcomes of PK/TK assessments are to

• select compounds with the maximum potential of reaching the target;
• determine the appropriate route of administration to deliver the drug (typically oral);
• understand how the drug blood levels relate to efficacy or toxicity in order to choose efficacious and safe doses;
• facilitate appropriate dose sections for rodent and/or nonrodent species in toxicology testing and drug safety evaluation;
• decide on the frequency and duration of dosing in order to maintain adequate drug concentration at target for disease modification; and
• accurately predict the PK in humans profile prior to clinical studies.

Figure 1.2 The relationship between drug oral bioavailability and interindividual variability reported as coefficient of variation (%).

Hellriegel et al. 1996 [7]. Reproduced with permission of John Wiley & Sons.

A PK/TK study involves dosing animals or humans with NCE and collect blood samples at predefined time points. After sample preparation and quantification, a concentration-time profile is generated (Figure 1.3). In drug discovery, preliminary PK studies are usually conducted in rodents to evaluate the extent of drug exposure in vivo. These rodent studies are commonly followed by studies in nonrodents such as dogs or monkeys to better characterize the PK profile of the compound and to support safety risk assessment studies. Pharmacokinetic scaling, also known as allometry, is a discipline that was extensively used in the past to predict human PK profile using preclinical data and in predicting the drug human half-life, dose, and extent of absorption. This approach is based on empirical observations that various physiological parameters are a function of body size. The allometric methods assume that the same metabolic and disposition processes in the species evaluated are correlated with those observed in humans. However, the cytochrome P450 enzymes in the rat are not the same as those in humans, and thus, may exhibit altered disposition of the compound or even produce different metabolite patterns (see Chapter 2) [9, 10]. Similarly, uptake and efflux transporters in the animal species may differ in substrate specificity or rate, as compared to humans, and thus may confound predictions of human PK [11]. Accurate prediction of human pharmacokinetic profile is imperative to minimize drug failure in development due to pharmacokinetic liability. More detailed description of methods in predicting human PK is beyond the scope of this chapter, but can be found in many excellent reviews [12-15]. An in-depth discussion of various PK concepts and their applications can be found in various references [16, 17].

Figure 1.3 Estimation of the area under the plasma concentration-time curve (AUC).

1.2 TOXICITY ASSESSMENT IN DRUG DISCOVERY AND DEVELOPMENT

Several toxicology studies are conducted during early drug discovery and all the way to the late stages of drug development before a new drug application (NDA) filing is made. In spite of comprehensive toxicity assessment in early- and late-stage discovery, attrition of NCEs in clinical studies is not uncommon owing to disconnect in predictions of risk in humans based upon preclinical data obtained from cell culture and animal models. Nevertheless, extensive preclinical assessment and appropriate scaling and modeling tools will improve predictions. In general, the correlation between human and animal toxicities is good for conditions such as cardiovascular, hematological, and gastrointestinal diseases and the poorest correlation for adverse drug reactions such as idiosyncratic reactions, skin rash, hypersensitivity, and hepatotoxicity. Toxicology testing in drug discovery is initiated by the high-throughput screening, which is followed up by definitive tests. Screening refers to the methods that yield rapid and comprehensive data often using in vitro tools. The origin of any toxicological or safety outcome is multifactorial and complex and thus demands for use of sophisticated systems for definitive assessment. Thus, many pharmaceutical companies are also introducing in vivo (i.e., animals) toxicology studies as early as possible, quite often in the lead optimization (LO) stage. Extensive and appropriate toxicology studies of varying duration ranging from acute, single dose to chronic, repeat dose in rodent and nonrodent species are needed to establish safe human clinical trials. Acute toxicity (single dose-ranging) studies in preclinical species are performed to support selection of a drug candidate for potential advancement to repeat-dose toxicology studies and ultimately to enable initial FIH clinical trials. The objective of such studies is to identify a dose at which the major adverse effects are observed. These studies are usually carried out in rodents, following a single dose up to a limit of 2000 mg/kg. The information obtained may be translated to select the dose levels for the first in-human studies and also to give an indication of potential effects of acute overdose in humans.

Early drug development starts with candidate compound selection. Repeat-dose toxicity studies (7-14 days in duration) in both rodent and nonrodent species are used to better refine safety margins, PK/PD modeling, and set appropriate dosages for the subsequent good laboratory practice (GLP) 1-month general toxicology and safety pharmacology (i.e., cardiovascular testing in a nonrodent; CNS and respiratory function tests in a rodent) studies that proceeds the investigational new drug (IND) application before starting FIH clinical trials. Toxicokinetic assessment is based on the multiple samples obtained throughout the duration of the study along with the PK data. Such data are critical to define a margin of safety between the no observed adverse effect level (NOAEL) and the projected plasma concentrations achieved in human. It is generally considered that a 100-fold safety factor (rodent-to-human exposure ratio) from the most sensitive species NOAEL provides good safety margin in clinical studies. However, our enhanced capability of understanding interspecies sensitivity and detecting more and more subtle effects may warrant a more flexible approach. The toxicology assessment profile includes, for example, the maximum tolerated dose (MTD), safety margins and therapeutic index, target organ toxicities, most sensitive preclinical species, and reversibility of an effect/toxicity. Biomarkers characterization and preclinical to clinical translation can also be investigated in these GLP toxicology studies.

Later drug development includes Phases I-IV. Phase I (FIH) starts with a single dose escalation, then multiple dosing in normal healthy subjects. These studies are used to establish human safety profile and MTD. Phase II defines the efficacy/safety of candidate profile in target patient population (e.g., rheumatoid arthritis), drug-drug interactions, and proof of concept (POC) before proceeding into Phase III. Several repeat-dose toxicology studies (general toxicology, embryo-fetal and developmental, fertility, juvenile, carcinogenicity) of longer duration (3 months and up to 2 years) in both rodent and nonrodent species are conducted to support clinical trials of longer duration in patients.

The purpose of this chapter is to introduce the fundamentals of PK and TK, and their applications to drug discovery and development. It also presents the fundamentals of computational analysis of the data derived from the estimated concentrations in the biological matrices such as plasma. Finally, the implications of species differences, genomics, and exposure of the metabolites in determining the safe dose in the first...