Early Clinical Development

The primary goals in early clinical development are to establish safety, PK, and pharmacodynamics, and also to provide guidance on a dose range expected to be efficacious, in both single-dose and multiple-dose studies. The dose range for Phase I studies is usually fairly wide because of the uncertainties with respect to interspecies scaling and lack of predictability based on preclinical data. The plasma drug concentration time profiles are used to determine AUC, half-life, Cmsx, tmax, dose-proportionality, and extent of accumulation upon multiple dosing. In the absence of PK data from intravenous dosing, interpretation of PK data from a non-intravenous dosing route must be done carefully to avoid erroneous conclusions.

Two general types of biopharmaceutic studies are often conducted in order to assess the comparability and suitability of products for their intended clinical use. A relative BA study is a relative comparison of two or more formulations with respect to PK properties, normally AUC, Cmax, tmax and half-life. Such BA studies are usually done early in a drug's development cycle before significant experience has been gained in human subjects, normally to assess the relative performance of a new formulation as compared with a reference. For example, a solution dosage form may be used for Phase I studies because of the need for dosing flexibility, but eventually a switch to a solid dosage form is desired. In order to compare the relative exposure from each formulation at a given dose (or range of doses), a two-way crossover BA study could be performed in a small number of subjects and the BA of the test formulation determined relative to the reference formulation. Because of the limited number of subjects used in this type of study, the study tends not to be sufficiently powered to establish statistical equivalence among various formulations but the data can be used to guide development decisions or to support a formulation change in a non-pivotal clinical study. Relative BA studies can also be used to evaluate the effect of an alternate route of administration on the drug's PK profile, evaluate drug product variables (e.g., particle size of the API) on clinical performance or to screen for effects of physiological factors (fed vs. fasted state, gastric pH effects) affecting drug absorption.

Another type of study that may be conducted in the course of drug development is an absolute BA study, which is a comparison of AUC of a test formulation to the intravenous route, which is considered to have a BA of 100%. These types of studies are extremely valuable yet not always done because of limitations related to feasibility of developing an intravenous formulation for a highly insoluble drug substance.

A bioequivalence study, on the other hand, is a distinct type of BA study with the objective of assessing statistical equivalence among different treatment groups. These studies are typically done at or before a stage of development in which the clinical data will be generated to establish the efficacy of the drug. The criteria for establishing bioequivalence are much more strict than with a relative BA study and include a statistical assessment of PK parameters including AUC, Cmax, tmax, and half-life. The number of subjects required for this type of study is higher than that required for a relative BA study. The actual number for any individual drug candidate is dependent on the desired statistical power as well as the variance of the measures (e.g., AUC). For example, a drug with a large degree of variability in AUC would require more subjects to establish bioequivalence than a drug with less variability, and a desire for a higher degree of statistical confidence in the results (power of the study) would also require inclusion of a greater number of subjects. Bioequivalence studies may be conducted to switch a formulation during a Phase III clinical study, to establish equivalence of a generic product to the respective branded product, or to support manufacturing changes postapproval (FDA, 1995; FDA, 2000). The reader is referred to Chapter 8.

Pharmacokinetic studies are also done at various stages of the drug development process to assess factors other than formulation that could impact a drug's physiological behavior. As mentioned previously, the GI tract is a complex system that includes not only biological membranes but also fluid, pH modifiers, food, enzymes, and bile salts. The interplay of these variables can alter the way a drug is absorbed from a dosage form. PK studies to assess effects of food (fasted vs. high or low-fat meal) are used to establish whether any dosing restrictions relative to meal time need to be included on a drug product's label. Dosing with a meal can impact absorption either positively or negatively depending on the nature of the drug and the mechanism of interaction. For example, a high fat meal or secretion of bile salts in the small intestine may serve to solubilize a lipidic drug. The GI pH can also be altered in the presence of food and could potentially impact the disintegration/dissolution of a pH-sensitive API. Food-effect studies are described in Chapter 10.

The pH in the GI tract can not only be affected by food but also by physiological differences among patients (normal stomach pH varies normally between pH 1 and 5) or concomitant administration of pH-modifying agents (Lui et al., 1986). The previous discussion of compound ionization and absorption highlights the need to understand and control any pH effects that influence the dissolution and absorption rates. For compounds with potential for showing pH-dependent absorption, a human PK study to evaluate the effect of pH modification (e.g., using preadministration of an H2-receptor antagonist) on AUC and Cmax may be appropriate. These PK studies to screen for pH effects can be performed preclinically in animals, and/or during clinical development. The data from such a study can be used to guide additional formulation optimization to minimize the pH-liability.

A drug-drug interaction study is another type of clinical PK study that is typically performed on a clinical drug candidate to assess the impact of concomitant administration of other drugs on the PK behavior of the drug of interest. Interactions can arise due to metabolic factors (CYP450 interactions, enzyme induction) or competition for an active transporter. Results from in vitro screens can be used to assess the risk of drug interactions due to a CYP-related mechanism and to design meaningful clinical drug-drug interaction studies.

A variety of additional specialized PK studies can be performed to evaluate differences in physiology in special populations on drug product performance. Examples of special populations include children, renally impaired patients, and the elderly, in which the PK may be significantly altered relative to typical adult human subjects based on differences in metabolism and clearance. In these populations, dose and/or dosing regimens may need to be adjusted to account for any differences. The description of these types of studies are beyond the scope of this chapter.

During the early phases of drug development, numerous studies are done to build a fundamental understanding of the qualitative and quantitative nature of what the body does to a drug (PK) in addition to what the drug does to the body (safety and efficacy). The biopharmaceutics knowledge gained in early development can be used as a basis for designing clinical efficacy trials. A fundamental understanding of the biopharmaceutics properties early in the drug development process allows the development scientist to evaluate a comprehensive and integrated set of data and design development strategies that are meaningful and appropriate for any individual compound.

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