Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors. Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety. It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans. Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes. The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU. This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes.

Estimating the starting dose for entry into humans: principles and practice.

BACKGROUND: Selection of the starting dose for the entry into humans (EIH) study is an essential first step in clinical drug development. OBJECTIVES: This paper is a review of different approaches that may be used to calculate the starting dose, presents the results of a current practice survey that reflect practice patterns at a large pharmaceutical company, and discusses selected topics related to the calculation of the starting dose. RESULTS: The methods used in the field of oncology for cytotoxic compounds are usually derived from a dose associated with some toxicity in animals multiplied by a safety factor. In therapeutic areas other than oncology, methods may be classified as four different approaches: (1) dose by factor methods that utilize the no observable adverse effect level (NOAEL) from pre-clinical toxicology studies multiplied by a safety factor; (2) the similar drug approach that may be used when clinical data are available for another compound of the same chemical class as the investigational drug; (3) the pharmacokinetically guided approach that uses systemic exposure rather than dose for the extrapolation from animal to man; and (4) the comparative approach that consists of utilizing two or more methods to estimate a starting dose and then critically comparing the results to arrive at the optimal starting dose. A "real-life" example illustrates the use of each method. Advantages, limitations, and underlying assumptions of each of the methods are discussed. The results of the survey showed that the pharmacokinetically guided approach is the most commonly used method, followed by dose by factor methods. CONCLUSION: The task of estimating the starting dose is moving beyond empirical methods to those that are increasingly more systematic and theory based.