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.

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.