Preclinical Development Preparation for Phase I Clinical Studies

Once a drug candidate is chosen for clinical development, additional biopharma-ceutical assessment is conducted to build on existing knowledge and experience. A clinical candidate must be tested in formal animal safety studies in multiple species in order to establish a safety profile and provide guidance on the choice of clinical doses. For these studies, the dose range is typically much higher than that expected to be used in humans, and this aspect offers some specific challenges with respect to dosing and dose proportionality. Solutions are highly desirable for dosing because they are homogeneous systems that are easy to administer to animals (particularly rodents), offer dose flexibility, and have the potential for maximizing in vivo exposure by avoiding issues with dissolution. However, poorly soluble compounds may lack sufficient solubility to prepare highly concentrated solutions, and pharmaceutically acceptable non-aqueous vehicles or suspensions must be used if a liquid vehicle is necessary. Regardless of the formulation used, maximizing exposure in these studies is important. Because of the high doses that may be used to establish the safety multiples relative to clinical doses, there is potential for saturating transport mechanisms leading to decreased relative exposure with increasing dose. Saturation of metabolic processes could also lead to the opposite problem with sudden increases in relative exposure with increasing dose.

Preclinical in vivo biopharmaceutics studies can also be conducted, if necessary, to evaluate the relative in vivo performance of different API forms (including free acids/bases, salts, polymorphs) and clinical formulations. As discussed above, exposure can be significantly affected by solubility and rate of dissolution, which in turn are influenced by the form of the drug substance and formulation used. In vitro dissolution is a first step in screening API forms and potential clinical formulations. From the formulation perspective, the scientist may be interested in the relative differences in exposure between two different types of formulations (e.g., solution vs. tablet, or tablet vs. liquid-filled capsule) in order to provide insight into the critical factors affecting performance for that particular compound. Absolute predictability of drug product performance in humans based on animal data is not possible considering differences in metabolism and absorption from one species to another. However, preclinical screens are useful for assessing rank orders and gaining insight into the significance of factors such as particle size or dosage form type. An additional consideration for Phase I clinical studies is the relationship between the formulations used in safety and clinical studies and their respective PK behavior since the data from the preclinical safety studies are critical for defining the initial clinical development plan and starting clinical dose (which is determined based on the relative safety multiples established in preclin-ical safety studies).

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