The preclinical development stage encompasses aspects of both drug discovery and drug development. The process to identify a potential drug candidate is an iterative one, as discovery scientists strive to synthesize candidate compounds with appropriate activity and maximal potency at the intended target, maximal safety profile, and desirable ADME properties. The definition of "desirable" properties will be variable considering the therapeutic target and class of compounds, but typical goals are to minimize frequency of dosing, maximize BA, avoid interactions with efflux transport systems (e.g., P-gp) and metabolic enzymes (CYPs), reach target organ or tissue (particularly important for CNS activity), and avoid adverse effects (e.g., for oncology compounds to maximize delivery to the tumor and minimize to healthy tissues). Depending on the desired therapeutic action, the target blood concentration-time profile must be considered with respect to Cmax, tmax, AUC, clearance, accumulation, and dose proportionality. Species effects are also an important consideration since ADME can often be species-specific and therefore the performance in humans may not be readily predictable from animal data.
In vitro/ex vivo techniques to assess ADME properties include in vitro CYP screens to assess potential for metabolic liabilities and drug interactions, transporter screens against known targets and efflux pumps, in vitro metabolism in the presence of isolated hepatocytes or microsomes (various species to assess inter-species differences), and transport across cell culture model systems as surrogates for passive membrane transport. These screens are used to eliminate candidates with a high potential for ADME liabilities that could negatively impact utility in a clinical setting. Preclinical ADME studies in vivo using various animal models are also necessary to assess blood concentration-time profiles, AUC, BA, Cmax, tmax, dose proportionality, accumulation upon multiple dosing or enzyme induction. Intravenous delivery is necessary for determining absolute BA, clearance, and volume of distribution. Specialized studies can be designed to better understand the fundamental mechanisms of intestinal absorption, including bile-duct cannu-lation to look for biliary excretion and portal vein studies to evaluate extent of absorption and first-pass metabolism.
The physical-chemical properties of the drug candidate, such as solubility, stability, and lipophilicity, influence the in vivo performance and must be considered for any drug candidate (Venkatesh and Lipper, 2000). The solubility affects the choice of dosing vehicle used in preclinical testing and is often a major challenge, with many drug candidates having solubility at best in the low |g/mL range and requiring nonaqueous solvents for administration. In some cases, pharmacologic effects resulting from the dosing vehicle can become dose-limiting or confound the in vivo results. Stability of compounds is another factor that must be evaluated as it affects the integrity of the material being dosed, could potentially lead to generation of degradants with distinct pharmacologic action or toxicity, and also impacts the handling and shelf-life of a pharmaceutical product. As with solubility, standard criteria for acceptable stability are difficult to define absolutely. Specific requirements are defined depending on the route of administration, safety concerns with degradants, and potential for stabilization of the drug compound in a formulation using appropriate excipients.
Often referred to as "developability" or "drugability," these biopharmaceutical criteria have become increasingly important in the choice of drug candidates (Sun et al., 2004). While achieving high in vitro target potency is critical, highly potent compounds with poor biopharmaceutical performance may not be able to achieve the desired therapeutic effect under practical dosing conditions. As discussed previously, there is no set of standard criteria for developable candidates, but rather the complete package of data must be assessed by the entire project team so that they consider all of the interrelated factors and can ultimately decide whether a particular compound with specific and selective receptor binding activity also has potential to be a safe and efficacious therapeutic agent for treatment of a disease in a patient. In addition, the therapeutic area and medical need influence recommendations on developable candidates (e.g., dosing frequency). For example, dosing four times daily may be acceptable for a life-threatening illness for which no other treatment is available, while it may not be acceptable for a chronic-use medication for which patient compliance is critical.
Was this article helpful?
Now if this is what you want, you’ve made a great decision to get and read this book. “How To Cure Yeast Infection” is a practical book that will open your eyes to the facts about yeast infection and educate you on how you can calmly test (diagnose) and treat yeast infection at home.