Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the opportunity to integrate key input parameters from different sources to not only estimate PK parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. Using examples from the literature and our own company, we have shown how PBPK techniques can be utilized through the stages of drug discovery and development to increase efficiency, reduce the need for animal studies, replace clinical trials and to increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however, some limitations need to be addressed to realize its application and utility more broadly.

Optimising drug properties can be an important strategy to limit penetration into the CNS and offers advantages in reducing the risk of undesirable neurological effects When considering the design of these drugs it is important to consider the relative influx and efflux rates at the relevant biological membranes The highest degree of restriction at the brain is probably achievable by utilising active transport to exclude compounds from the brain Affinity for the efflux transporters Pgp and BCRP has been achieved in two in-house chemistry programmes by increasing polar surface area, which resulted in highly orally bioavailable low CNS penetrant compounds in preclinical species.

ABSTRACT:The relationship between rat pharmacokinetics and physicochemical parameters [the partition coefficient between octanol and buffer at pH 7.4 (log D (7.4) ) and pK a ] was studied for a series of tetrahydropyran compounds. Sixteen compounds ranging in log D (7.4) 0.1 to 1.8 were administered intravenously to rats, and the pharmacokinetic parameters were determined from blood concentration time curves. Across the series, a weak correlation was observed between log D (7.4) and blood clearance, suggesting that log D (7.4) values less than 0.5 were required to prevent clearance at hepatic blood flow. In terms of the volume of distribution (V d ), the compounds fell into three distinct subseries characterized by the number of basic centers and differences in ionization of each basic center at physiological pH. These were referred to as the monobasic, weak second base, and strong second base subseries. All the compounds exhibited V d greater than body water, as would be expected from their lipophilic and basic nature. For a given clog P, the strong second base subseries showed higher V d than the weak second base subseries, which in turn exhibited higher values than the monobasic subseries. In addition, for the weak second base subseries, V d could be tuned by modulating the pK a of the second basic center. This relationship was rationalized in respect to the interactions of the ionizable centers with phospholipid heads in the cell membrane and/or lysosomal trapping. Compounds in the weak second base subseries showed optimal V d , and when combined with a log D (7.4) of 0.1, driving to moderate blood clearance, one compound showed the optimal pharmacokinetic profile.The optimization of absorption, distribution, metabolism, and excretion properties and prediction of human pharmacokinetics have become important parts of the early selection process in drug discovery. It is well known that the physicochemical properties of a molecule (lipophilicity, molecular weight, hydrogen bonding potential, and pK a ) influence the pharmacokinetic profile of a molecule, and the desirable absorption, distribution, metabolism, and excretion properties have been defined (Smith, 2001;van De Waterbeemd et al., 2001). In this article, we describe how the modulation of lipophilicity and pK a within a series of tetrahydropyran (THP) histamine type 3 receptor (H 3 ) antagonists was used to optimize rat pharmacokinetic parameters and to select an appropriate compound for further progression.The objective of the H 3 antagonist program was to rapidly accelerate a candidate compound to proof-of-concept studies in allergic rhinitis. For the disease target in question, an orally administered compound with a once/twice-daily dosing regimen was key to development. Neither central nervous system penetration nor central nervous system exclusion was requisite in the candidate as the site of action was peripheral. In-house medicinal chemistry resulted in the identification of a number of potent H 3 antagonists containing a THP core (Figs. 1 and 2)...

Based on the human PK data obtained from the microdose study and subsequent modelling, PF-05089771 provided the best opportunity to explore Nav1.7 blockade for the treatment of acute or chronic pain conditions.

Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain.