Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development-Industry Case Studies.

In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug-drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions.

Alternative to LRRK2-IN-1 for Pharmacological Studies of Parkinson's Disease.

BACKGROUND/AIMS: LRRK2 (leucine-rich repeat protein kinase 2) is one of the most commonly accepted genes associated with Parkinson's disease (PD). The overexpression of disease-associated mutations in LRRK2 is toxic to the cells, while reduction or elimination of LRRK2 expression promotes cell health and growth. Thus, the identification of an LRRK2 inhibitor with good physiochemical and pharmacokinetic properties is of great interest for the treatment of PD. METHODS: In this study, we have investigated LRRK2 compounds, LRRK2-IN-1 and Compound 1, in vitro and in vivo to determine how suitable they are as a selective LRRK2 tool compound. RESULTS: We report that Compound 1, patented by GSK, is a potent and selective LRRK2 inhibitor with good blood-brain barrier permeability as reflected by its high brain to plasma ratio in rats. In addition, Compound 1 can significantly promote neurite outgrowth in a primary cortical culture, indicating an optimistic cellular function of this compound in a biological system. In contrast, LRRK2-IN-1 is a less selective LRRK2 inhibitor and has low brain penetration. Furthermore, LRRK2-IN-1 is cyto- and genotoxic, while Compound 1 does not exhibit any toxicity. CONCLUSIONS: These results suggest that Compound 1 may be a superior tool compound than LRRK2-IN-1 to advance future pharmacological research on LRRK2.

Behavioural effects and kinetics in brain in response to inhalation of constant or fluctuating toluene concentrations in the rat.

The toxicity of exposure by inhalation to organic solvents may not only be related to the total external dose, but also to the pattern of exposure. In this study the impact of the exposure scenario on the behavioural effects of the model solvent toluene in rats was investigated. Rats were exposed for 7.5h to either a constant concentration or fluctuating concentrations at total external dose levels of 20,000ppmh and 10,000ppmh. Different effects on measures of visual discrimination performance were observed in rats exposed to a constant or fluctuating concentrations, and when rats were tested immediately or sometime after the end of exposure to fluctuating concentrations. Motor activity was also differently affected by different exposure scenarios. Physiologically based toxicokinetic (PBTK) modelling was used to predict the toxicokinetics of toluene induced by these different exposure scenarios. The model was calibrated by measuring toluene concentrations in blood and brain during and after exposure. The results show that the acute effects of toluene on behaviour do not depend only on the concentration and duration of exposure, but primarily on the pattern of exposure.

Application of physiologically based toxicokinetic modelling to study the impact of the exposure scenario on the toxicokinetics and the behavioural effects of toluene in rats.

The toxicity of inhalatory exposure to organic solvents may not only be related to the total external dose, but also to the pattern of exposure. In this study physiologically based toxicokinetic (PBTK) modelling has been used to study the impact of the exposure scenario on the toxicokinetics and the behavioural effects of the model solvent toluene in rats. After construction of the model with parameters from literature, toxicokinetic data were collected from rats exposed to either a constant concentration or fluctuating concentrations at total external dose levels of 20,000 and 10,000 ppm x h for model validation. At the same exposure conditions the effects on learned performance were evaluated in separate groups of rats using a visual discrimination task. In general, the PBTK model provided reliable predictions of the toxicokinetics of toluene at different exposure scenarios, but it also tended to underestimate the blood and brain concentrations in the descending parts of the tissue concentration-time curves. At these high dose levels the differences in toxicokinetics between the constant and the fluctuating exposure groups were relatively small. The visual discrimination experiments demonstrated a slowing of response speed and disinhibition of responding in all toluene-exposed groups. The results suggest that the brain concentration of toluene is one of the major determinants of its effect on disinhibition of responding.