The impact of dosing interval in a novel tandem oral dosing strategy: enhancing the exposure of low solubility drug candidates in a preclinical setting.

In drug discovery, time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical or pharmacokinetic properties that limit the in vivo exposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity. This issue is more significant for efficacy and target safety studies where high drug exposures are desired. When solubility issues are confronted, enabling formulations are often required to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. Previously, we introduced a gastrointestinal (GI) transit time-based novel oral tandem dosing strategy that enhanced in vivo exposures in rats. In this study, a refined time interval versus dose theory was tested. The resulting in vivo exposures based on altering frequency and doses were compared, and significant impacts were found.

A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation.

Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), and it is up-regulated in many inflammatory conditions, including but not limited to cancer, arthritis, and multiple sclerosis. LPA signaling causes angiogenesis, mitosis, cell proliferation, and cytokine secretion. Inhibition of autotaxin may have anti-inflammatory properties in a variety of diseases; however, this hypothesis has not been tested pharmacologically because of the lack of potent inhibitors. Here, we report the development of a potent autotaxin inhibitor, PF-8380 [6-(3-(piperazin-1-yl)propanoyl)benzo[d]oxazol-2(3H)-one] with an IC(50) of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role in producing LPA in plasma and at the site of inflammation was tested in a rat air pouch model. The specific inhibitor PF-8380, dosed orally at 30 mg/kg, provided >95% reduction in both plasma and air pouch LPA within 3 h, indicating autotaxin is a major source of LPA during inflammation. At 30 mg/kg PF-8380 reduced inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen. Inhibition of plasma autotaxin activity correlated with inhibition of autotaxin at the site of inflammation and in ex vivo whole blood. Furthermore, a close pharmacokinetic/pharmacodynamic relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound for elucidating LPA's role in inflammation.

Utilizing a novel tandem oral dosing strategy to enhance exposure of low-solubility drug candidates in a preclinical setting.

Time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical drug discovery programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical and pharmacokinetic properties that limit the in vivo exposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity that creates an issue for efficacy and target safety studies, where high drug exposures are desired. When solubility issues are encountered, enabling formulations are often used to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. In our study, two drug candidates with poor aqueous solubility were dosed in rats as simple suspension formulations using a novel tandem dosing strategy, which employs dosing orally in 2.5 h increments up to three times to simulate an oral infusion by avoiding saturation of absorption associated with bolus dosing. These compounds were also dosed using the same suspension formulations and a standard dosing strategy. The resulting in vivo exposures were compared. It was found that this novel tandem dosing strategy significantly improved the in vivo exposures.

Aqueous versus non-aqueous salt delivery strategies to enhance oral bioavailability of a mitogen-activated protein kinase-activated protein kinase (MK-2) inhibitor in rats.

A potent pyridine-containing MK2 inhibitor has recently been internally discovered. In pre-clinical dosing, the low solubility of the neutral form limited oral bioavailability and dose escalation in toxicity studies. A mesylate salt was developed as part of a formulation strategy to enhance both oral bioavailability and dose escalation orally in pre-clinical rat studies. Several non-aqueous systems were used to deliver the mesylate salt, which resulted in varied oral bioavailability. It was found that administration of an aqueous chaser immediately after dosing drastically increased the oral bioavailability of the salt. This finding implies that the quantity of water present in vivo is an important consideration when evaluating salts of free bases with low aqueous solubility in pre-clinical in vivo rat models where limited aqueous vehicle may be presented.