In Vitro Lipolysis Model to Predict Food Effect of Poorly Water-Soluble Drugs Itraconazole, Rivaroxaban, and Ritonavir.

It is desirable to predict positive food effect of oral formulations due to food mediated dissolution enhancement of lipophilic drugs. The objective was to assess the ability of in vitro lipolysis to anticipate a positive food effect. Tested formulations included rivaroxaban and itraconazole, where some formulations, but not all, exhibit a positive food effect in vivo in humans. Amorphous solid dispersion formulations of ritonavir, which exhibit a negative food effect in vivo in humans, were also studied. Fe-lipolysis and Fa-lipolysis media representing fed and fasted intestinal conditions were used. Results show frequent agreement between in vitro lipolysis predictions and in vivo human outcomes. For rivaroxaban, food effect of unformulated active pharmaceutical ingredient (API) and products were correctly predicted where 2.5 mg and 10 mg strengths did not show any food effect; however, 20 mg did show a positive food effect. For itraconazole, all four products were correctly predicted, with Sporanox, Sempera, and generic capsules having a food effect, but Tolsura not having a positive food effect. For ritonavir, lipolysis predicted a positive food effect for API and Norvir tablet and powder, but Norvir products have negative food effect in vivo in humans. Overall, the lipolysis model showed favorable predictability and merits additional evaluation.

A robust, viable, and resource sparing HPLC-based logP method applied to common drugs.

Reliable, experimentally determined partition coefficient P (logP) for most drugs are often unavailable in the literature. Many values are from in silico predictions and may not accurately reflect drug lipophilicity. In this study, a robust, viable, and resource sparing method to measure logP was developed using reverse phase high performance liquid chromatography (RP-HPLC). The logP of twelve common drugs was measured using calibration curves at pH 6 and 9 that were created using reference standards with well-established logP. The HPLC method reported here can be used for high throughput estimation of logP of commonly used drugs. LogP values here showed general agreement with the other few HPLC-based literature logP values available. Additionally, the HPLC-based logP values found here agreed partially with literature logP values found using other methodologies (±10%). However, there was no strong agreement since there are few experimentally determined literature logP values. This paper shows a facile method to estimate logP without using octanol or computational approaches. This method has excellent promise to provide reliable logP values of commonly used drugs available in literature. A larger pool of reliable logP values of commonly drugs has promise to improve quality of medicinal chemistry and pharmacokinetic (PK) models.

Applicability of the grip strength and automated von Frey tactile sensitivity tests in the mouse photothrombotic model of stroke.

Improvement of impaired neurological function(s) is a primary endpoint in experimental stroke recovery studies, making the choice and nature of the functional tests crucial for proper execution and interpretation of such studies. Currently, there are a limited number of neurological tests which reliably evaluate functional deficit in mice over a long period of time after stroke. In this study, we evaluated the applicability of forepaw grip strength and automated von Frey tactile sensitivity tests to assess forelimb dysfunction in mice following photothrombosis in the sensorimotor cortex, and compared them with two well-established tests, grid-walking and cylinder, for up to 21days after stroke. Our results indicate that the length of time required to conduct the two new tests is comparable to that of the grid-walking and cylinder tests, however the data from the new tests is obtained and ready for analysis upon completion of the testing session. In addition, our observations indicate that the automated von Frey test detected substantial and sustained deficit in the withdrawal threshold of the mice on all evaluation days after stroke, whereas the forepaw grip strength test was only marginally sensitive to document functional impairment. Our data demonstrate that the automated von Frey tactile sensitivity test is a time efficient and sensitive method which can be used together with other established tests to evaluate long-term functional outcome in the mouse photothrombotic stroke model.