Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1.

Purpose: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models.

Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models.

Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper.

Purpose: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window.

Effects of mineral oil administration on the pharmacokinetics, metabolism and pharmacodynamics of atorvastatin and pravastatin in mice and dogs.

We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that facilitated the characterization of the main metabolite (M1) of atorvastatin, a lipophilic statin, in C57BL/6NCrl mice. The chemical structure of M1 in mice was confirmed as ortho-hydroxy β-oxidized atorvastatin.

The effectiveness of quality control samples in pharmaceutical bioanalysis.

The use of quality control (QC) samples in bioanalysis is well established and consistent with regulatory guidance. However, a systematic evaluation of whether QC samples serve the intended purpose of improving data quality has not been undertaken. The Translational and ADME Sciences Leadership Group (TALG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) conducted an evaluation to assess whether closer agreement is observed when comparing pharmacokinetic data from two passed runs, than when comparing data from failed and passed (retest) runs.

Overcoming analytical challenges to generate data critical to understanding lipid nanoparticle-delivered modified mRNA biodistribution.

Chemically modified mRNA offers a novel approach to treat disease. Due to susceptibility to extracellular nucleases , dosed modified mRNA therapeutics can benefit from encapsulation within novel delivery systems, such as lipid nanoparticles (LNPs). To understand the holistic effect of dosing LNP-encapsulated modified mRNA therapeutics can require bioanalysis of several components including the mRNA, protein and LNP.

Feedback from the European Bioanalysis Forum liquid microsampling consortium: microsampling: assessing accuracy and precision of handheld pipettes and capillaries.

Microsampling in preclinical pharmacokinetics (PK) studies is currently widely adopted across the pharmaceutical industry. The European Bioanalysis Forum liquid microsampling consortium member companies assessed the accuracy and precision of handheld pipettes and microcapillaries at volumes of less than 10 μl. The following key factors on pipetting performance were also evaluated: Pipette type (positive displacement, air displacement and microcapillary), experience of user and the liquid type.

Feedback from the European Bioanalysis Forum liquid microsampling consortium: capillary liquid microsampling and assessment of homogeneity of the resultant samples.

Following the completion of a detailed experimental protocol into the potential inhomogeneity of capillary liquid microsamples, which was performed at seven European Bioanalysis Forum member companies, the summary and conclusion on the data are reported here. It has been demonstrated that it is possible to generate homogeneous samples using these microsampling techniques; that the resultant microsamples can be accurate and precise and that capillary liquid microsampling data can be consistent with conventional larger volume plasma samples. However, the data contain some variability which is contributed to by the different range of experiences that each investigating site had with these techniques.

Validation of an ultrasensitive LC-MS/MS method for PTH 1-34 in porcine plasma to support a solid dose PK study.

Background: The bioanalysis of Teriparatide (PTH 1-34) is extremely challenging due to the low plasma concentrations present at a therapeutic level. An LC-MS/MS-based method was developed that detected PTH 1-34 at 15 pg/ml in porcine plasma, and was validated using the bioanalytical method validation guidelines.

Results: The analytical methodology demonstrated good linearity over a range of 15-1000 pg/ml, and demonstrated good precision and accuracy.