Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase

ABSTRACT: The Veliparib absorption was high. Dosed radioactivity was widely distributed in rat tissues. The majority of drug-related material was excreted in urine as unchanged drug (approximately 54, 41, and 70% of the dose in rats, dogs, and humans, respectively). A lactam M8 and an amino acid M3 were two major excretory metabolites in animals. In the circulation of animals and humans, veliparib was the major drug-related component, and M8 was one of the major metabolites. Monooxygenated metabolite M2 was significant in the rat and dog, and M3 was also significant in the dog. Veliparib biotransformation occurred on the pyrrolidine moiety via formation of a lactam, an amino acid, and an N-carbamoyl glucuronide, in addition to oxidation on benzoimidazole carboxamide and sequential glucuronidation. In vitro experiments using recombinant human cytochrome P450 (P450) enzymes identified CYP2D6 as the major enzyme metabolizing veliparib with minor contributions from CYP1A2, 2C19, and 3A4. Veliparib did not inhibit or induce the activities of major human P450s. Veliparib was a weak P-glycoprotein (P-gp) substrate, showing no P-gp inhibition. Taken together, these studies indicate a low potential for veliparib to cause clinically significant P-gp or P450-mediated drug-drug interactions (DDIs). Overall, the favorable dispositional and DDI profiles of veliparib should be beneficial to its safety and efficacy

The Influence of Repair Pathways on the Cytotoxicity and Mutagenicity Induced by the Pyridyloxobutylation Pathway of Tobacco-Specific Nitrosamines

Tobacco-specific nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N′-nitrosonornicotine (NNN), are considered to be human carcinogens. Both compounds are metabolized to pyridyloxobutylating intermediates that react with DNA to form adducts such as 7-[4-(3-pyridyl)-4-oxobut-1-yl]-guanine (7-pobG), O2-[4-(3-pyridyl)-4-oxobut-1-yl]-cytosine (O2-pobC), O2-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxythymidine (O2-pobdT), O6-[4-(3-pyridyl)-4-oxobut-1-yl]-2′-deoxyguanosine (O6-pobdG) and 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing adducts. The role of specific DNA adducts in the overall genotoxic activity of the pyridyloxobutylation pathway is not known. One adduct, O6-pobdG, is mutagenic. To characterize the mutagenic and cytotoxic properties of pyridyloxobutyl DNA adducts, the impact of DNA repair pathways on the cytotoxic and mutagenic properties of the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) was investigated in Chinese hamster ovary (CHO) cell lines proficient or deficient in O6-alkylguanine DNA alkyltransferase (AGT), deficient in both AGT and base excision repair (BER), or deficient in both AGT and nucleotide excision repair (NER). The repair of the four pyridyloxobutyl DNA adducts was determined in the same cell lines via sensitive LC-MS/MS methods. NNKOAc was more cytotoxic in the cell lines lacking AGT, BER and NER repair pathways. It also induced more mutations in the hprt gene in the BER and NER deficient cell lines. However, AGT expression did not influence NNKOAc’s mutagenicity despite efficient repair of O6-pobdG. Analysis of the hprt mutational spectra indicated that NNKOAc primarily caused point mutations at AT base pairs. GC to AT transition mutations were a minor contributor to the overall mutation spectrum, providing a rationale for the observation that AGT does not protect against the overall mutagenic properties of NNKOAc in this model system. The only adduct affected by the absence of effective NER was O2-pobdT. Slower repair of O2-pobdT in NER deficient cells was associated with increased AT to TA transversion mutations, supporting the hypothesis that these mutations are caused by O2-pobdT. Together, these data support a hypothesis that the pyridyloxobutylation pathway generates multiple mutagenic and toxic adducts

Automatic Position Detection and Posture Recognition of Grouped Pigs Based on Deep Learning

The accurate and rapid detection of objects in videos facilitates the identification of abnormal behaviors in pigs and the introduction of preventive measures to reduce morbidity. In addition, accurate and effective pig detection algorithms provide a basis for pig behavior analysis and management decision-making. Monitoring the posture of pigs can enable the detection of the precursors of pig diseases in a timely manner and identify factors that impact pigs’ health, which helps to evaluate their health status and comfort. Excessive sitting represents abnormal behavior when pigs are frustrated in a restricted environment. The present study focuses on the automatic recognition of standing posture and lying posture in grouped pigs, which shows a lack of recognition of sitting posture. The main contributions of this paper are as follows: A human-annotated dataset of standing, lying, and sitting postures captured by 2D cameras during the day and night in a pig barn was established, and a simplified copy, paste, and label smoothing strategy was applied to solve the problem of class imbalance caused by the lack of sitting postures among pigs in the dataset. The improved YOLOX has an average precision with an intersection over union threshold of 0.5 (AP0.5) of 99.5% and average precision with an intersection over union threshold of 0.5–0.95 (AP0.5–0.95) of 91% in pig position detection; an AP0.5 of 90.9% and an AP0.5–0.95 of 82.8% in sitting posture recognition; a mean average precision with intersection over union threshold of 0.5 (mAP0.5) of 95.7% and a mean average precision with intersection over union threshold of 0.5–0.95 (mAP0.5–0.95) of 87.2% in all posture recognition. The method proposed in our study can improve the position detection and posture recognition of grouped pigs effectively, especially for pig sitting posture recognition, and can meet the needs of practical application in pig farms

Considerations and recommendations for assessment of plasma protein binding and drug-drug interactions for siRNA therapeutics

At the time of writing, although four siRNA therapeutics have been approved for human use, no official regulatory guidance specific to this modality is available. In the absence of guidance, preclinical development for siRNA followed a hybrid of the small molecule (ICH M3(R2)) and biologics (ICH S6(R1)) guidance documents. However, siRNA differs significantly from small molecules and protein-based biologics in both its physicochemical and absorption, distribution, metabolism and excretion (ADME) properties, and its mechanism of action. Consequently, certain reports typically included in filing packages for small molecule or biologics may benefit from adaption, or even omission, from an siRNA filing. In this white paper, members of the ‘siRNA plasma protein binding and drug-drug interaction working group’ in the IQ consortium discuss the relevance of two such reports---the plasma protein binding (PPB) evaluation and the drug-drug interaction (DDI) risk assessment---to support siRNA regulatory filings. Publicly available siRNA approval packages and the literature were systematically reviewed to examine the role of siRNA PPB and DDIs in ADME, safety and translation. This information has been summarized into two decision trees to help guide industry to decide when siRNA PPB and DDI studies are warranted

Mitigating the Metabolic Liability of Carbonyl Reduction: Novel Calpain Inhibitors with P1′ Extension

Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer’s disease (AD). 2-(3-Phenyl-1<i>H</i>)-pyrazol-1-yl)­nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and <i>in vivo</i> efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays. Using cytosolic clearance as a tailored <i>in vitro</i> ADME assay coupled with <i>in vitro</i> hepatocyte metabolism enabled the identification of analogues with enhanced stability against carbonyl reduction. These efforts led to the identification of P1′ modified calpain inhibitors with significantly improved pharmacokinetic profile including P1′ <i>N</i>-methoxyamide <b>23</b> as potential candidate compound for non-central nervous system indications