Sex-Biased Expression of Pharmacogenes Across Human Tissues

Individual response to drugs is highly variable and largely influenced by genetic variants and gene-expression profiles. In addition, it has been shown that response to drugs is strongly sex-dependent, both in terms of efficacy and toxicity. To expand current knowledge on sex differences in the expression of genes relevant for drug response, we generated a catalogue of differentially expressed human transcripts encoded by 289 genes in 41 human tissues from 838 adult individuals of the Genotype-Tissue Expression project (GTEx, v8 release) and focused our analysis on relevant transcripts implicated in drug response. We detected significant sex-differentiated expression of 99 transcripts encoded by 59 genes in the tissues most relevant for human pharmacology (liver, lung, kidney, small intestine terminal ileum, skin not sun-exposed, and whole blood). Among them, as expected, we confirmed significant differences in the expression of transcripts encoded by the cytochromes in the liver, CYP2B6, CYP3A7, CYP3A5, and CYP1A1. Our systematic investigation on differences between male and female in the expression of drug response-related genes, reinforce the need to overcome the sex bias of clinical trials.

Sex-biased Expression of Pharmacogenes Across Human Tissues

Individual response to drugs is highly variable and largely influenced by genetic variants and gene-expression profiles. Also, it has been shown that response to drugs is strongly sex-dependent, both in terms of efficacy and toxicity. To expand current knowledge on sex differences in the expression of genes relevant for drug response, we generated a catalogue of differentially expressed human transcripts encoded by 289 genes in 41 human tissues from 838 adult individuals of the Genotype-Tissue Expression project (GTEx, v8 release) and focused our analysis on relevant transcripts implicated in drug response. We have detected significant sex-differentiated expression of 99 transcripts encoded by 59 genes in the tissues most relevant for human pharmacology (Liver, Lung, Kidney, Small intestine terminal ileum, Skin not sun-exposed, and Whole Blood). Among them, as expected, we observed significant differences in the expression of transcripts encoded by the cytochromes in the liver, CYP2B6, CYP3A7, CYP3A5, and CYP1A1. Our systematic investigation on differences between male and female in the expression of drug response related genes, reinforce the need to overcome the sex bias of clinical trials.

Reductive Cytochrome P450 Reactions and Their Potential Role in Bioremediation

Cytochrome P450 enzymes, or P450s, are haem monooxygenases renowned for their ability to insert one atom from molecular oxygen into an exceptionally broad range of substrates while reducing the other atom to water. However, some substrates including many organohalide and nitro compounds present little or no opportunity for oxidation. Under hypoxic conditions P450s can perform reductive reactions, contributing electrons to drive reductive elimination reactions. P450s can catalyse dehalogenation and denitration of a range of environmentally persistent pollutants including halogenated hydrocarbons and nitroamine explosives. P450-mediated reductive dehalogenations were first discovered in the context of human pharmacology but have since been observed in a variety of organisms. Additionally, P450-mediated reductive denitration of synthetic explosives has been discovered in bacteria that inhabit contaminated soils. This review will examine the distribution of P450-mediated reductive dehalogenations and denitrations in nature and discuss synthetic biology approaches to developing P450-based reagents for bioremediation.

How to Interpret an Investigator’s Brochure for Meaningful Risk Assessment: Results of an AGAH Discussion Forum

Purpose A discussion forum was hosted by the Association for Applied Human Pharmacology (AGAH e.V.) to critically debate how to interpret and optimise the Investigator’s Brochure (IB) for meaningful risk assessment of early clinical trials. Materials and Methods Four topics were specifically discussed: deficiencies/uncertainties in IBs, guidance for the investigator, reference safety information, and potential risks for human subjects associated with inadequate non-clinical safety assessment in the IB. In each case, 43 participants took part in a real-time online survey with pre-defined questions to capture the audience’s opinion. Results The ‘Summary of Data and Guidance for the Investigator’ was considered as the section of the IB with the highest need for improvement with emphasis on readability, comprehensibility, timeliness of data, and appropriateness for risk assessment. It was suggested that the IB should at least be signed by the sponsor’s scientist responsible for the content on pharmacology and toxicology. It was agreed that sponsors should consider thoroughly whether changes to an IB constitute a substantial amendment, and that the IB should include a section on the change history. Non-clinical pharmacology studies with negative outcomes should be reported in the IB in order to avoid assessment bias. The reference safety information for expectedness assessment of suspected serious adverse reactions should be provided as a stand-alone section of the IB. Conclusion The overall consensus was that an optimised presentation of data will ensure the best possible understanding of a compound’s characteristics and an optimal benefit-risk assessment which will safeguard the participants in clinical trials.

Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development—A Drug Developer's Perspective

Psychiatric diseases have the lowest probability of success in clinical drug development. This presents not only an issue to address the unmet medical needs of patients, but also a hurdle for pharmaceutical and biotech industry to continue R&D in this disease area. Fundamental pharmacokinetic and pharmacodynamic principles provide an understanding of the drug exposure, target binding and pharmacological activity at the target site of action for a new drug candidate. Collectively, these principles determine the likelihood of testing the mechanism of action and enhancing the likelihood of candidate survival in Phase 2 clinical development, therefore, they are termed as the “three pillars of survival.” Human Phase 1 pharmacokinetic and pharmacodynamic studies provide evidence of the three pillars. Electroencephalogram (EEG) assessments and cognitive function tests in schizophrenia patients can provide proof of pharmacology and ensure that a pharmacological active regimen will be tested in Phase 2 proof of concept (POC) studies for the treatment of cognitive impairment associated with schizophrenia (CIAS).

The Association for Human Pharmacology in the Pharmaceutical Industry London Meeting October 2019: Impending Change, Innovation, and Future Challenges

The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) annual meeting focused on impending change, innovation, and future challenges facing early phase drug development as we move into the second decade of the 21th century. The meeting opened with discussion around the technical revolution in pharmaceutical medicine over the 4 decades since the AHPPI was founded and how transformative technologies have accompanied the introduction of processes such as physiologically based pharmacokinetic modeling. During the meeting examples were presented of how in terms of the development of new therapies, the classic phases of clinical drug development are becoming a thing of the past and the lines between the phases have begun to blur, particularly in the field of oncology. The contribution that monoclonal antibodies have made to medicine and the next chapter in their design and use was also discussed. A representative of the UK’s Medicine and Healthcare Products Regulatory Agency discussed the increasing numbers of requests to approve complex innovative design trials, how novel trial designs are impacting on the traditional linear “phase” approach to drug development and the common pitfalls associated with them. Guidance was provided from a regulator’s viewpoint on what was meant by the term “novel design” and how to submit successful trial applications for such complex trials. In an Oxford-style debate, the audience discussed the motion that “there is no longer a need to include placebo subjects in early clinical trials.” The keynote speaker focused on delivering change in complex environments such as the field of drug development. The afternoon session included presentations on the challenges associated with drug product design, the complexities within non-oral dosage forms and proposed new methods of formulations for drug delivery. Presentations were also given on advances in mechanistic and computational pharmacokinetic modeling and how they have proved to be valuable tools to rationalize and facilitate the process of drug development.

Quorum Sensing in Cyanobacteria and the Origin of Blooms. Lessons for Human Pharmacology

Quorum Sensing (QS) is a bacterial communication system. [...]