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Welcome to a truly phenomenal Issue of the British Journal of Clinical Pharmacology. In this issue, you will find an excellent state‐of‐the‐art Themed Issue on Immuno‐oncology, ‘guest‐edited’ by BJCP editors, Professor Jennifer Martin from the University of Newcastle in Australia and Professor Lionel Lewis from Dartmouth College and Dartmouth‐Hitchcock Medical Center in New Hampshire, two experienced MD clinical pharmacologists and superb oncology experts. They managed to put together a Themed Issue with nine papers on various (clinical and translational pharmacology‐related) aspects and developments of CAR T‐Cells, Immune Checkpoint Inhibitors as well as the interaction between radiation therapy and the innate immune response. I hope, but secretly I am actually convinced, that you will find all nine papers most interesting and a great way to learn more about immuno‐oncology, even if you might already be an expert in this field.
‘But wait, there is more!’
The September issue of BJCP is not restricted to immuno‐oncology. Below, we summarize most of the other papers that are part of this issue, all important and most definitely worth reading.
In this issue, we have two short contributions from editorial board members that both highlight issues which are most relevant for patient care: an Editorial from Emre Eskazan from Istanbul, Turkey, who discusses the difficulties of treating patients with chronic myeloid leukemia when they also have COVID‐19; and Elena Enioutina from Salt Lake City, UT and Catherine Sherwin from Dayton, OH, detail in their Spotlight Commentary, the growing need to pay attention to toxicity associated with herbal medicines, an important issue that BJCP is paying more and more attention to. In this very issue, a letter to the editor from Bruno Revol et al. from Grenoble, France, describes an interaction between ginger and crizotenib in a patient with lung cancer.
Chronic myeloid leukaemia and the use of tyrosine kinase inhibitors in the days of COVID‐19 pandemic
Ahmet Emre Eşkazan
DOI: 10.1111/bcp.14353
Why we need to pay attention to toxicity associated with herbal medicines
Elena Y. Enioutina, Kathleen M. Job and Catherine M.T. Sherwin
DOI: 10.1111/bcp.14340
Pharmacokinetic herb‐drug interaction between ginger and crizotinib
Bruno Revol, Elodie Gautier‐Veyret, Capucine Arrivé, Nathalie Fouilhé Sam‐Laï, Anne McLeer‐Florin, Hélène Pluchart, Julian Pinsolle and Anne‐Claire Toffart
DOI: 10.1111/bcp.13862
This issue also contains a number of clinical drug development papers:
Kerbusch et al. from Princeton, NJ, applied extensive modeling to data pooled from three randomized controlled trials to better understand the relationship between dose and effect of the IL23p19 monoclonal antibody tildrakizumab in the treatment of moderate to severe chronic plaque psoriasis. Their extensive analysis was boiled down to an easy‐to‐understand message: patients with moderate‐to‐severe psoriasis should receive 100‐mg subcutaneous tildrakizumab every twelve weeks, while patients with a body weight >90 kg may benefit from a higher dose (200‐mg every twelve weeks).
Exposure–response characterisation of tildrakizumab in chronic plaque psoriasis: Pooled analysis of 3 randomised controlled trialsKerbusch
Thomas Kerbusch, Hanbin Li, Russell Wada, Petra M. Jauslin and Larissa Wenning
DOI: 10.1111/bcp.14280
A second dermatology drug development paper comes from Isfahan, Iran. The paper dovetails slightly with Valenti Gomez's paper from London (part of the Themed Issue on Immuno‐oncology) which describes the relationship between radiation therapy and the innate immune response in cancer. In contrast to the paper from Gomez though, which is focused on therapeutic opportunities, Laleh Shariati et al. focus on a side effect from radiotherapy, radiation dermatitis. Their randomized double‐blind placebo‐controlled study demonstrates that doxepin cream prevents dermatitis grade 2 or higher during post‐operative breast irradiation in cancer patients.
Protective effects of doxepin cream on radiation dermatitis in breast cancer: A single arm double‐blind randomized clinical trialShariati
Laleh Shariati, Alireza Amouheidari, Hajar Naji Esfahani, Alireza Abed, Shaghayegh Haghjooy Javanmard, Ismail Laher, Ahmad Ghasemi and Golnaz Vaseghi
DOI: 10.1111/bcp.14238
Devalingam Mahalingam from San Antonio, TX, and colleagues from all over the world, describe the results from their first‐in‐human phase I study which aimed to assess the safety, dose‐limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and antitumor activity of the oxMIF (oxidized form of macrophage migration inhibitory factor) monoclonal antibody imalumab in patients with advanced solid tumours. MIF is a pleiotropic, pro‐inflammatory cytokine that plays a key role in regulating innate immunity, especially macrophage functionality and differentiation. Its oxidized form OxMIF may play a role in carcinogenesis and cancer‐associated inflammation and has been identified as a potential therapeutic target for certain cancers. This study identified an MTD as well as a biologically active dose for imalumab but overall its antitumor activity was deemed relatively modest. The authors suggest that the activity of this novel immunotherapeutic drug may be enhanced by combining it with other anticancer agents.
Phase I study of imalumab (BAX69), a fully human recombinant antioxidized macrophage migration inhibitory factor antibody in advanced solid tumours
Devalingam Mahalingam, Manish R. Patel, Jasgit C. Sachdev, Lowell L. Hart, Niels Halama, Ramesh K. Ramanathan, John Sarantopoulos, Dirk Völkel, Ashraf Youssef, Floris A. de Jong and Apostolia Maria Tsimberidou
DOI: 10.1111/bcp.14289
Bruton Tyrosine Kinase (BTK) inhibitors have shown promise in multiple disease areas, including immune‐mediated and inflammatory diseases and cancers. Ian Catlett et al. from Bristol Meyers Squib in Princeton, NJ, describe the first‐in‐human study of their new potent, highly selective, oral, small‐molecule, covalent BTK inhibitor branebrutinib. The study evaluated safety, pharmacokinetics and pharmacodynamics (BTK occupancy in whole blood lysates) of branebrutinib in healthy participants. Overall, the PK, PD, safety and tolerability findings of this study support further clinical development of branebrutinib in immune‐mediated diseases. Branebrutinib appears to have better safety and tolerability than less selective BTK inhibitors that have already been approved, as the rash typical of EGFR inhibition was not observed even with 14 days of 100% BTK occupancy.
Safety, pharmacokinetics and pharmacodynamics of branebrutinib (BMS‐986195), a covalent, irreversible inhibitor of Bruton's tyrosine kinase: Randomised phase I, placebo‐controlled trial in healthy participants
Ian M. Catlett, Miroslawa Nowak, Sudeep Kundu, Naiyu Zheng, Ang Liu, Bing He, Ihab G. Girgis and Dennis M. Grasela
DOI: 10.1111/bcp.14290
The fifth clinical drug‐development study investigated the effect of hepatic impairment on the pharmacokinetics of the oral poly (ADP‐ribose) aromatase inhibitor olaparib. Christian Rolfo from Baltimore, MA, and colleagues from all over the world, were able to demonstrate that there was no significant influence of mild or moderate hepatic impairment on the PK and safety of olaparib in patients with advanced solid tumors. Dose reductions of olaparib are therefore not needed in patients with mild or moderate hepatic impairment.
Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment
Christian Rolfo, Nicolas Isambert, Antoine Italiano, L. Rhoda Molife, Jan H.M. Schellens, Jean‐Yves Blay, Thomas Decaens, Rebecca Kristeleit, Olivier Rosmorduc, Regina Demlova, Myung‐Ah Lee, Alain Ravaud, Katerina Kopeckova, Maria Learoyd, Wendy Bannister, Gershon Locker and Judith de Vos‐Geelen
DOI: 10.1111/bcp.14283
There are also two most interesting clinical pharmacogenetics papers in this issue:
The first one from Groningen, The Netherlands and Tomsk, The Russian Federation, describes a study into the potential influence of ABCB1 gene polymorphisms on antipsychotic‐induced hyperprolactinemia in schizophrenic patients. No association was found between any of the eight investigated SNPs and the prevalence of antipsychotic drug‐induced HPRL in the total group of patients with schizophrenia, all using antipsychotic drugs. However, the rs2032582 (G2677T) variant was found to be negatively associated with risperidone/paliperidone‐induced hyperprolactinemia. The investigators, Lisanne Geers et al., concluded from this most interesting data that further research to the influence of polymorphisms in the P‐gp gene on the functionality and efficacy of the P‐gp transporter and the related influence on the plasma levels of several antipsychotic drugs is needed.
Association between 8 P‐glycoprotein (MDR1/ABCB1) gene polymorphisms and antipsychotic drug‐induced hyperprolactinaemia
Lisanne M. Geers, Ivan V. Pozhidaev, Svetlana A. Ivanova, Maxim B. Freidin, Amand F. Schmidt, Dan Cohen, Anastasiia S. Boiko, Diana Z. Paderina, Olga Yu Fedorenko, Arkadiy V. Semke, Nikolay A. Bokhan, Bob Wilffert, Jos G.W. Kosterink, Daan J. Touw and Anton J.M. Loonen
DOI: 10.1111/bcp.14288
In the second clinical pharmacogenetics (and also drug development) study Yifan Zhang and colleagues from Shanghai, China, aimed to investigate the impact of CYP2C19 polymorphisms on the pharmacokinetics of clopidogrel and vicagrel, a novel P2Y12 receptor inhibitor in development in China. The active metabolite of both vicagrel and clopidogrel is the same but the pathways leading to its formation and the contribution of CYP2C19 in the process is substantially different. The single center, randomized, open‐label, 2‐period cross‐over, clopidogrel‐controlled, multiple‐dose study demonstrated that CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in poor metabolizers were even higher than to clopidogrel in intermediate metabolizers; this may therefore be a promising drug.
Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y12 inhibitor
Yifan Zhang, Xiaoxue Zhu, Yan Zhan, Xiaojiao Li, Cai Liu, Yunting Zhu, Hong Zhang, Haijing Wei, Yu Xia, Hongbin Sun, Yongqiang Liu, Xiaojuan Lai, Yanchun Gong, Xuefang Liu, Yongguo Li, Yanhua Ding and Dafang Zhong
DOI: 10.1111/bcp.14296
As we all know, prescription drug abuse disorders are not restricted to the abuse of opioids. Pregabalin is e.g. a major concern, which in the UK has already led to reclassification of gabapentoids. Tricia Chiu et al. from Sydney, Australia, looked into pharmaceutical prescription claims for a 10% sample of Australians taking pregabalin and their data clearly suggest substantial inappropriate use of the drug. The Australians are now also considering steps to minimize harm and abuse of pregabalin.
Patterns of pregabalin initiation and discontinuation after its subsidy in Australia
Tricia Chiu, Jonathan Brett, Sallie‐Anne Pearson and Andrea L. Schaffe
DOI: 10.1111/bcp.14276
And finally, all papers in this issue are highly relevant. One of them though seems especially relevant as it describes a high‐impact clinical drug development trend that some welcome and others worry about. Tobias Polak and colleagues from Rotterdam identified, characterized and compared all Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals that included real‐world data on efficacy from expanded access (EA) programs. Their results show that sponsors and regulators increasingly include real‐world data from EA programs in the efficacy profile of a treatment. The indications of the approved treatments are characterized by orphan designation and high unmet medical need. I truly hope that this study will generate extensive discussion. I think it's needed.
Expanded Access as a source of real‐world data: An overview of FDA and EMA approvals
Tobias B. Polak, Joost van Rosmalen and Carin A. Uyl – de Groot
DOI: 10.1111/bcp.14284
Issue highlights. Br J Clin Pharmacol. 2020;86:1671–1673. 10.1111/bcp.14520