Expert Opinion on Drug Metabolism & Toxicology

Nicholson, Jeremy K; Everett, Jeremy R; Lindon, John C

doi: 10.1517/17425255.2012.646987pmid: 22248264

Pharmacometabonomics describes the use of metabolic profiling of biofluids, tissues and tissue extracts to predict, prior to dosing, the beneficial and adverse effects of an intervention such as drug administration. The approach not only is analogous to pharmacogenomics but also is sensitive to environmental factors such as the gut microbiome. Recent applications of pharmacometabonomics are presented and the extension to the use of longitudinal sampling is introduced. Clinical and other human applications of pharmacometabonomics are highlighted and possible future clinical applications of pharmacometabonomics and longitudinal pharmacometabonomics are discussed. These include clinical trials of new drugs either at the first-into-man stage or later in Phase II and III trials, and assessment of individual patients or groups of patients for particular therapies (personalised and stratified medicine approaches). Since metabonomics approaches are sensitive to both the host genome effects and the gut microbiome, pharmacometabonomics has particular utility for studying the host–microbiome interactions and for assessing new therapies that target the gut bacteria. Since the microbiome also has implications for nutrition and drug pharmacokinetics, such metabolic profiling approaches are likely to of use in such studies. It is anticipated that as metabonomics analytical and statistical technologies continue to develop, more applications will be realised and these should find use in real clinical situations, even monitoring patients in real time.

Deng, Rong; Jin, Feng; Prabhu, Saileta; Iyer, Suhasini

doi: 10.1517/17425255.2012.643868pmid: 22248267

Introduction: The number of monoclonal antibodies available for clinical use and under development has dramatically increased in the last 10 years. Understanding their pharmacokinetics and pharmacodynamics is essential for selecting the right clinical candidate, correct dose and regimen for a target indication. Areas covered: This article reviews the existing literature and knowledge of monoclonal antibodies. Specifically, the authors discuss monoclonal antibodies with respect to their pharmacokinetics (including absorption, distribution and elimination) and their pharmacodynamics. The authors also look at the pharmacokinetic/pharmacodynamic relationship, scaling from preclinical to clinical studies and selection of the first-in-human dose. Expert opinion: Monoclonal antibodies have complex pharmacokinetic and pharmacodynamic characteristics that are dependent on several factors. Therefore, it is important to improve our understanding of the pharmacokinetics and pharmacodynamics of monoclonal antibodies from a basic research standpoint. It is also equally important to apply mechanistic pharmacokinetic/pharmacodynamic models to interpret the experimental results and facilitate efforts to predict the safety and efficacy of monoclonal antibodies.

Pellegatti, Mario

doi: 10.1517/17425255.2012.652084pmid: 22248306

Introduction: The last two decades have brought many fundamental changes to the drug development process. One such change is the importance of preclinical pharmacokinetics, which has become an essential part of early drug discovery. Furthermore, bioanalytical methods have become more sensitive and the identification and quantitation of metabolites can now be carried out on limited amount of biological material. There has also been a change in regulatory expectations, which are now particularly focused on the safety of human metabolites. Areas covered: The focus of this paper is on some ‘traditional' in vivo ADME studies: excretion balance, metabolic profile and WBA in the toxicological species. These studies, performed with radiolabeled material, have a long history: and are a regular presence in submission dossiers. This paper reviews their value in the perspective of the contemporary drug development process. Expert opinion: These experiments may sometimes still be relevant to explain toxicological findings or for other special purposes but should not be considered required pieces of the registration dossiers. An appropriate investigation of samples coming from safety evaluation and human Phase I studies and the knowledge generated during the lead optimization phase provide, in most instances, all the DMPK information needed to take decisions in the drug development process.

Chan, Alexandre; Ng, Terence Rong De; Yap, Kevin Yi-Lwern

doi: 10.1517/17425255.2012.645804pmid: 22191471

Introduction: Depression is a condition that often arises in patients with cancer. As in many cases, the simultaneous use of anticancer drugs (ACD) and antidepressants (AD) may result in potential drug interactions that can lead to worsened medical outcomes and poorer quality of life in these patients. It is therefore essential that such interactions are carefully considered when treating patients for depression who already have cancer. Areas covered: The objective of this article is to discuss the potential anticancer–antidepressant drug (ACD–AD) interactions that may be clinically important in cancer patients. This systematic review describes the drug–drug interactions (DDIs) encountered for each tumour type so that oncology practitioners can target specific sections of the paper based on their specific clinical interests and specialties. Expert opinion: From our knowledge, there is currently no oncology-specific database that allows for DDI searches by both individual ACDs and multiple-agent chemotherapy regimens. Therefore, one-stop consolidated databases like OncoRx have been developed to reduce the time and effort for conducting DDI searches. The authors believe that epigenetic therapy combined with the rapid development of the semantic web can improve the scientific knowledge and lead to the development of new databases in the near future with novel strategies of detecting DDIs, so that the pharmaceutical care of cancer patients will ultimately be improved.

Przybylak, Katarzyna R; Cronin, Mark TD

doi: 10.1517/17425255.2012.648613pmid: 22248266

Introduction: Drug-induced liver injury (DILI) is one of the most important reasons for drug attrition at both pre-approval and post-approval stages. Therefore, it is crucial to develop methods that will detect potential hepatotoxicity among drug candidates as early and quickly as possible. However, the complexity of hepatotoxicity endpoint makes it very difficult to predict. In addition, there is still a lack of sensitive and specific biomarkers for DILI that consequently leads to a scarcity of reliable hepatotoxic data, which are the key to any modelling approach. Areas covered: This review explores the current status of existing in silico models predicting hepatotoxicity. Over the past decade, attempts have been made to compile hepatotoxicity data and develop in silico models, which can be used as a first-line screening of drug candidates for further testing. Expert opinion: Most of the predictive methods discussed in this review are based on the structural properties of chemicals and do not take into account genetic and environmental factors; therefore, their predictions are still uncertain. To improve the predictability of in silico models for DILI, it is essential to better understand its mechanisms as well as to develop sensitive toxicogenomics biomarkers, which show relatively good differentiation between hepatotoxins and non-hepatotoxins.

Pereira, Claudia V; Nadanaciva, Sashi; Oliveira, Paulo J; Will, Yvonne

doi: 10.1517/17425255.2012.645536pmid: 22248238

Introduction: Nowadays the ‘redox hypothesis’ is based on the fact that thiol/disulfide couples such as glutathione (GSH/GSSG), cysteine (Cys/CySS) and thioredoxin ((Trx-(SH)2/Trx-SS)) are functionally organized in redox circuits controlled by glutathione pools, thioredoxins and other control nodes, and they are not in equilibrium relative to each other. Although ROS can be important intermediates of cellular signaling pathways, disturbances in the normal cellular redox can result in widespread damage to several cell components. Moreover, oxidative stress has been linked to a variety of age-related diseases. In recent years, oxidative stress has also been identified to contribute to drug-induced liver, heart, renal and brain toxicity. Areas covered: This review provides an overview of current in vitro and in vivo methods that can be deployed throughout the drug discovery process. In addition, animal models and noninvasive biomarkers are described. Expert opinion: Reducing post-market drug withdrawals is essential for all pharmaceutical companies in a time of increased patient welfare and tight budgets. Predictive screens positioned early in the drug discovery process will help to reduce such liabilities. Although new and more efficient assays and models are being developed, the hunt for biomarkers and noninvasive techniques is still in progress.

Pistollato, Francesca; Bremer-Hoffmann, Susanne; Healy, Lyn; Young, Lesley; Stacey, Glyn

doi: 10.1517/17425255.2012.639763pmid: 22248265

Introduction: Pluripotent stem cell (PSC) lines offer a unique opportunity to derive various human cell types that can be exploited for human safety assessments in vitro and as such contribute to modern mechanistically oriented toxicity testing. Areas covered: This article reviews the two major types of PSC cultures that are currently most promising for toxicological applications: human embryonic stem cell lines and human induced PSC lines. Through the review, the article explains how these cell types will improve the current safety evaluations of chemicals and will allow a more efficient selection of drug candidates. Additionally, the article discusses the important issues of maintaining PSCs as well as their differentiation efficiency. Expert opinion: The demonstration of the reliability and relevance of in vitro toxicity tests for a given purpose is mandatory for their use in regulatory toxicity testing. Given the peculiar nature of PSCs, a high level of standardization of undifferentiated cell cultures as well as of the differentiation process is required in order to ensure the establishment of robust test systems. It is, therefore, of pivotal importance to define and internationally agree on crucial parameters to judge the quality of the cellular models before enrolling them for toxicity testing.

Patson, Brian; B Cohen, Roger; Olszanski, Anthony J.

doi: 10.1517/17425255.2012.652947pmid: 22248343

Introduction: The role of angiogenic inhibitors is clearly established in the treatment of diverse malignancies. The field of antiangiogenesis is expanding rapidly, with an increasing number of agents currently approved by the FDA. Axitinib is a vascular endothelial growth factor receptor (VEGFR)-specific inhibitor currently being developed for the treatment of various malignancies. The pharmacokinetic (PK) properties of axitinib may provide a selective treatment effect while minimizing adverse reactions and enhancing safety. It is paramount that health-care providers understand the properties and nuances of each agent inclusive of PK variability in the patient population as well as current safety and tolerability data. Areas covered: This article provides a comprehensive and critical review of the PK properties of axitinib as they relate to safety and tolerability, as well as potential pharmacodynamic and efficacy parameters. Expert opinion: Axitinib is a unique VEGFR tyrosine kinase inhibitor (TKI), which acts through greater receptor specificity compared with many other VEGFR TKIs. An understanding of axitinib's PK characteristics and common adverse events may allow for a tailored dosing approach in patients with cancer, in an attempt to maximize efficacy while minimizing toxicity.

Acheampong, Paul; Ford, Gary A

doi: 10.1517/17425255.2012.652615pmid: 22248305

Introduction: Alteplase is the only approved drug for thrombolysis in acute ischaemic stroke (AIS) after its initial use in acute myocardial infarction (AMI). Its role in functional recovery is time-dependent while its major adverse effect, intracranial haemorrhage, is dose-dependent. These underline the importance of the pharmacokinetics of alteplase to its clinical use. Areas covered: The authors discuss the pharmacology of alteplase with a major focus on its pharmacokinetics based on literature obtained from the OVID electronic database and other institutional resources. Expert opinion: The pharmacokinetic profile of alteplase is almost entirely derived from studies in AMI. Differences in the pathophysiology of AMI and AIS mean it cannot be assumed that the pharmacokinetics of alteplase is similar in these two populations. During AMI, cardiac function and, hence, hepatic perfusion and clearance of alteplase may be impaired. The relatively older population in AIS may have impaired metabolic clearance which may increase plasma concentrations. The concurrent use of medications such as nitrates in the management of elevated blood pressure during AIS thrombolysis is also associated with reduced plasma concentrations of alteplase. Again, differences in clot size and type between AMI and AIS and between subtypes of AIS may influence response to alteplase. There is an inherently higher risk of intracranial haemorrhage in AIS compared to AMI emanating from cerebral infarction and BBB disruption. Accordingly, stroke-specific pharmacokinetics of alteplase and its relationship to efficacy and safety outcomes are required.