Expert Opinion on Drug Metabolism & Toxicology

Peters, Godefridus J; Honeywell, Richard J

doi: 10.1517/17425255.2015.1041255pmid: 25940025

Serdjebi, Cindy; Milano, Gérard; Ciccolini, Joseph

doi: 10.1517/17425255.2015.985648pmid: 25495470

Introduction: Nucleosidic analogs such as pyrimidine and purine derivatives are mainstay in the field of treating cancers, both in adults and in children. All these drugs act as antimetabolite compounds, that is, they interfere with the ability of cancer cells to synthesize the nucleosides or the nucleotides necessary for proliferation and progression. As with most cytotoxics, maintaining patients in their therapeutic window is challenging, and predicting changes in drug exposure is critical to ensure an optimal efficacy/toxicity balance.Areas covered: Among the antimetabolites, a small but widely prescribed number of drugs (i.e., gemcitabine, capecitabine, cytarabine, azacytidine) share a same metabolic pattern driven by a liver enzyme, cytidine deaminase (CDA), coded by a gene displaying several genetic and epigenetic polymorphisms. Consequently, CDA activity is erratic, ranging from deficient to ultra-rapid deaminator patients, with subsequent impact on drug pharmacokinetics and pharmacodynamics eventually. This review provides an update on the variety of clinical studies and case-reports investigating on CDA status as a marker for clinical outcome in cancer patients treated with nucleosidic analogs.Expert opinion: Whereas sorting patients on the basis of their CDA genotype remains tricky because of unclear genotype-to-phenotype relationships, developing functional strategies (i.e., phenotype-based status determination) could help to use CDA status as a biomarker for developing adaptive dosing strategies with nucleosidic analogs.

Wojtuszkiewicz, Anna; Assaraf, Yehuda G; Maas, Marielle JP; Kaspers, Gertjan JL; Jansen, Gerrit; Cloos, Jacqueline

doi: 10.1517/17425255.2015.993316pmid: 25495223

Introduction: Aberrant pre-mRNA splicing in cancer is emerging as an important determinant of oncogenesis, response to treatment and anticancer drug resistance. At the same time, the spliceosome has become a target for a novel class of pre-clinical chemotherapeutics with a potential future application in cancer treatment. Taken together, these findings offer novel opportunities for the enhancement of the efficacy of cancer therapy.Areas covered: This review presents a comprehensive overview of the molecular mechanisms involved in splicing and current developments regarding splicing aberrations in relation to several aspects of cancer formation and therapy. Identified mutations in the various components of the spliceosome and their implications for cancer prognosis are delineated. Moreover, the contribution of abnormal splicing patterns as well as deregulated splicing factors to chemoresistance is discussed, along with novel splicing-based therapeutic approaches.Expert opinion: Significant progress has been made in deciphering the role of splicing factors in cancer including carcinogenesis and drug resistance. Splicing-based prognostic tools as well as therapeutic options hold great potential towards improvements in cancer therapy. However, gaining more in-depth molecular insight into the consequences of mutations in various components of the splicing machinery as well as of cellular effects of spliceosome inhibition is a prerequisite to establish the role of splicing in tumor progression and treatment options, respectively.

Joerger, Markus

doi: 10.1517/17425255.2015.983074pmid: 25394848

Introduction: The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. Despite years of research, the optimal dosing regimen (weekly vs 3-weekly) and optimal dose is still controversial, as is the value of pharmacological personalization of taxane dosing.Areas covered: This review provides an overview of the pharmacological properties of the taxanes, including metabolism, pharmacokinetics–pharmacodynamics and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most active and safe regimen (paclitaxel, docetaxel, nab-paclitaxel), the recommended initial dose (cabazitaxel) and pharmacological dosing individualization.Expert opinion: Taxanes share the characteristics of extensive hepatic metabolism and biliary excretion, the need for dose adaptation in patients with liver dysfunction, and substantial pharmacokinetic variability even after taking into account known covariates. Data from clinical studies suggest that optimal scheduling of the taxanes is dependent not only on the specific taxane compound, but also on the tumor type and line of treatment. Finally, treating oncologists should be aware of the substantial risk for drug–drug interactions that is a direct consequence of the complex hepatic metabolism of the taxanes.

Da Silva, Candido G; Honeywell, Richard J; Dekker, Henk; Peters, Godefridus J

doi: 10.1517/17425255.2015.1006626pmid: 25633410

Introduction: Small molecule tyrosine and serine-threonine kinase inhibitors (TKIs and STKIs) are emerging drugs that interfere with downstream signaling pathways involved in cancer proliferation, invasion, metastasis and angiogenesis. The understanding of their pharmacokinetics, the identification of their transporters and the modulating activity exerted on transporters is pivotal to predict therapy efficacy and to avoid unwarranted drug treatment combinations.Areas covered: Experimental or in silico data were collected and summarized on TKIs and STKIs physico-chemical properties, which influence their transport, metabolism and efficacy, and TKIs and STKIs as influx transporter substrates and inhibitors. In addition, the uptake by tumor cell influx transporters and some factors in the tumor microenvironment affecting the uptake of TKIs and STKIs by cancer cells are briefly covered.Expert opinion: Membrane transporters play an important role in the pharmacokinetics and hence the efficacy of anticancer drugs, including TKIs and STKIs. These drugs are substrates and inhibitors of various transporters. Drug resistance may be bypassed not only by identifying the proper transporter but also by selective combinations, which may either downregulate or increase transporter activity. However, care has to be taken because this profile might be disease, drug and patient specific.

Ciccolini, Joseph; Fanciullino, Raphaelle; Serdjebi, Cindy; Milano, Gérard

doi: 10.1517/17425255.2015.1008447pmid: 25690018

Introduction: Breast cancer has benefited from a number of innovative therapeutics over the last decade. Cytotoxics, hormone therapy, targeted therapies and biologics can now be given to ensure optimal management of patients. As life expectancy of breast cancer patients has been significantly stretched and that several lines of treatment are now made available, determining the best drug or drug combinations to be primarily given and the best dosing and scheduling for each patient is critical for ensuring an optimal toxicity/efficacy balance.Areas covered: Defining patient’s characteristics at the tumor level (pharmacogenomics) and the constitutional level (pharmacogenetics) is a rising trend in oncology. This review covers the latest strategies based upon the search of relevant biomarkers for efficacy, resistance and toxicity to be undertaken at the bedside to shift towards precision medicine in breast cancer patients.Expert opinion: In the expanding era of bioguided medicine, identifying relevant and clinically validated biomarkers from the plethora of published material remains an uneasy task. Sorting the variety of genetic and molecular markers that have been investigated over the last decade on their level of evidence and addressing the issue of drug exposure should help to improve the management of breast cancer therapy.

Narayan, Vivek; Vaughn, David

doi: 10.1517/17425255.2015.1005600pmid: 25604887

Introduction: Neoadjuvant cisplatin-based combination chemotherapy remains the standard of care for surgically fit patients with muscle-invasive bladder cancer (MIBC). However, significant practice variability exists both in the use of neoadjuvant chemotherapy (NACT) and in the utilized regimens.Areas covered: This review summarizes the available evidence on the pharmacokinetic, toxicology and efficacy considerations for determining appropriate neoadjuvant therapy in MIBC. This article consists of material obtained via PubMed, Medline and EMBASE literature searches up to November 2014.Expert opinion: The role of NACT in MIBC cancer is well established. Common barriers to the successful use of NACT are the toxicities of therapy, the presence of underlying renal dysfunction, the time delay to definitive surgery and the potential for an inadequate treatment effect. The key finding from published NACT trials is that patients who successfully attain a complete pathologic response at the time of radical cystectomy can achieve durable long-term survivals. Although recent investigations into dose-dense NACT regimens have provided intriguing results, alterations in dose intensity alone are unlikely to provide substantial clinical improvements. Further research into NACT should be directed towards the investigation of novel neoadjuvant therapies and to the evaluation of biomarkers predictive of complete pathologic response or decreased toxicities with standard cisplatin-based NACT.

Block, Michael

doi: 10.1517/17425255.2015.1037276pmid: 25940026

Introduction: Modeling and simulation have become important means of answering questions relevant to the development of a drug, making it possible to assess risks early and to reduce costs. Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models contribute to a comprehensive understanding of the drug, covering specific questions from early discovery through lifecycle management stages. As for other disease areas, in oncology, PBPK and PD models are important topics that remain to be addressed.Areas covered: This review describes current PBPK and PD approaches, their applicability in drug development in general and specifically in the area of oncology. It discusses the current status and then focuses on key challenges and the potential for future use. It provides cases in which modeling currently cannot answer the questions and assesses the requirements to close gaps for PBPK/PD in oncology.Expert opinion: PBPK/PD models have led to improvements in identifying risks and reducing costs during the drug development process. Nevertheless, there is a lot of potential, where more rigorous integration of biological knowledge and specific experimental design would result in a more comprehensive biological picture. Ideally, such approaches would reveal the extent to which preclinical work can be extrapolated to clinical settings, thus enabling reliable prediction and, ultimately, reducing failed trials in clinical oncology.

Singh, Jasmeet C; Lichtman, Stuart M

doi: 10.1517/17425255.2015.1037277pmid: 25940027

Introduction: The aging of the population will increase the number of breast cancer patients requiring treatment in both the adjuvant and metastatic setting. Hormones, chemotherapy and targeted drugs all have a role in treatment. Older patients have been underrepresented in clinical trials making evidence-based decisions difficult. The increase in comorbidity and aging, polypharmacy and changes in function make pharmacotherapy decisions more complicated. Knowledge of the issues is critical in the prescribing of effective and safe therapy. There are factors associated with advancing age that can result in pharmacokinetic and pharmacodynamic variations in processing of hormonal agents, chemotherapy and targeted drugs.Areas covered: A review of the literature pertaining to pharmacokinetic changes in aging in breast cancer was untaken. Studies are reviewed involving single agents and some combinations.Expert opinion: Older patients should be considered for standard therapies. Their specific problems need to be evaluated by geriatric-specific assessment including functional status, end organ dysfunction and polypharmacy. There are few instances for age-related changes in pharmacokinetics and when present are usually not clinically significant. When changes are present, they are often the result of comorbidity, drug interactions and drug scheduling issues. The older patients may be more sensitive to certain toxicities such as cardiac toxicity, neuropathy and myelosuppression.

Popilski, Hen; Stepensky, David

doi: 10.1517/17425255.2015.1030391pmid: 25813659

Introduction: Solid tumors are characterized by complex morphology. Numerous factors relating to the composition of the cells and tumor stroma, vascularization and drainage of fluids affect the local microenvironment within a specific location inside the tumor. As a result, the intratumoral drug/drug delivery system (DDS) disposition following systemic or local administration is non-homogeneous and its complexity reflects the differences in the local microenvironment. Mathematical models can be used to analyze the intratumoral drug/DDS disposition and pharmacological effects and to assist in choice of optimal anticancer treatment strategies.Areas covered: The mathematical models that have been applied by different research groups to describe the intratumoral disposition of anticancer drugs/DDSs are summarized in this article. The properties of these models and of their suitability for prediction of the drug/DDS intratumoral disposition and pharmacological effects are reviewed.Expert opinion: Currently available mathematical models appear to neglect some of the major factors that govern the drug/DDS intratumoral disposition, and apparently possess limited prediction capabilities. More sophisticated and detailed mathematical models and their extensive validation are needed for reliable prediction of different treatment scenarios and for optimization of drug treatment in the individual cancer patients.