Current Drug Metabolism - Volume 18, Issue 8, 2017

Background: Prostate cancer is a common malignancy with highly molecular heterogeneity responsible for a wide spectrum of clinical behavior. To date, several treatment options are available, whose selection is currently based mainly on clinical criteria. Given the weakness of conventional imaging and PSA assay, the identification of a prognostic and predictive biomarker for choosing the appropriate treatment and monitoring its efficacy is a very topical issue in prostate cancer management. Circulating tumor cells (CTCs) have substantial promise for early tumor diagnosis, disease recurrence and metastatic spread monitoring as well as for biological tumor characterization, thus representing a reliable translational real-time biomarkers of prostate cancer. Conclusion: This paper summarized the main data available about CTCs detection, their prognostic value, and their potential predictive role for metastatic prostate cancer patients management.

Background: Immune checkpoint inhibitors have revolutionized the treatment of many malignancies with over a dozen new United States Food and Drug Administration (FDA) approvals in the past six years. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors, gathering prognostic and predictive information about FDA-indicated tumors is prudent. Method: PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including Renal Cell Carcinoma (RCC) and urothelial carcinoma. Each FDAapproved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. The majority of PD-1/PDL1 inhibitor clinical trials use proprietary IHC antibodies with undefined validation data. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers. There is a wealth of recent publications using antibody clones to characterize tumor PD-1/PD-L1 expression profiles. Results: PD-1 is expressed on lymphocytes. PD-L1 is expressed on both tumor cells and immune cells. IHC staining appears in membranous fashion. A cutoff of at least 5% tumor cell PD-L1 staining for positivity has worked for most studies. Caution should be observed when employing tissue microarray techniques. Conclusion: RCC has been the most studied of the genitourinary malignancies for PD-L1 expression. The atezolizumab- approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in urothelial carcinoma. With familiarity of the current FDA guidelines, published medical literature, and general immunohistochemical considerations, the use of immune checkpoint biomarkers can continue to flourish.

Background: To date more than 3000 miRNA sequences have been described in humans and registered at miRBase since their discovery. However, the functions of only a few of these miRNAs have been experimentally determined using deep sequencing technology. Aberrant miRNA expression has been associated with differentiation, invasion and metastasis in several cancers. In this context, recent reports have suggested that miRNAs play important roles in the regulation of target genes by binding to complementary regions of messenger transcripts to repress their translation or regulate degradation. In addition, the expression profiles of certain miRNAs can function biologically as oncogenes and tumor suppressor genes. Method: In this review, we summarize the relationship between miRNAs expression and Bladder Cancer (BC). A comprehensive review of the literature has shown a differential expression between malignant and normal tissues, and that miRNAs could be the driving molecules of the BC progression. Similarly, the expression levels of miRNAs in urine and blood samples of BC patients have been demonstrated to be different from healthy people, a finding that might have diagnostic value. Conclusion: In conclusion, the understanding of miRNAs mechanisms and cell distribution provides new opportunities for diagnosis, prognostic, disease monitoring and personalized therapy of BC patients.

Background: Urine may represent a convenient source of biomarkers for the early detection of Prostate Cancer (PCa) since it contains secreted prostatic products and exfoliated tumor cells. Furthermore, urine is easy to collect with non-invasive procedures which are repeatable. Method: Several urinary biomarkers for PCa have been proposed in the past but only one (PCA3) has been approved for clinical use and even this is not widely utilized in the routine practice. Most of these, particularly the proteins, were abandoned due to lack of confirmation. DNA markers have been proposed but they are less suitable compared to other malignancies, such as bladder cancer due to the limited amount of DNA somatic alterations in PCa compared to gene fusions and pathway activations. Conclusion: RNA biomarkers are still the most promising and particularly miRNA and AMACR mRNA but the main weaknesses that prevented the full clinical implementation are the absence of a validated of the cut-off levels and the identification of consistent reference standards.

Background: Neonatal seizures are the most common clinical manifestation of Central Nervous System (CNS) dysfunction and are associated with various neurological sequelae. There are currently no evidence-based guidelines for the management of neonatal seizures and currently used drugs such as phenobarbital, and phenytoin have limited efficacy and potential toxicities. Newer second line anticonvulsant, levetiracetam, has been used in refractory neonatal seizures despite limited data and off-label use. Objective: In this review, we will discuss various pharmacological properties of levetiracetam when used in neonatal population. Methods: A PubMed search for MEDLINE was undertaken to look for studies using the terms “Levetiracetam”, AND “Neonates” as key words from year 1995 to January 2017. Relevant articles were selected and information was extracted about pharmacokinetics, pharmacodynamics and clinical uses of levetiracetam in neonates. Results: Levetiracetam is an active, water-soluble S-enantiomer of racemic pyrrolidine acetamide which exerts its antiepileptic action by binding to the synaptic vesicle protein within the brain. Metabolism of levetiracetam does not include the CYP P450 system and it is mainly eliminated through kidneys after rapid absorption. Also, no significant interactions with other drugs have been identified. Unlike other commonly used antiepileptic drugs, levetiracetam is not bound to plasma proteins, thereby, reducing the chances of toxicity and severe, life threatening side effects have not been reported. In fact, it has been shown to prevent neuro-degeneration after hypoxia/ischemia in rodent models of epilepsy. Conclusion: Levetiracetam has been emerging as a potential therapeutic option for refractory neonatal convulsions owing to its non-hepatic elimination, linear pharmacokinetics, low protein binding and better safety profile.

Background: Seizures are aetiologically and clinically heterogeneous neurological disorders that are currently treated using a wide array of drugs, belonging to equally heterogeneous chemical classes. Some of them are known as “antiepileptic drugs” (AEDs), due to their main field of use, while others (such as benzodiazepines) are frequently used for other conditions as well as for seizures. Due to their different chemical properties and mechanisms of activity, the metabolic characteristics of anti-seizure drugs can vary widely, also producing big differences in terms of safety, efficacy and therapeutic suitability. Methods: Scopus and PubMed databases were searched for the most significant papers centered on metabolism and analysis of the following antiepileptics: carbamazepine, oxcarbazepine, lamotrigine, phenytoin, ethosuximide, gabapentin, vigabatrin, topiramate, levetiracetam and valproic acid. Results: The most important studies on the metabolic characteristics of several AEDs are reported and briefly discussed in this review; moreover, the analytical methods used to determine biological levels of these drugs during therapy are also described and commented upon, and their main characteristics highlighted. Other AEDs, and notes on polypharmacy, will be included in the second part of this series.

Background: Drug-Drug Interactions (DDI) by modulation of drug transporters or drug metabolizing enzymes are common in multi-drug therapy. DDI potential of any new drug is assessed by conducting separate clinical studies using relevant probe substrates, which involves additional resource and cost. Recently, several endogenous compounds have been evaluated as substrates of transporters and enzymes that could be assessed as part of early clinical trials along with the assessment of drug pharmacokinetics, pharmacodynamics and safety studies. This enables an early readout on potential DDIs avoiding or minimally delaying the conduct of definitive DDI studies until later in clinical development. Method: This review describes various endogenous biomarkers reported for drug transporters and metabolizing enzymes with their advantages and limitations. Conclusion: Furthermore, the authors describe strategies to adopt while exploring a new endogenous biomarker, and factors to be considered in selection of biomarkers with the current challenges and opportunities.

Background: Human Immunodeficiency Virus (HIV) entry inhibitors target the first step of the HIV life cycle and efficiently inhibit HIV from infecting the immune cells which is a key prerequisite for viral spread. Because of their unique mechanism of action on cell-cell transmission, they may provide a promising perspective for the treatment of AIDS. Method: Maraviroc (MVC) and Enfuvirtide (ENF) have been approved by the FDA for the treatment of HIV-1 infection. Attachment inhibitors (BMS-663068 and TNX-355) and co-receptor inhibitors (PRO-140 and cenicriviroc (CVC)) have reached phase II or III clinical trials. These entry inhibitors show beneficial pharmacokinetics and substantial reductions of plasma HIV-1 RNA load in HIV infected patients. Results: Most entry inhibitors are generally safe, without serious Adverse Event (AE) or AE leading to discontinuation. The pharmacokinetics of MVC, CVC and BMS-663068 was affected by CYP3A4 inhibitors or inducers. The FDA has proposed that the dosage of MVC (300 mg, BID, orally) be adjusted to half or two-fold for patients if it is combined with a major CYP3A4 inhibitor or inducer, respectively. Researchers suggested that the dosage of CVC (50-75 mg, QD, orally) may also need adjustment but the dosage of BMS-663068 (600 mg, BID, orally) does not. Conclusion: The standard, recommended ENF dosage is 90 mg BID, injected subcutaneously for adults, and 2 mg/kg BID, up to a maximum dose of 90 mg, injected subcutaneously for pediatric patients. TNX-355 (10-15 mg/kg, BID, intravenously) and PRO-140(5-10 mg/kg, BID, intravenously; 324 mg, biweekly, subcutaneously) are administered by intravenous infusion or subcutaneous injection.