Expert Opinion on Drug Metabolism & Toxicology

doi: 10.1517/17425255.2015.1109821pmid: 26488741

Hegen, Harald; Auer, Michael; Deisenhammer, Florian

doi: 10.1517/17425255.2015.1094055pmid: 26419922

Introduction: Interferon-β (IFNβ) is well established as a disease-modifying treatment for patients with multiple sclerosis. Several preparations of the biopharmaceutical are available differing in protein structure, formulation, dose as well as frequency and route of administration. Recently, a pegylated form of IFNβ has been marketed.Areas covered: Following a PubMed database search, we provide an overview of what is presently known about the pharmacokinetics (PK) of IFNβ including its absorption, distribution, metabolism and elimination. Also, we discuss the association with clinically relevant issues such as treatment efficacy, adverse events and anti-drug antibodies.Expert opinion: IFNβ has a bioavailability of ∼ 30% after subcutaneous or intramuscular administration, shows peak serum concentrations within several hours, has a half-life of < 1 day and is eliminated by a renal and hepatic pathway. PK parameters do not substantially differ between the types of IFNβ and routes of administration; only pegylation of IFNβ results in substantially increased and prolonged PK. Although no clinical dose–effect relationship could be established, there is an association of IFNβ dose with magnetic resonance imaging outcome parameters. Furthermore, there is an association of IFNβ serum levels with the occurrence of adverse events and anti-drug antibodies.

Koo, Seok Hwee; Lo, Ying Li; Yee, Jie Yin; Lee, Edmund Jon Deoon

doi: 10.1517/17425255.2015.1104298pmid: 26489003

Introduction: Drug transporters are differentially expressed in many polarized tissues. The varied distribution and expression of transporters determines the net transcellular transport and influences the disposition of many clinically used drugs. ATP-binding cassette (ABC) and Solute Carrier (SLC) transporters interact dynamically to mediate the passage of drugs across cells. The variable expression of drug transporters could be attributed to genetic and non-genetic factors, which accounts for the differences in drug response among individuals, in terms of both efficacy and adverse effects.Areas covered: The authors provide the background of ABC and SLC transporters, and highlight the fact that their expression is cell-specific and the study of a transporter in isolation is not an adequate measure of its function. The technologies and approaches to characterize the function of transporters, as well as the genetic and non-genetic factors underlying their variable expression in specific cells and among individuals were reviewed.Expert opinion: Many studies have utilized tissue homogenization techniques to isolate mRNA for quantifying transporter expression levels. We highlight that transporter expression is cell-specific and mRNA expression does not always reflect its total functionality. In addition, transporter expression in immortalized cell lines may not mirror its expression in the target tissue site.

Jackson, Brian C.; Thompson, David C.; Charkoftaki, Georgia; Vasiliou, Vasilis

doi: 10.1517/17425255.2016.1108406pmid: 26558415

Introduction: Dead enzymes are gene products (proteins) that lack key residues required for catalytic activity. In the pre-genome era, dead enzymes were thought to occur only rarely. However, they now have been shown to represent upwards of 10% of the total enzyme population in many families. The aldehyde dehydrogenase (ALDH) gene family encodes proteins that, depending on the isozyme, may be either catalytically-active or -inactive. Importantly, several ALDHs exhibit biological activities independent of their catalytic activity. For many of these, the physiological and pathophysiological functions remain to be established.Areas covered: This article reviews the non-enzymatic functions of the ALDH superfamily. In addition, a search for additional non-catalytic ALDH records is undertaken. Our computational analyses reveal that there are currently 182 protein records (divided into 19 groups) that meet the criteria for dead enzymes.Expert Opinion: Dead enzymes have the potential to exert biological actions through protein-protein interaction and allosteric modulation of the activity of an active enzyme. In addition, a dead enzyme may also influence availability of substrate for other active enzymes by sequestering substrate, and/or anchoring the substrate to a particular subcellular space. A large number of putatively non-catalytic ALDH proteins exist that warrant further study.

Douros, Antonios; Grabowski, Katja; Stahlmann, Ralf

doi: 10.1517/17425255.2015.1098617pmid: 26457865

Introduction: Oxazolidinones are synthetic antimicrobials with strong bacteriostatic activity against Gram-positive organisms. Recently, tedizolid phosphate was approved for clinical use becoming the second agent of this class after linezolid available in clinical practice. Areas covered: Oxazolidinone pharmacology including structure-activity relationships, mode of action, pharmacokinetics, drug–drug interactions, and adverse drug reactions is reviewed. Furthermore, bacterial resistance, approved indications, use in paediatric populations, and tuberculosis treatment with oxazolidinones are discussed, and differences in indications and pharmacotoxicological properties between the two approved agents are elucidated. A MEDLINE PubMed search for articles published in English from January 1960 to June 2015 was completed using the terms: oxazolidinone, oxazolidinone-induced toxicity, oxazolidinone pharmacokinetics, serotonin syndrome, oxazolidinone drug–drug interactions, antituberculotic treatment. Expert opinion: Linezolid illustrates an important antimicrobial in several Gram-positive infections especially when methicillin-resistant Staphylococcus aureus strains are involved. Myelosuppression and neuropathy are toxicities of high relevance particularly in case of prolonged treatment periods. The significance of linezolid in the treatment of extensively drug-resistant tuberculosis has to be further investigated. Tedizolid phosphate represents a welcome addition in our anti-infective arsenal, and future research will clarify its role in indications other than the already approved acute bacterial skin infections.

Enioutina, Elena Yu; Constance, Jonathan E; Stockmann, Chris; Linakis, Matthew W; Yu, Tian; Rower, Joseph E; Balch, Alfred H; Sherwin, Catherine M

doi: 10.1517/17425255.2015.1108963pmid: 26535960

Introduction: Neonatal patients, because of the inability of their immune system to properly respond to microbial challenge, are highly susceptible to viral infections. Immunoglobulins, monoclonal antibody and antiviral drugs are used for prophylaxis and treatment of viral diseases in neonates. Neonates and, especially, preterm infants differ in drug absorption, distribution, metabolism and excretion from adults and older children.Areas covered: This review will evaluate deficiencies of neonatal immune responses to microbial challenge that predispose newborns to viral infections, clinical manifestations and the treatment of viral diseases in neonates. We focus on published studies describing antiviral drug pharmacokinetics in neonates and make recommendations on the dosing of these drugs, allowing achievement of maximal clinical benefits in neonates.Expert opinion: While some efforts were undertaken to study pharmacokinetics and pharmacodynamics of antiviral drugs, much more needs to be done. Current data indicate that the pharmacokinetics of antiviral drugs may vary significantly depending on gestational age, maturation processes of drug-metabolizing enzymes and renal clearance. Specifics of pharmacokinetics of antiviral drugs need to be taken into consideration when they are prescribed to neonates and infants.

Syn, Nicholas Li-Xun; Yong, Wei-Peng; Lee, Soo-Chin; Goh, Boon-Cher

doi: 10.1517/17425255.2015.1108964pmid: 26548636

Introduction: In the era of genomic medicine, it is increasingly recognized that ethnogeographic differences in drug pharmacology exist between Asian and other populations. This is particularly pertinent to oncology, where drugs forming the backbone of chemotherapy often have narrow therapeutic windows and are frequently dosed close to maximally tolerable levels.Areas covered: At the population level, ancestry is important because historical–biogeographical confluences have shaped population genetics and pharmacoethnicity in the Asian race through allelic differentiation and interethnic differences in inheritance patterns of linkage disequilibrium. At the individual level, cis- and trans-acting germline polymorphisms and somatic mutations in genes encoding drug-metabolizing enzymes and transporters act in a multifactorial manner to determine drug disposition phenotype and clinical response in Asian cancer patients. A growing body of evidence also finds that complex genetic interactions and regulation, including a multiplicity of gene control mechanisms, are increasingly implicated in genotype–phenotype correlates than has hitherto been appreciated – potentially serving as the mechanistic links between hits in non-coding regions of genome-wide association studies and drug toxicity. Together, these genetic factors contribute to the clinical heterogeneity of drug disposition in Asian cancer patients.Expert opinion: This topic has broad relevance for the optimization and individualization of anticancer strategies in Asians.

Céspedes-Garro, Carolina; Fricke-Galindo, Ingrid; Naranjo, María Eugenia G; Rodrigues-Soares, Fernanda; Fariñas, Humberto; de Andrés, Fernando; López-López, Marisol; Peñas-Lledó, Eva M; LLerena, Adrián

doi: 10.1517/17425255.2015.1111871

Lo, Louisa; Patel, Dainik; Townsend, Amanda R; Price, Timothy J

doi: 10.1517/17425255.2015.1112787pmid: 26572750

Introduction: Integration of targeted therapy and additional chemotherapy options has improved median overall survival (OS) in patients with unresectable metastatic colorectal cancer (mCRC). Cetuximab and panitumumab are examples of targeted therapies, specifically against the epidermal growth factor receptor (EGFR). This review focuses on Panitumumab, a fully human IgG2 monoclonal antibody, which inhibits key oncogenic downstream cell signalling pathways. Panitumumab and cetuximab have improved tumour response rate, progression-free survival, and OS in mCRC patients in whom the RAS (Rat Sarcoma) gene is of Wild Type (WT) status.Areas covered: The EGFR signalling pathway and preclinical, Phase I and Phase II clinical studies on the pharmacokinetic, pharmacodynamic and safety evaluation of panitumumab are presented. Phase III studies utilising panitumumab in the first, second and third line setting in mCRC are also described.Expert opinion: Panitumumab exhibits excellent pharmacokinetics and pharmacodynamics by way of uncomplicated dosing, non-existent drug interactions, minimal infusion reactions and manageable side effects, making it a suitable target for combination treatments. However, innate and acquired resistances are still obstacles. To overcome this, experimented strategies are ongoing, particularly in patients with Her-2 and BRAF gene alterations. Novel biomarkers to improve patient selection and second-generation targeted antibodies are in development.

Skledar, Susan J.; Lachell, Carsten M.; Chelly, Jacques E.

doi: 10.1517/17425255.2015.1112788pmid: 26565744

Introduction: The fentanyl iontophoretic transdermal system (ITS) is a patient-controlled transdermal system allowing needle-free administration of on-demand doses of Fentanyl of 40 µg over a 10-min period up to 80 doses or over a 24-h period. It is indicated in opioid naïve patients for the treatment of acute postoperative pain in the hospitalized patients for up to 72 h.Areas covered: It has been demonstrated to be effective and safe in randomized trials and to provide comparable analgesia versus morphine intravenous (i.v.) patient-controlled analgesia (PCA) with adverse events similar between groups.Expert opinion: Fentanyl ITS has shown high patient satisfaction rates, and was described by patients and investigators as easy and convenient to use. These properties make this technology interesting when considering perioperative pain management. In the present health care environment additional data are required to establish the cost-benefit ratio of this technology in optimizing patient’s recovery from surgery.