New drug development (NDD) for intractable diseases such as cancer and Alzheimer's disease has been challenging in recent years because it is difficult to evaluate the therapeutic efficacy of new drugs and the response of individual patients. Thus biomarkers might be a useful tool to facilitate NDD because they can be used to evaluate accurately drug responses. Biomarkers include proteins, metabolites, and genetic targets; imaging data and can also be used in pre-clinical studies, clinical trials, and post-marketing surveillance. In pre-clinical studies, biomarkers are used as an index of the pharmacological and toxicological effects of a new drug, which may help to predict the clinical response. In clinical studies, biomarkers are widely used as an index of clinical efficacy and safety for dose-adjustment and for patient selection. In post-clinical studies, biomarkers may facilitate the evaluation of drug responses, as well as aid improvements in drug efficacy. Several points should be considered for biomarker-guided NDD. First, the clinical study design is very important and must be suitable to permit the use of the relevant biomarkers. The analytical methods should be carefully evaluated, and evidence should be provided regarding the physiological significance and relevance of the biomarker with regard to its intended use. Regulatory sciences are required to resolve these issues and bridge the gap between basic science and clinical studies that involve biomarkers.
Drug-induced liver injury is a main reason of regulatory action pertaining to drugs, including restrictions to clinical indications and withdrawal from the marketplace. Acetaminophen (APAP) is a commonly used and effective analgesic/antipyretic agent and relatively safe drug even in long-term treatment. However, it is known that APAP at therapeutic doses may cause hepatotoxicity in some individuals. Hence great efforts have been made to identify risk factors for APAP-induced chronic hepatotoxicity. We investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model. We employed daytime restricted fed (RF) rats as a modified-nutritional state model for human APAP-induced hepatotoxicity. RF and ad libitum fed (ALF) rats were given APAP at 0, 300, and 500 mg/kg for 3 months. Plasma and urinary glutathione-related metabolomes and liver function parameters were measured during the dosing period. Endogenous metabolites forming at different levels between the RF and ALF rats could be potential predisposition biomarkers for APAP-induced hepatotoxicity. In addition, RF rats were considered a useful model to estimate the contribution of nutritional state of patients to APAP-induced chronic hepatotoxicity. In this article we report our current research focusing on nutritional state as risk factor for APAP-induced chronic hepatotoxicity and our findings of hepatotoxicity biomarkers.
Mogamulizumab (Moga; KW-0761) is a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody engineered to exert potent antibody-dependent cellular cytotoxicity (ADCC). A collaborative investigation with industry in preclinical studies has demonstrated in vitro and in vivo efficacy via ADCC for adult T-cell leukemia/lymphoma (ATLL) and CCR4-positive peripheral T-cell lymphoma (PTCL). In a phase I study, once-weekly administration of mogamulizumab (0.01-1.0 mg/kg) for 4 weeks was well tolerated. In a phase II study of once-weekly mogamulizumab (1.0 mg/kg) for 8 weeks in relapsed/refractory ATLL patients, an overall response rate of 50% including 30% complete response rate with a median progression-free survival of 5.2 months was observed. The drug was subsequently approved by Pharmaceuticals and Medical Devices Agency(PMDA) in March 2012. Because CCR4 is abundantly expressed on the surface of effector regulatory T cells, a phase I study is being conducted to enhance antitumor immune response in patients with solid tumors. However, approximately 60% of patients receiving mogamulizumab experience skin eruption with 19% showing grade ≥3 rash. Postmarketing surveillance of mogamulizumab revealed a 3-4% incidence rate of skin-related serious adverse events (SAEs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Therefore we initiated a search for predictive genomic biomarkers in the blood of patients with ATLL or solid tumors prior to treatment with mogamulizumab for not only efficacy but also immune-related SAEs. We believe the results of this study may lead to safer and more efficient use of this agent in the near future.
To prevent adverse drug reactions in the post-marketing phase, therapeutic drug monitoring and various laboratory tests have been used for decades. Recently, data on associations between drug adverse reactions and biomarkers based on “omics” technologies/studies have been increasing. Using genomic biomarkers, patients at high risk for developing side effects can be distinguished before initiating medical treatment, allowing the choice of an appropriate drug/initial dosage regimen. Biomarkers based on proteomics or metabolomics can detect the onset of adverse reactions at an earlier stage than can be accomplished with classical laboratory tests. However, the clinical use of drug safety-related biomarkers is still limited compared with biomarkers that predict drug efficacy of, for example, molecular-targeted drugs. In this symposium, genomic biomarkers associated with the safety of anticancer drugs and idiosyncratic adverse reactions are introduced and compared between Japan and other countries. Prospective studies evaluating the application of screening tests to prevent adverse drug reactions are also shown, and steps necessary to accelerate the use of drug safety-related biomarkers are discussed.
Biomarkers (BM) are gradually being recognized as useful tools to evaluate drugs from development through post-approval periods. In the past decade, practical use of BM has advanced particularly in the field of anti-cancer drug development. Regardless of the use of BM, approximately 10% of key clinical trials for new drug applications of anti-cancer drugs were conducted as multiregional clinical trials. In the era of globalization of drug development, common understanding regarding the usefulness and limitations of BM availabilities in drug evaluation will contribute to provide better evidence in multiple clinical trials. However, only two guidelines regarding BM, i.e., terminologies of pharmacogenomics (E15 guideline) and document format in BM qualification submission to regulatory agencies (E16 guideline), have been harmonized in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) so far. It is important to strengthen international harmonization and collaboration among academia, industry, and regulatory agencies, followed by the establishment of an international guideline on the application of BM in drug evaluation. This article outlines the regulatory perspective on remaining challenges and current Pharmaceuticals and Medical Devices Agency (PMDA) activities for use of BM in drug evaluation.
Since there is accumulating evidence to indicate that introduction of early palliative care for cancer patients may improved their quality of life or survival rates, the number of patients receiving pain relief by narcotic analgesics in conjunction with chemotherapy is predicted to increase. Therefore to provide effective combination treatments it is important to evaluate basic evidence regarding drug-drug interactions between anti-cancer drugs and narcotics. We have focused on P-glycoprotein (P-gp), a drug efflux transporter, in small intestine where the absorption process of drugs administered via oral route is greatly limited. Then, we revealed that repeated oral treatment with etoposide (ETP) increases P-gp levels in the small intestinal membrane via RhoA/ROCK activation, leading to decrease in analgesia of morphine, a P-gp substrate drug, with alteration of its disposition after oral administration. Furthermore, we found that activation of ezrin/radixin/moesin (ERM), scaffold proteins that regulate plasma membrane localization or function of certain plasma membrane proteins such as P-gp, are involved in this mechanism. Of particular interest is that among ERM proteins, radixin may contribute, at least in part, to increased expression of P-gp in the small intestine under repeated oral treatment with ETP.
The transport of opioid analgesics across the blood-brain barrier (BBB) is an important determinant of their therapeutic effects. The human brain is protected by the BBB, which consists of brain capillary endothelial cells linked with tight junctions. It is well established that the polarized expression of numerous transporters and receptors at the brain capillary endothelial cells controls the blood-brain exchange of nutrients, waste products deriving from neurotransmitter substances, and drugs. Morphine is a substrate of P-glycoprotein and the P-glycoprotein-mediated efflux transport at the BBB maintains a lower unbound concentration of morphine in the brain compared with plasma. On the other hand, oxycodone has 3 times higher unbound concentration in the brain than plasma, suggesting an active transport mechanism of oxycodone across the BBB into the brain. In vitro transport study using BBB model cells showed that oxycodone is efficiently transported by a proton-coupled organic cation antiporter. Human BBB model cells also retain the proton-coupled organic cation antiporter. Although adjuvant analgesics include many cationic drugs that interact with oxycodone transport across the BBB at relatively high concentrations, these drugs would enhance the antinociceptive effects of oxycodone with little effect on oxycodone pharmacokinetics, including brain distribution at therapeutically or pharmacologically relevant concentrations. These findings support the idea that proton-coupled organic cation antiporter-mediated transport of oxycodone at the BBB plays a role in determining the therapeutic efficacy of this opioid analgesic drug.
It is known that morphine is less effective for patients with neuropathic pain, accounting for approximately 70% of cancer patients with severe pain. One of the causes of the decline is reported as a decreased function of the μ-opioid receptor, which binds to the active metabolites of morphine in the mesencephalic ventral tegmental area. However, the details of this mechanism are not understood. We hypothesized that a decrease in the concentration of morphine in the brain reduces its analgesic effect on neuropathic pain, and found that the analgesic effect of morphine was correlated with its concentration in the brain. We examined the reason for the decreased concentration of morphine in the brain in case of neuropathic pain. We discovered increased P-glycoprotein (P-gp) expression in the small intestine, increased expression and activity of UGT2B in the liver, and increased P-gp expression in the brain under conditions of neuropathic pain. In this symposium, we argue that low brain morphine concentration is considered one of the causes of lower sensitivity to morphine in neuropathic pain patients.
Use of prescription opioids for cancer pain according to the World Health Organization analgesic ladder has been accepted in Japan. Although oxycodone and fentanyl are commonly used as first-line analgesics, a few clinical reports have been published on interindividual variations in their pharmacokinetics and clinical responses in cancer patients. (1) Some factors relating to CYP2D6, CYP3A, ATP-binding cassette sub-family B member 1 (ABCB1), and opioid receptor mu 1 (OPRM1) involve oxycodone pharmacokinetics and sensitivity in humans. The relations between their genetic variations and clinical responses to oxycodone are being revealed in limited groups. In our study, the impact of genetic variants and pharmacokinetics on clinical responses to oxycodone were evaluated in Japanese populations. (2) Opioid switching improves the opioid tolerance related to the balance between analgesia and adverse effects. Some patients have difficulty in obtaining better opioid tolerance in recommended conversion ratios. The activities of CYP3A, ABCB1, and OPRM1 contribute to the interindividual variations in clinical responses to fentanyl in cancer patients. However, the variations in opioid switching remain to be clarified in clinical settings. In our study, genetic factors related to interindividual variations in clinical responses in opioid switching to fentanyl were revealed in Japanese populations. In this symposium review, the possibility of approaches to personalized palliative care using opioids based on genetic variants of CYP2D6, CYP3A5, ABCB1, and OPRM1 is discussed.
Radiation therapy kills cancer cells in part by flood of free radicals. Radiation ionizes and/or excites water molecules to create highly reactive species, i.e. free radicals and/or reactive oxygen species. Free radical chain reactions oxidize biologically important molecules and thereby disrupt their function. Tissue oxygen and/or redox status, which can influence the course of the free radical chain reaction, can affect the efficacy of radiation therapy. Prior observation of tissue oxygen and/or redox status is helpful for planning a safe and efficient course of radiation therapy. Magnetic resonance-based redox imaging techniques, which can estimate tissue redox status non-invasively, have been developed not only for diagnostic information but also for estimating the efficacy of treatment. Redox imaging is now spotlighted to achieve radiation theranostics.
Tissue redox status is one of the most important parameters to maintain homeostasis in the living body. Numerous redox reactions are involved in metabolic processes, such as energy production in the mitochondrial electron transfer system. A variety of intracellular molecules such as reactive oxygen species, glutathione, thioredoxins, NADPH, flavins, and ascorbic acid may contribute to the overall redox status in tissues. Breakdown of redox balance may lead to oxidative stress and can induce many pathological conditions such as cancer, neurological disorders, and aging. Therefore imaging of tissue redox status and monitoring antioxidant levels in living organisms can be useful in the diagnosis of disease states and assessment of treatment response. In vivo redox molecular imaging technology such as electron spin resonance imaging (ESRI), magnetic resonance imaging (MRI), and dynamic nuclear polarization (DNP)-MRI (redox molecular imaging; ReMI) is emerging as a viable redox status imaging modality. This review focuses on the application of magnetic resonance technologies using MRI or DNP-MRI and redox-sensitive contrast agents.
For indirect tissue observation, electron-spin, Overhauser-enhanced, dynamic nuclear polarization magnetic resonance imaging (DNP-MRI) is a useful technique. However, its sensitivity and resolution are low compared with the clinical MRI apparatus. By switching to electron spin resonance (ESR) excitation, the magnetic field of the NMR detection, field cycle technique, which aims to improve resolution, was proposed. However, the effect of eddy currents or current value was altered unsatisfactorily. A team at Kyushu University proposed a new DNP-MRI technique capable of improving NMR detection field by preparing in advance a magnetic field, which was connected by the sample transport system. By developing a mobile MRI method that can be used while moving, and fastening the sample in a disk that rotates at a constant speed, they have developed a circular transport DNP-MRI method that greatly reduces the load on the sample. The circular transport DNP-MRI system comprises a circular sample transport system, detection of an MRI magnetic field of 1.5 T, and ESR excitation magnetic field of 20 mT. The developed DNP-MRI had a clear glass tube phantom and resolution of 0.15 mm, and was successful in imaging multiple radical resonant points. It has been commercialized by Japan Redox Limited. In the process of equipment commercialization, a new digital spectrometer has been developed, which expanded the MRI apparatus.
Altered antioxidant status has been implicated in schizophrenia. Microglia are major sources of free radicals such as superoxide in the brain, and play crucial roles in various brain diseases. Recent postmortem and imaging studies have indicated microglial activation in the brain of schizophrenia patients. Animal models that express some phenotypes of schizophrenia have revealed the underlying microglial pathology. In addition, minocycline, an antibiotic and the best known inhibitor of microglial activation, has therapeutic efficacy in schizophrenia. We have recently revealed that various antipsychotics directly affect microglia via proinflammatory reactions such as oxidative stress, by in vitro studies using rodent microglial cells. Based on these findings, we have suggested that microglia are crucial players in the brain in schizophrenia, and modulating microglia may be a novel therapeutic target. In this review paper, we introduce our hypothesis based on the above evidence. The technique of in vivo molecular redox imaging is expected to be a powerful tool to clarify this hypothesis.
Therapeutic drug monitoring (TDM) of vancomycin (VCM) is recommended to minimize its nephrotoxicity and maximize efficacy. Recently, the concept of systemic inflammatory response syndrome (SIRS) has been introduced to describe a clinical state resulting from the actions of complex intrinsic mediators in an acute-phase systemic response. However, there are few reports on the pharmacokinetics of VCM in patients with SIRS. This study investigated the effect of SIRS on the pharmacokinetics of VCM by analyzing the predictability of TDM and pharmacokinetic parameters in 31 non-SIRS patients and 52 SIRS patients, with stratification by SIRS score. The mean prediction error (ME) and mean absolute prediction error in SIRS score 2 and 3 patients differed from those in non-SIRS patients. The ME in the score 4 group showed a negative value. In the comparison of pharmacokinetic parameters by SIRS score, a significantly lower CLvcm value was observed at score 4 compared with scores 2 and 3, a higher Vd value was observed at score 4 compared with non-SIRS and at score 3, and a longer T1/2 was observed at score 2. In the comparison of patient characteristics by SIRS score, albumin, aspartate aminotransferase, and alanine aminotransferase levels showed differences among the scores. However, no correlation was observed between VCM pharmacokinetics and these three laboratory parameters. These findings suggest that the pharmacokinetics of VCM may be affected by the pathology of SIRS rather than by patient characteristics.
The KJ method (named for developer Jiro Kawakita; also known as affinity diagramming) is widely used in participatory learning as a means to collect and organize information. In addition, the World Café (WC) has recently become popular. However, differences in the information obtained using each method have not been studied comprehensively. To determine the appropriate information selection criteria, we analyzed differences in the information generated by the WC and KJ methods. Two groups engaged in sessions to collect and organize information using either the WC or KJ method and small group discussions were held to create “proposals to improve first-year education”. Both groups answered two pre- and post- session questionnaires that asked for free descriptions. Key words were extracted from the results of the two questionnaires and categorized using text mining. In the responses to questionnaire 1, which was directly related to the session theme, a significant increase in the number of key words was observed in the WC group (p=0.0050, Fisher's exact test). However, there was no significant increase in the number of key words in the responses to questionnaire 2, which was not directly related to the session theme (p=0.8347, Fisher's exact test). In the KJ method, participants extracted the most notable issues and progressed to a detailed discussion, whereas in the WC method, various information and problems were spread among the participants. The choice between the WC and KJ method should be made to reflect the educational objective and desired direction of discussion.