Clinical Pharmacology Studies Research Articles

ECG Evaluation as Part of the Clinical Pharmacology Strategy in the Development of New Drugs: A Review of Current Practices and Opportunities Based on Five Case Studies.

The International Conference on Harmonization (ICH) E14 document was revised in 2015 to allow concentration-corrected QT interval (C-QTc) analysis to be applied to data from early clinical pharmacology studies to exclude a small drug-induced effect on QTc. Provided sufficiently high concentrations of the drug are obtained in the first-in-human (FIH) study, this approach can be used to obviate the need for a designated thorough QT (TQT) study. The E14 revision has resulted in a steady reduction in the number of TQT studies and an increased use of FIH studies to evaluate electrocardiogram (ECG) effects of drugs in development. In this review, five examples from different sponsors are shared in which C-QTc analysis was performed on data from FIH studies. Case1 illustrates a clearly negative C-QTc evaluation, despite observations of QTc prolongation at high concentrations in nonclinical studies. In case2 C-QTc analysis of FIH data was performed prior to full pharmacokinetic characterization in patients, and the role of nonclinical assays in an integrated risk assessment is discussed. Case3 illustrates a positive clinical C-QTc relationship, despite negative nonclinical assays. Case4 demonstrates a strategy for characterizing the C-QTc relationship for a nonracemic therapy and formulation optimization, and case5 highlights an approach to perform a preliminary C-QTc analysis early in development and postpone the definitive analysis until proof of efficacy is demonstrated. The strategy of collecting and storing ECG data from FIH studies to enable an informed decision on whether and when to apply C-QTc analysis to obviate the need for a TQT study is described.

Abstract 1843: Dianhydrogalactitol (VAL-083) for the treatment of glioblastoma multiforme (GBM): Impact of glucose transporters for crossing the blood brain barrier (BBB)

Abstract Glucose transporters at the blood brain barrier (BBB) maintain the continuous high glucose and energy demands of the brain. These transporters have been targets for the creation of therapeutic molecules as a means to cross the BBB. The BBB has been a major limitation for the successful development of treatments for brain tumors. To date, only a limited number of lipophilic small chemical entities, which can cross the BBB, have been approved for the treatment of GBM. These include the nitrosoureas such as carmustine (BCNU) and lomustine (CCNU) and temozolomide (TMZ). VAL-083 is a di-epoxide substituted hexitol sugar (galactitol). It has a molecular weight of 146 and is highly water soluble. VAL-083 is active against several GBM cell lines and animal models and acts as a DNA targeting agent rapidly forming cross-links at the N7 position of guanine, resulting in lethal DNA double strand breaks and cancer cell death. Its is active in GBM patients, both newly diagnosed and recurrent. Furthermore, its activity is independent of the DNA repair enzyme MGMT which limits the effectiveness of O6 guanine alkylating agents such as the nitrosoureas and TMZ.In clinical pharmacology studies, VAL-083 rapidly accumulates in the cerebrospinal fluid (CSF) and brain tumor tissue. Studies with radiolabeled VAL-083 have shown a half-life of ~ 20 h in CSF vs 2h for plasma post-IV infusion. Recent clinical studies in newly diagnosed GBM patients demonstrated levels of VAL-083 in CSF at least as high as in plasma two hours post infusion (ratio 1.24 ± 0.35). In comparison, peak TMZ concentrations in the CSF are ~30% of that of the plasma.Due to its structural similarity with glucose, we have initiated in vitro glucose transporter studies to identify if SGLTs (sodium dependent glucose cotransporters) or GLUTs (glucose transporters) are contributing to brain penetration. Our initial studies evaluated VAL-083 as a substrate of the human SGLT1 and SGLT2 SLC (solute carrier) transporters. HEK293 cells expressing either the SGLT1 or SGLT2 transporter were exposed to VAL-083 at 3 and 15 µM for 2 and 20 min. The probe substrate methyl-α-D- glucopyranoside (AMG) was used as a positive control, as well as comparison against the reference inhibitors phloridzin dihydrate (100 µM, 20 min) for SGLT1 and dapagliflozin (0.3 µM, 10 min) for SGLT2. Surprisingly, no transporter-specific accumulation of VAL-083 by SGLT1 or SGLT2 was observed. Ongoing studies in CaCo-2 cells are investigating whether VAL-083 is transported via other glucose transporters including GLUT1. GLUT1 is expressed on erythrocytes and the endothelial cells of the BBB and may be highly relevant to the uptake of VAL-083 into brain tissue. The results of these studies will be reported at the meeting. Citation Format: John M. Langlands, Sarath Kanekal, Anne Steino, Armando Mendez, Zoltan Karman, Beata Martonne Toth, Krisztina Heredi-Szabo, Dennis Brown. Dianhydrogalactitol (VAL-083) for the treatment of glioblastoma multiforme (GBM): Impact of glucose transporters for crossing the blood brain barrier (BBB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1843.

A Review on Clinical and Preclinical Pharmacological Studies in Muskmelon Fruit

Muskmelons are extensively cultivated throughout India particularly in the hot and dry North-Western are as belongs to family Cucurbitaceae. Muskmelon, also referred to as ‘sweet melon,’ got its name from its strong musky smell. It is a yellow-coloured fruit with tempting sweetness and a pleasant aroma. Generally, muskmelon fruit is eaten fresh or made salad or as a dessert. Seed kernels are used in soups and stews as a thickening, emulsifying, fat binding and flavouring agent. Muskmelon has rich calories, carbohydrate, protein, dietary fibre, sodium, vitamin A, folic acid, niacin, Vitamin C it is also nutrient enriched with good quantities of calcium, magnesium, potassium and carotenoids, does not have fat, cholesterol or saturated fat and have high content of polyphenol antioxidants which enhance the immune function and cardiovascular system. Polyphenols regulates nitric oxide that assists in prevention of heart attacks and also strengthens blood vessels. It can be used for weight loss purposes. During summer, it prevents dehydration of body and replenishes water content and electrolytes in the body. Musk melon is scientifically proven for its useful medicinal values such as Analgesic and Anti-inflammatory Activity, Anti-oxidant and Anti-Vitiligo Effect, Anti-ulcer activity, Anti-cancer activity, Hepato-protective activity, Diuretic effect, Anti-diabetic activity, Antibacterial activity, Antifungal activity. In this review, the effort has been made to focus on the pharmacological activities of the Muskmelon.

What is the value of faster acting prandial insulin? Focus on ultra rapid lispro.

Rapid‐acting insulins (RAIs) have been instrumental in the management of diabetes because of their improved postprandial glucose (PPG) control compared with regular human insulin. However, their absorption rate and time action following subcutaneous administration still falls short of the normal physiological response to meal consumption, increasing the risk of early postmeal hyperglycaemia and late postmeal hypoglycaemia. Increased demand for faster acting insulins, which can quickly control PPG excursions without increasing the risk of late hypoglycaemia, led to the development of ultra‐rapid–acting insulins, including ultra‐rapid lispro (URLi). URLi is a novel formulation of insulin lispro with accelerated absorption driven by two excipients: treprostinil, which increases local vasodilation, and citrate, which increases local vascular permeability. Clinical pharmacology studies consistently showed an earlier onset and shorter duration of action with URLi compared with Lispro. In a head‐to‐head study with Faster aspart, Aspart and Lispro, URLi was absorbed faster, provided earlier insulin action, and more closely matched physiological glucose response than the other insulins tested. URLi's unique pharmacokinetic properties increase its potential for improved PPG control beyond that achieved with RAIs. Indeed, in pivotal phase 3 trials, URLi was superior to Lispro for PPG control both at 1 and 2 hours after a meal in type 1 and type 2 diabetes with multiple daily injections, and in type 1 diabetes with continuous subcutaneous insulin infusion. This was achieved without increasing the risk of hypoglycaemia. In this review, we focus on the clinical and pharmacological evidence for URLi in the treatment of diabetes and discuss the potential benefits and considerations with URLi compared with RAIs.

Validation and Clinical Application of a Liquid Chromatography-Ultraviolet Detection Method to Quantify Dolutegravir in Dried Blood Spots.

BackgroundDolutegravir is currently the preferred component of first-line antiretroviral therapy. To facilitate clinical pharmacology studies in key populations, quantitative analytical methods compatible with microsampling and adaptable to resource-limited settings are desirable. The authors developed and validated a liquid chromatography-ultraviolet detection method to quantify dolutegravir in dried blood spots (DBS).MethodsCalibration standards and quality control samples were prepared by spotting 50 μL of dolutegravir-spiked whole blood on each circle of DBS cards. Three spots (two 6-mm punches/spot) were extracted with methanol. Chromatographic separation was achieved with gradient elution of acetonitrile/potassium phosphate monobasic buffer (pH 5) on a reverse-phase C18 column (flow rate, 1 mL/min) using pioglitazone as the internal standard. UV detection was performed at 260 nm. In the clinical pharmacokinetic study, DBS from finger prick was collected from participants (n = 10) at 8 time points over 12 h post-dosing, with paired plasma at 1 and 12 h. The method was used to quantify dolutegravir, estimating pharmacokinetic parameters. Agreement between DBS and plasma concentrations was evaluated using linearity and Bland-Altman plots.ResultsThe method was validated over the concentration range of 0.4-10 μg/mL, accuracy was 102.4-114.8%, and precision was 3.4-14.7%. The mean recovery was 42.3% (%CV: 8.3). The mean (±standard deviation) dolutegravir concentration in DBS was 37.5% (±3.8%) lower than that in the plasma. DBS-derived and measured plasma concentrations showed strong correlation with linearity (R2 = 0.9804) and Bland-Altman plots. Means (%CV) of AUC, Cmax, and C24 from the DBS-derived plasma concentration were 37.8 (23.2) μg.h/mL, 2.7 (24.7) μg/mL and 1.34 (31.6) μg/mL, respectively.ConclusionsThe application of this simple, accurate, and precise method will expand opportunities for clinical assessment of dolutegravir in resource-limited settings.

A Review on Bioanalytical Method Development and Validation by Liquid Chromatography–Tandem Mass Spectrometry

The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development, culminating in a marketing approval. The objective of this paper is to review the sample preparation of drug in biological matrix and to provide practical approaches for determining selectivity, specificity, limit of detection, lower limit of quantitation, linearity, range, accuracy, precision, recovery, stability, ruggedness, and robustness of liquid chromatographic methods to support pharmacokinetic (PK), toxicokinetic, bioavailability, and bioequivalence studies. Bioanalysis, employed for the quantitative determination of drugs and their metabolites in biological fluids, plays a significant role in the evaluation and interpretation of bioequivalence, PK, and toxicokinetic studies. Selective and sensitive analytical methods for quantitative evaluation of drugs and their metabolites are critical for the successful conduct of pre-clinical and/or biopharmaceutics and clinical pharmacology studies.

Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species.

Background:The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer’s disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors.Objective:To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans.Methods:The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey’s post hoc test and clinical data used summary statistics.Results:LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aβ1–40 and 0.228±0.244 nM for Aβ1–42 in PDAPP neuronal cultures. In dogs, CSF Aβ1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ1–42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans.Conclusion:LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

Clinical pharmacology to support monoclonal antibody drug development

<abstract> <p>Clinical pharmacology is a multidisciplinary function playing a critical role in the monoclonal antibody development. Besides the requirements of understanding pharmacology, pharmacokinetics, model simulation, biostatistics and immunogenicity, wisely implementation of tactics and strategies to fulfill the agencies' requirements per guidance documents are critical. In this review, clinical pharmacology studies categorized as required, target dependent, development strategy dependent, and not usually needed are discussed. The review ends with the outlook of recent initiations in the clinical pharmacology such as the application of QSP with the integration of AI and machine learning technologies.</p> </abstract>

Clinical Pharmacology in Drug Development for Rare Diseases in Neurology: Contributions and Opportunities.

Several challenges are associated with rare disease drug development in neurology. In this article, we summarize the US Food and Drug Administration's experience with clinical drug development for rare neurological diseases and discuss clinical pharmacology's critical contributions to drug development for rare diseases. We used publicly available information to identify and screen drug products approved for rare neurological indications between 1983 and 2019. We highlighted cases in which clinical pharmacology contributed to the evidence of drug efficacy, dose selection for pivotal clinical trials, dose optimization based on intrinsic and extrinsic factors, pharmacokinetic bridging for formulations, and efficacy bridging across different racial groups. Fifty-one approved drug products were identified since the introduction of the Orphan Drug Act in 1983. Interestingly, the number of approvals in the last few years increased significantly, probably due to advances in genomic research and targeted drug modalities. Evaluation of dose selection in patient populations showed that in 52% of cases, the sponsors did not evaluate efficacy for more than one or two dose levels throughout the development program. Clinical pharmacology studies to evaluate the effect of intrinsic or extrinsic factors were adequately characterized in most of the applications. With the expansion of model informed drug development applications, (e.g., quantitative systems pharmacology and deep learning neural network models), the role and impact of clinical pharmacology is expected to grow exponentially in the next decade and enhance the development of novel treatment modalities for neurological rare diseases.

Biosimilars: evolution of approaches to the development, regulation, life cycle control and interchangeability management

The legal framework for biosimilar medicinal product was first established in 2004 in the European Union and later in the USA. Since then, based on the scientific and regulatory experience with biosimilarity assessment, regulatory approaches have evolved considerably. A clear understanding of the capabilities of each development stage in assessing comparability in terms of power to identify differences and assess their relevance to the final clinical outcome gradually accumulated. In addition to the commitment to the biosimilarity approach, it is important to comply with the general requirements applicable to any drugs produced at an industrial scale. Experience showed that the demonstration of biosimilarity based on a range of analytical and functional tests and mainly clinical pharmacological studies is universal and allows extrapolating therapeutic indications. The establishment of biosimilar interchangeability, since the active substance by definition is a version of the active substance of the corresponding reference biological product, can introduce additional difficulties. A single approach to the establishment of biosimilar interchangeability has not yet been developed.

Cycloserine and Linezolid for Tuberculosis Meningitis: Pharmacokinetic Evidence of Potential Usefulness.

The ability of antituberculosis drugs to cross the blood-brain barrier and reach the central nervous system is critical to their effectiveness in treating tuberculosis meningitis (TBM). We sought to fill a critical knowledge gap by providing data on the ability of new and repurposed antituberculosis drugs to penetrate into the cerebrospinal fluid (CSF). We conducted a clinical pharmacology study among patients treated for TBM in Tbilisi, Georgia, from January 2019 until January 2020. Serial serum and CSF samples were collected while patients were hospitalized. CSF was collected from routine lumbar punctures with the timing of the lumbar puncture alternating between 2 and 6 hours to capture early and late CSF penetration. A total of 17 patients treated for TBM (8 with confirmed disease) were included; all received linezolid, with a subset receiving cycloserine (5), clofazimine (5), delamanid (4), and bedaquiline (2). All CSF measurements of bedaquiline (12), clofazimine (24), and delamanid (19) were below the limit of detection. The median CSF concentrations of cycloserine at 2 and 6 hours were 15.90 and 15.10 µg/mL with adjusted CSF/serum ratios of 0.52 and 0.66. CSF concentrations of linezolid were 0.90 and 3.14 µg/mL at 2 and 6 hours, with adjusted CSF/serum ratios of 0.25 and 0.59, respectively. CSF serum linezolid concentrations were not affected by rifampin coadministration. Based on moderate to high CSF penetration, linezolid and cycloserine may be effective drugs for TBM treatment, whereas the utility of bedaquiline, delamanid, and clofazimine is uncertain given their low CSF penetration.

Insights and lessons learned from a prospective clinical pharmacology study in allogeneic hematopoietic stem cell transplant during the COVID-19 pandemic.

Insights and lessons learned from a prospective clinical pharmacology study in allogeneic hematopoietic stem cell transplant during the COVID-19 pandemic.

Maternal-Fetal Pharmacology of Drugs: A Review of Current Status of the Application of Physiologically Based Pharmacokinetic Models.

Pregnancy and the postpartum period are associated with several physiological changes that can alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. For certain drugs, dosing changes may be required during pregnancy and postpartum to achieve drug exposures comparable to what is observed in non-pregnant subjects. There is very limited data on fetal exposure of drugs during pregnancy, and neonatal exposure through transfer of drugs via human milk during breastfeeding. Very few systematic clinical pharmacology studies have been conducted in pregnant and postpartum women due to ethical issues, concern for the fetus safety as well as potential legal ramifications. Over the past several years, there has been an increase in the application of modeling and simulation approaches such as population PK (PopPK) and physiologically based PK (PBPK) modeling to provide guidance on drug dosing in those special patient populations. Population PK models rely on measured PK data, whereas physiologically based PK models incorporate physiological, preclinical, and clinical data into the model to predict drug exposure during pregnancy. These modeling strategies offer a promising approach to identify the drugs with PK changes during pregnancy to guide dose optimization in pregnancy, when there is lack of clinical data. PBPK modeling is also utilized to predict the fetal exposure of drugs and drug transfer via human milk following maternal exposure. This review focuses on the current status of the application of PBPK modeling to predict maternal and fetal exposure of drugs and thereby guide drug therapy during pregnancy.

Diversity and Inclusion in Drug Development: Rethinking Intrinsic and Extrinsic Factors with Patient Centricity.

Diversity and Inclusion in Drug Development: Rethinking Intrinsic and Extrinsic Factors with Patient Centricity.

Maxacalcitol Pharmacokinetic-Pharmacodynamic Modeling and Simulation for Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis.

Maxacalcitol was approved in Taiwan in 2018 as the first active vitamin D3 injection for secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis. However, no data from any clinical study with maxacalcitol in Taiwanese patients is available. This analysis aimed to evaluate the profiles of parathyroid hormone (PTH) and calcium (Ca) concentrations in Taiwanese SHPT patients on hemodialysis and maxacalcitol. We developed population pharmacokinetic (PK) and pharmacodynamic (PD) models using a modeling and simulation approach. The data for these analyses were obtained from two studies: a clinical pharmacology study in Japanese patients and an ethnic comparison study in healthy Japanese and -Taiwanese volunteers. We then conducted a simulation study with a PK-PD model comprising the PK and PD models developed here. Serum maxacalcitol concentration profile was modeled using a two-compartment model that took into consideration the distribution of concentrations below the lower limit of quantification. An ethnic difference in clearance was included in the PK model as a covariate. A PD model that used a PTH/Ca feedback loop best described the observed data. There were no significant differences in Ca or PTH concentrations between Taiwanese and Japanese based on the simulation results from our PK-PD model, even though maxacalcitol exposure was approximately 40% higher in Taiwanese than in Japanese. On the basis of these population PK and PD analyses and the clinical study conducted in Japan, there is no clinically relevant difference between Taiwanese and Japanese in terms of serum Ca or PTH levels.

Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers.

AimsWhereas intravenous administration of Toll‐like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies.MethodsEighteen healthy male volunteers received 2 or 4 intradermal 5 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate.ResultsLPS elicited a visible response and returned to baseline at 48 hours. Erythema, perfusion and temperature were statistically significant (P < .0001) over a 24‐hour time course compared to saline. The protein response was dominated by an acute interleukin (IL)‐6, IL‐8 and tumour necrosis factor response followed by IL‐1β, IL‐10 and interferon‐γ. The cellular response consisted of an acute neutrophil influx followed by different monocyte subsets and dendritic cells.DiscussionIntradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well‐tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti‐inflammatory investigational compounds in proof of pharmacology studies.

The necessary conduct: Exploratory multiregional clinical trials in East Asia.

Various studies have highlighted the importance of ethnic differences. The consideration of ethnic differences in the field of individualized pharmacotherapy is imperative. Therefore, various organizations and networks across countries should aim to conduct multicountry and multiregional clinical trials (MRCTs). If there is solid evidence available to evaluate the existence of ethnic differences between the same regional areas, it will lead to an increase in the efficiency of drug development. The purpose of this paper was to compare the approval dosing regimen among four Asian countries (Korea, Japan, China, and Taiwan) and elucidate the readiness and current status of the implementation of the International Conference on Harmonization (ICH) E17 guidelines on MRCTs. Reducing unnecessary clinical trials via multinational clinical trials in East Asian countries is also suggested. The approved dosing regimens for some drugs in the four Asian countries were similar; however, some differences might be caused by differences in legislation, even though there were no ethnic differences. This indicates that there are several roles to be expected of the Asia Clinical Pharmacology study network for exploratory MRCTs, which would lead to the accumulation of evidence for MRCTs, ultimately accelerating the efficiency of drug development in East Asian countries. The exposure of the new treatment to the necessary patients through collaborative research coordination and simultaneous multinational subject recruitment would serve its role in providing East Asia with specific personalized medicine with a high treatment success rate.

Are clinical pharmacology studies still needed in childhood acute lymphoblastic leukemia?

Not available.

The New S7B/E14 Question and Answer Draft Guidance for Industry: Contents and Commentary.

In August 2020, the International Council on Harmonisation (ICH) released a new draft document, which for the first time combined nonclinical (S7B) and clinical (E14) Questions and Answers (Q&As) into 1 document. FDA describes the revision as a “value proposition”: if the human ether‐à‐go‐go assay and the in vivo study are performed in a standardized way, the number of dedicated thorough QT (TQT) studies can be reduced. In this article, we describe and discuss the Q&As that relate to clinical ECG evaluation. If supported by negative standardized nonclinical assays, Q&A 5.1 will obviate the need for a TQT study in the case that a >2‐fold exposure margin vs high clinical scenario cannot be obtained. Q&A 6.1 addresses drugs that are poorly tolerated in healthy subjects and cannot be studied at high doses or in placebo‐controlled studies; it therefore mainly applies to oncology drugs. It will enable sponsors to claim that a new drug has a “low likelihood of proarrhythmic effects” in the case that the mean corrected QT effect is <10 milliseconds at the time of market application. The E14 2015 revision allowed application of concentration–corrected QT analysis on data from routinely performed clinical pharmacology studies, for example, the first‐in‐human study and the proportion of dedicated TQT studies has since steadily decreased. It can be foreseen that the proposed new revision will further reduce the number of TQT studies. To achieve harmonization across regulatory regions, it seems important to reach consensus within the International Council on Harmonisation group on the new threshold proposed in 6.1. For this purpose, the Implementation Working Group has asked for public comments.

Dotinurad: a novel selective urate reabsorption inhibitor for the treatment of hyperuricemia and gout

ABSTRACT Introduction Gout is an inflammatory disease triggered by deposition of urate crystals secondary to longstanding hyperuricemia, and its management implies both the treatment of flares and management of hyperuricemia. Dotinurad is a selective urate reabsorption inhibitor (SURI), potently inhibits urate transporter 1 in the apical surface of renal proximal tubular cells, and has been approved for the treatment of gout and hyperuricemia in Japan. Areas covered This overview of dotinurad covers nonclinical and clinical pharmacology studies in special populations and its efficacy and safety in Japanese hyperuricemic patients with and without gout. Expert opinion Dotinurad, as an SURI, is expected to inhibit urate reabsorption more effectively than conventional urate-lowering agents. It is noninferior to benzbromarone or febuxostat in reducing serum urate levels in hyperuricemic patients with or without gout. Its efficacy is not attenuated in patients with mild to moderate renal impairment or with hepatic impairment. At a maintenance dose of 2 or 4 mg once daily, most patients achieved the target serum urate level of ≤6 mg/dL in a long-term study. No findings that raised safety concerns, including liver injury, were identified. Dotinurad is expected to be a new therapeutic option in hyperuricemic patients with and without gout.