In silico prediction of ADME and pharmacokinetics: Report of an expert meeting organised by COST B15

The computational approach is one of the newest and fastest developing techniques in pharmacokinetics, ADME (absorption, distribution, metabolism, excretion) evaluation, drug discovery and toxicity. However, to date, the software packages devoted to ADME prediction, especially of metabolism, have not yet been adequately validated and still require improvements to be effective. Most are 'open' systems, under constant evolution and able to incorporate rapidly, and often easily, new information from user or developer databases. Quantitative in silico predictions are now possible for several pharmacokinetic (PK) parameters, particularly absorption and distribution. The emerging consensus is that the predictions are no worse than those made using in vitro tests, with the decisive advantage that much less investment in technology, resources and time is needed. In addition, and of critical importance, it is possible to screen virtual compounds. Some packages are able to handle thousands of molecules in a few hours. However, common experience shows that, in part at least for essentially irrational reasons, there is currently a lack of confidence in these approaches. An effort should be made by the software producers towards more transparency, in order to improve the confidence of their consumers. It seems highly probable that in silico approaches will evolve rapidly, as did in vitro methods during the last decade. Past experience with the latter should be helpful in avoiding repetition of similar errors and in taking the necessary steps to ensure effective implementation. A general concern is the lack of access to the large amounts of data on compounds no longer in development, but still kept secret by the pharmaceutical industry. Controlled access to these data could be particularly helpful in validating new in silico approaches.     

Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery

Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans; therefore, these mice are useful for predicting human drug metabolism and PK. In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery.     

A decade of machine learning-based predictive models for human pharmacokinetics: Advances and challenges

Traditionally, in vitro and in vivo methods are useful for estimating human pharmacokinetics (PK) parameters; however, it is impractical to perform these complex and expensive experiments on a large number of compounds. The integration of publicly available chemical, or medical Big Data and artificial intelligence (AI)-based approaches led to qualitative and quantitative prediction of human PK of a candidate drug. However, predicting drug response with these approaches is challenging, partially because of the adaptation of algorithmic and limitations related to experimental data. In this report, we provide an overview of machine learning (ML)-based quantitative structure–activity relationship (QSAR) models used in the assessment or prediction of PK values as well as databases available for obtaining such data.     

MODFIT: a pharmacokinetics computer program

This paper presents a computer program, MODFIT, written in FORTRAN, primarily for use on the Digital Equipment Company VAX series computers for the mathematical analysis of concentration-time data. Drug data generated from biological fluids and tissues may be fitted by a variety of different models. For many models, parameter starting estimates are program generated prior to automatic nonlinear regression analysis using a modified Davidon-Fletcher-Powell algorithm. The output of results is extensive and plotting facilities are available. Explicit and differential equation models may be fitted to single dose data and simulations using all models (single or repeat dose) may be employed to generate drug concentration-time data with plotting output. The package has been tested on numerous data with no problems regarding local function minima. Some comparisons with existing programs have been made and MODFIT compares well with respect to robustness, efficiency, and ease of use.     

Tritium: a coming of age for drug discovery and development ADME studies

Owing to recent developments in tritium chemistry and analysis, high‐quality tritium‐labelled drugs can now be prepared simply, cheaply and in timescales commensurate with those needed for rapid drug discovery in adsorption, distribution, metabolism and excretion (ADME) projects. Such ³H‐labelled drugs are enabling high‐quality decision‐making at key points in the drug discovery process, thus ensuring more effective research projects, a key issue in commercial success. In addition, tritium‐labelled compounds continue to play a significant role in ADME studies later in the pharmaceutical development process. This is especially so for highly potent and hence low‐dose agents, for drugs with complex structures and for those compounds that undergo molecular fragmentation as a result of metabolism.     

Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil

Aim It has been reported that verapamil and atorvastatin are inhibitors of both P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A4, and verapamil is a substrate of both P-gp and CYP3A4. Thus, it could be expected that atorvastatin would alter the absorption and metabolism of verapamil. Methods The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared after oral administration of verapamil (60 mg) in the presence or absence of oral atorvastatin (40 mg) in 12 healthy volunteers. Results Pharmacokinetics of verapamil were significantly altered by the coadministration of atorvastatin compared with those of without atorvastatin. For example, the total area under the plasma-concentration time curve to the last measured time, 24 h, in plasma (AUC_{0−24 h}) of verapamil increased significantly by 42.8%. Thus, the relative bioavailability increased by the same magnitude with atorvastatin. Although the AUC_{0−24 h} of norverapamil was not significantly different between two groups of humans, the AUC_{0−24 h, norverapamil}/ AUC_{0−24 h, verapamil} ratio was significantly reduced (27.5% decrease) with atorvastatin. Conclusion The above data suggest that atorvastatin could inhibit the absorption of verapamil via inhibition of P-gp and/or the metabolism of verapamil by CYP3A4 in humans.     

新型转移去势抵抗性前列腺癌治疗药物恩杂鲁胺

摘 要本文综述了恩杂鲁胺在治疗去势抵抗性前列腺癌中的药理学,药动学,临床有效性和安全性。恩杂鲁胺是第2代的雄激素受体拮抗药,其可抑制雄激素信号传导通路的多个靶点,包括抑制雄激素与雄激素受体的结合,同时抑制雄激素受体的核移位以及与DNA的相互作用。Ⅲ期随机对照研究证实恩杂鲁胺可以有效延缓转移性去势抗拒前列腺癌的进展,降低其前列腺特异性抗原水平,进展时间、延长总生存期和首次骨骼相关事件发生时间,恩杂鲁胺为去势抵抗前列腺癌患者提供了新的治疗手段,且不良反应少、耐受性良好。     

治疗慢性丙型肝炎新药Sofosbuvir

鉴于丙型肝炎病毒（HCV）感染全球高发趋势,目前治疗方案因禁忌、严重不良反应等导致其使用的局限性,因此需要一种更有效、安全、简便、不适宜干扰素治疗的治疗药物.Sofosbuvir是具有这些特性的直接抗病毒药物,为HCV NS5 B聚合酶的尿苷核苷酸类似物抑制药,可有效对抗多种基因型HCV感染,具有良好的安全性和耐受性.本文综述Sofosbuvir的作用机制、药动学、不良反应、药物相互作用及临床试验.     

Using virtual reality for drug discovery: a promising new outlet for novel leads

ABSTRACT

Introduction: Virtual reality (VR) environments are increasingly being used by researchers in various fields in addition to being increasingly integrated into various areas of human life, ranging from videogames to different industrial uses. VR can be used to create interactive and multimodal sensory stimuli and thus offers unique advantages over other computer-based approaches for scientific research and molecular-level applications. Consequently, VR is starting to be used in novel drug development, such as in drug discovery, and rational drug design.

Areas covered: In this review, the authors discuss the basic development of VR technology, including the available hardware and software. The latest advances of VR technology in novel drug development are then detailed, and the VR programs that can be applied in relevant studies are highlighted.

Expert opinion: VR will lead to a revolution in pharmaceutical development. However, there are still obstacles to the successful and extensive application of VR to drug development, including the demand for further improvements to the available hardware and software and the various limitations described with regard to accuracy and precision. As technology continues to improve, the barriers to the widespread adoption of VR will diminish and VR technologies will play an increasingly important role in novel drug development.     

A cell-based drug delivery system for lung targeting: I. Preparation and pharmacokinetics

A drug-loaded tumor cell (DLTC) system has been developed for lung metastasis-targeting drug delivery. Doxorubicin was loaded into B16-F10 murine melanoma cells (96 microg/10(6) cells). The loading process led to the death of all the carrier cells. The diameter of DLTC was 15.03+/-2.36 microm (mean +/- SD). The amount and rate of doxorubicin being released from the DLTC mainly depended on the drug loading and carrier cell concentration. Over a 6-month storage in phosphate buffered saline (PBS) at 4 degrees C, the decrease in intracellular drug concentration and the carrier cell number were less than 25% and 5%, respectively. After a bolus injection of 30 microg doxorubicin in either DLTC form or free solution into the mice tail veins, drug deposit in the lung from DLTC was 3.6-fold of that achieved by free drug solution. The latter resulted in higher drug content in liver and spleen. Extensive trypsinization of DLTC reduced its lung targeting effect by 30%, and the density of surface adhesion molecule GM3 on DLTC surface by 25%. In conclusion, this DLTC system demonstrated a lung-targeting activity that may be partially attributed to its specific surface characteristics.     

A model for the dose-dependent pharmacokinetics of chiorophenoxy acid herbicides in the rat: The effect of enterohepatic recycling

A two-compartment pharmacokinetic model has been developed to describe the time course of chlorophenoxy acid herbicides, such as 2,4-dichlorophenoxy acetic acid (2,4-D), 2,4,5-trichlorophenoxy acetic acid (2,4,5-T), and 2- [2,4,5- trichlorophenoxy]propionic acid (2,4,5-TCPPA), in the plasma, urine, and bile of rats. The model assumes that saturable renal transport and extensive enterohepatic circulation are operative during the distribution and elimination of these compounds. The model was validated by comparing the predicted plasma concentrations and urinary and biliary excretion rates with those reported previously in the literature. The model is capable of predicting the changes in plasma and urinary elimination during bile duct cannulation and suggests that the nonlinear elimination of these compounds is dramatically influenced by enterohepatic circulation.     

Imaging Mass Spectrometry (IMS) for drug discovery and development survey: Results on methods,applications and regulatory compliance

Imaging mass spectrometry (IMS) is increasingly used for drug discovery and development to understand target enagement, tissue distribution, drug toxicity, and disease mechanisms, etc. However, this is still a relatively new technique that requires further development validation before it will be an acceptable technique to support regulated development of new drugs. Thus, best practices will need to be established to build more confidence and gain wider acceptance by the scientific community, pharmaceutical industry, and regulatory authorities. The Imaging Mass Spectrometry Society (IMSS) and the Japan Association for Imaging Mass Spectrometry (JAIMS) have conducted a thorough survey to gather information on the current state of IMS and to identify key issues. The survey was sent to researchers or managers in the position who are currently using IMS techniques in support of their drug discovery and development efforts and/or who plan to use such tools as best practices are established. The survey probes questions related to details regarding technical aspects of IMS, which includes data acquisition, data analysis and quantitation, data integrity, reporting, applications, and regulatory concerns. This international survey was conducted online through the Survey Monkey (https://www.surveymonkey.com) in both English and Japanese from September 14 through September 30, 2020.     

Gastric floating sustained-release tablet for dihydromyricetin: Development,characterization, and pharmacokinetics study

Dihydromyricetin (DHM) is a natural dihydroflavonol compound with quite a number of important pharmacological properties. However, its low solubility in water and poor stability in aqueous environment, have compromised drug efficacy of DHM, thus hindering its clinical use. The present study was to develop DHM-loaded gastric floating sustained-release tablet (DHM-GFT) to improve the bioavailability of DHM. DHM-GFT was prepared via powder direct compression. The formulation of tablet was optimized in terms of the floating ability and drug release rate. The optimized DHM-GFT exhibited short floating lag time of less than 10 s and long floating duration of over 12 h in acidic medium. It had a 12-hour sustained release of DHM, which proved its potential to develop as a twice-a-day dosing preparation. The physicochemical properties of DHM-GFT well satisfied the pharmacopoeial requirements. In addition, the results from pharmacokinetic studies demonstrated that, DHM-GFT could considerably prolong the in vivo residence time of drug and improve the bioavailability via good gastric floating ability and sustained drug release when compared to DHM powder. Therefore, DHM-GFT is promising to promote the application of DHM and merits studies for further development.     

治疗痤疮新药sarecycline概述

摘 要Sarecycline是过去40年来首个专门针对皮肤病设计的口服抗菌药,这种首创、窄谱四环素类药在临床研究中已被证明用药后3周可使皮肤炎性皮损显著改善,且有良好的安全性和耐受性,适用于治疗罹患中度至重度痤疮的患者。     

A scoping review of health professional curricula: Implications for developing integration in pharmacy

BackgroundIntegrated health professions curricula aim to produce graduates who are capable of meeting current and future healthcare needs. This is reflected in pharmacy education where integration is increasingly advocated by pharmacy regulators as the perceived optimal way of preparing students for registration as pharmacists. There is, however, no definition of integration. Integration can be described according to a model of horizontal, vertical or spiral integration. It can also be described by the themes used to integrate, such as a systems-based approach or by integrative teaching and learning approaches. The level of integration can also be described.ObjectiveThis scoping review aimed to explore health professions education literature to inform the optimal design of integrated pharmacy curricula. This review asks: what is meant by integration in health professions curricula?MethodsThe Arksey and O'Malley scoping review framework was utilised. Ovid MEDLINE, EMBASE, Scopus, Web of Science and ERIC were searched. Models of integration, themes for integration, integrative teaching and learning approaches, and level of integration were defined and supported data extraction.ResultsThere were 9696 records screened and of these 137 were included. The majority of studies (n = 88) described horizontal integration. Systems-based teaching (n = 56) was the most common theme reported. Various integrative teaching and learning approaches were described, including experiential (n = 43), case-based (n = 42) and problem-based (n = 38) learning. The majority of the curricula could be classified as levels 5–7 on Harden's ladder (n = 102). Perception outcomes were reported for 81 studies, and only 3 reported outcomes beyond perception. Reported outcomes were generally positive and included knowledge gains and increased motivation.ConclusionsThere is a need for integration to be explicitly defined by curriculum developers and researchers. Attention should be given to describing the model, theme, teaching and learning approach and level of integration. There remains a lack of evidence for integration.     

Solid lipid nanoparticles for nose to brain delivery of haloperidol: in vitro drug release and pharmacokinetics evaluation

In the present study, haloperidol (HP)-loaded solid lipid nanoparticles (SLNs) were prepared to enhance the uptake of HP to brain via intranasal (i.n.) delivery. SLNs were prepared by a modified emulsification–diffusion technique and evaluated for particle size, zeta potential, drug entrapment efficiency, in vitro drug release, and stability. All parameters were found to be in an acceptable range. In vitro drug release was found to be 94.16±4.78% after 24 h and was fitted to the Higuchi model with a very high correlation coefficient (R²=0.9941). Pharmacokinetics studies were performed on albino Wistar rats and the concentration of HP in brain and blood was measured by high performance liquid chromatography. The brain/blood ratio at 0.5 h for HP-SLNs i.n., HP sol. i.n. and HP sol. i.v. was 1.61, 0.17 and 0.031, respectively, indicating direct nose-to-brain transport, bypassing the blood–brain barrier. The maximum concentration (C_max) in brain achieved from i.n. administration of HP-SLNs (329.17±20.89 ng/mL, T_max 2 h) was significantly higher than that achieved after i.v. (76.95±7.62 ng/mL, T_max 1 h), and i.n. (90.13±6.28 ng/mL, T_max 2 h) administration of HP sol. The highest drug-targeting efficiency (2362.43%) and direct transport percentage (95.77%) was found with HP-SLNs as compared to the other formulations. Higher DTE (%) and DTP (%) suggest that HP-SLNs have better brain targeting efficiency as compared to other formulations.KEY WORDS: Brain targeting, Haloperidol, Intranasal route, Pharmacokinetics, Solid lipid nanoparticles     

Drug preference and mood in humans: Preference for d-amphetamine and subject characteristics

Forty-five normal, young, adult volunteers participated in a nine-session experiment. During the first four sessions, they received alternately 5 mg d-amphetamine or placebo. During the next five sessions, they chose between amphetamine and placebo. On the basis of the choice results, subjects retrospectively were divided into the following three groups: (1) five of five drug choices (N=16), (2) four of five drug choices (N=12); and (3) 0–3 of five drug choices (N=17). There was an overall average of 3.76 drug choices per subject. These groups were compared by demographic characteristics, drug use history, and several personality measures, but none predicted drug choice. However, subjects who chose drug on every occasion had significantly higher predrug scores on the anxiety, depression, and confusion subscales of the Profile of Mood States (POMS). The functional relationship between initial dysphoria and consistent amphetamine choosing remains an intriguing question.     

Influence of inflammatory disorders on pharmacokinetics of lisofylline in rats: implications for studies in humans

Abstract

1. Despite the number of favourable properties of lisofylline (LSF), clinical trials on this compound have not yielded the expected results yet.

2. The aims of this study were to evaluate the pharmacokinetics of LSF enantiomers in rats following intravenous, oral and subcutaneous administration of (±)-LSF and to assess the influence of experimental inflammatory disorders, such as multiple organ dysfunction syndrome and severe sepsis on LSF pharmacokinetics.

3. In addition, based on the results obtained an attempt was made to elucidate the possible reasons for the failure of LSF therapy in clinical trials carried out in patients with severe inflammatory disorders.

4. A subcutaneous route of (±)-LSF administration to rats is more favourable than an oral one due to a high bioavailability and a fast absorption of both LSF enantiomers. Pharmacokinetics of LSF in rats is significantly influenced by inflammatory diseases. Too low LSF serum levels might have been one of the reasons for clinical trial failures. A long-term i.v. infusion of LSF seems to be more effective compared to short-term multiple infusions that were used in clinical trials, as it may provide concentrations above IC₅₀ for inhibition of both TNF-alpha release and cAMP degradation in serum for a longer period of time.