Abstract:
:This meeting was convened to encourage the incorporation of empirical and mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modelling into safety pharmacology to improve the predictability of nonclinical investigations for human outcomes. These technologies make use of mathematical expressions relating measured variables to derive essential parameters for describing responses and predicting the behaviour of biological systems to a drug. Hence, empirical PK/PD modelling is intended to define the in vivo interrelationship between three basic entities: time; drug concentrations; and drug effects. The most widely applied equation relating drug bioresponses to plasma concentrations is the Hill sigmoidal E(max) model, which allows the calculation of drug potency (EC(50)) and intrinsic activity (E(max)). However, since the latter parameters depend on attributes of the drug and on the biological system itself, this approach can fail to accurately foretell drug concentration-effect behaviour, particularly between species. A particular phenomenon of PK/PD analysis is hysteresis, which refers to the delay of the bioresponse time-course with respect to exposure time-course, as this provides valuable information on the direct or indirect nature of the drug mechanism of action. The application of these concepts to the examination of the QT interval prolongation produced by dofetilide was discussed. A development surmounting the limitations of empirical PK/PD models is mechanism-based PK/PD modelling because its toolkits integrate specific mathematical expressions replicating the drug (e.g., affinity, intrinsic efficacy), and the physiological system (e.g., nonlinear, time-dependent, transduction processes), properties that play a crucial role in the cascade of biological events culminating in bioresponses. The usefulness of this approach was illustrated by a thorough analysis of nonclinical respiratory depressant and antinociceptive data on buprenorphine and fentanyl for successfully predicting the human safety and efficacy of these analgesic agents. Thus, PK/PD models can be viewed as in silico clones of drug and biological system activities that provide high-level knowledge that can avoid inappropriate attrition, and hasten the progress, of novel drugs, along the entire critical path of pharmaceutical development.
journal_name
Expert Opin Drug Safjournal_title
Expert opinion on drug safetyauthors
Cavero Idoi
10.1517/14740338.6.4.465subject
Has Abstractpub_date
2007-07-01 00:00:00pages
465-71issue
4eissn
1474-0338issn
1744-764Xjournal_volume
6pub_type
abstract:BACKGROUND:The abuse and diversion of pharmacological agents with CNS mechanisms of action is an important concern from governmental, regulatory, public health and safety perspectives. In recent years, there have been an increased number of reports concerning the abuse and diversion of quetiapine in forensic population...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740330802496883
更新日期:2008-11-01 00:00:00
abstract:BACKGROUND:This meta-analysis has been conducted to determine the risk of elevated transaminases associated with immune checkpoint inhibitors use in patients with cancer. METHODS:Studies eligible for our analysis included randomized Phase II and III trials of patients with cancer on ipilimumab, nivolumab, pembrolizuma...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,meta分析,评审
doi:10.1517/14740338.2015.1085969
更新日期:2015-10-01 00:00:00
abstract::Introduction: Secukinumab is a fully human monoclonal antibody which targets and neutralizes interleukin (IL)-17A, a cytokine that plays an important role in the pathophysiology of ankylosing spondylitis (AS). Secukinumab is the first IL-17A inhibitor approved for the treatment of AS. Areas covered: This paper aimed t...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章
doi:10.1080/14740338.2021.1851363
更新日期:2021-01-20 00:00:00
abstract:INTRODUCTION:Obesity is associated with an increased risk of cardiovascular morbidity and mortality. Four medications are approved by the US Food and Drug Administration (FDA) for chronic weight management when used as an adjunct to a reduced-calorie diet and increased physical activity in adults. These medications res...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章
doi:10.1080/14740338.2020.1806234
更新日期:2020-09-01 00:00:00
abstract:INTRODUCTION:Drug-induced parkinsonism (DIP) is the second most common cause of parkinsonism after idiopathic Parkinson's disease (iPD). Initially reported as a complication of antipsychotics, it was later recognized as a common complication of antidepressants, calcium channel antagonists, gastrointestinal prokinetics,...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.2013.787065
更新日期:2013-07-01 00:00:00
abstract::Introduction: Botulinum toxin (BoNT) is a protein secreted by the anaerobic Gram-negative bacterium Clostridium botulinum. Among the seven known subtypes, type A is the most commonly used in women to treat diseases. It primarily blocks presynaptic release of acetylcholine at the neuromuscular junction, resulting in te...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1080/14740338.2020.1707803
更新日期:2020-01-01 00:00:00
abstract::The problem of counterfeit drugs is increasingly becoming a top priority of drug regulatory agencies, licit pharmaceutical manufacturers and healthcare professionals, and is of rising concern among consumers. A review of the current literature reveals that counterfeiting is no longer isolated in developing nations, bu...
journal_title:Expert opinion on drug safety
pub_type: 社论
doi:10.1517/14740338.4.4.619
更新日期:2005-07-01 00:00:00
abstract:INTRODUCTION:Dolutegravir (DGV) is the newest integrase inhibitor approved for the treatment of HIV-1 infection in both treatment-naive and experienced adults and adolescents. This article reviews the safety of DGV for the treatment of HIV-1 infection. AREAS COVERED:The PubMed database was searched using the keywords ...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.2015.973845
更新日期:2015-01-01 00:00:00
abstract:INTRODUCTION:Regulatory authorities have a legal mandate to implement and maintain a Pharmacovigilance System designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance. Areas covered: This review maps the implementation of pharmacovigilance activities in Malta s...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1080/14740338.2017.1247806
更新日期:2017-01-01 00:00:00
abstract::Aerosolized delivery of a number of antimicrobial agents has been studied. Despite a theoretical soundness behind this strategy, full consideration of the potential toxicities associated with this mode of administration is imperative. Aerosolized amphotericin B, as both deoxycholate and lipid formulations, has been st...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.6.5.523
更新日期:2007-09-01 00:00:00
abstract:INTRODUCTION:Acne is a common skin condition of the pilosebaceous units that affects the young and old, ranges from moderate to severe and can be treated with an array of options. Topical retinoids are the initial treatment for acne due to their ability to treat comedones, the starting point of acne. AREAS COVERED:Taz...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章
doi:10.1517/14740338.2016.1117605
更新日期:2016-01-01 00:00:00
abstract::Introduction: Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas of skin-homing T-cells that initially or mainly manifest cutaneously. Treatment of CTCL is challenging given the disease states' varying presentation and prognosis. Systemic treatment options often lack comparative evidence and have relativ...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1080/14740338.2019.1643837
更新日期:2019-09-01 00:00:00
abstract::COX-2 selective inhibitors provide analgesia and blunt inflammation while also sparing the gastrointestinal tract from classic NSAID toxicity. Therapeutic effects are thought to result from inhibition of the inflammatory COX-2 isoform. Organ sparing is considered the result of preservation of homeostatic COX-1 enzyme ...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.1.1.53
更新日期:2002-05-01 00:00:00
abstract::A water soluble derivative of camptothecin, irinotecan (CPT-11) is effective against small-cell lung cancer (SCLC), as well as non-SCLC and gastrointestinal cancers. This extended review of recently concluded and ongoing studies focuses on irinotecan in the treatment of limited (LD) and extensive (ED) SCLC specificall...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.5.2.303
更新日期:2006-03-01 00:00:00
abstract::Sjögren's syndrome dry eye is an inflammatory disease accompanied by an impairment of the autonomous nervous system of the ocular surface. The therapy for this condition is shifting from the mere tear replacement to a more complex approach including an anti-inflammatory treatment. Clinical trials have evidenced that t...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.6.1.33
更新日期:2007-01-01 00:00:00
abstract:OBJECTIVE:The aim of this study is to evaluate the safety of cephalosporins, based on utilization and adverse drug events (ADEs). METHODS:This is a retrospective study using data on cephalosporins, obtained from Yangtze River hospital drug information and the Wuhan adverse drug reactions monitoring center database, fr...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,多中心研究
doi:10.1517/14740338.2012.699037
更新日期:2012-09-01 00:00:00
abstract::Methotrexate is a commonly prescribed antineoplastic and immune modulating compound that has gained wide acceptance in the management of rheumatoid arthritis, psoriasis, sarcoidosis and a number of neoplastic disorders. Although generally considered safe and easy to use, methotrexate has been associated with a number ...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.4.4.723
更新日期:2005-07-01 00:00:00
abstract:IMPORTANCE OF THE FIELD:HIV-infection has become a chronic disease in paediatric patients with the potential for long-term survival and exposure to antiretroviral (ARV) therapies for 2 decades longer than HIV-infected adults. On the other hand, the administration of ARV to HIV-infected pregnant women has greatly increa...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740330903579991
更新日期:2010-05-01 00:00:00
abstract:INTRODUCTION:There is now 16 years' worth of established results of various trials demonstrating the bortezomib efficiency in the treatment of multiple myeloma. Over this time, the introduction of bortezomib has been a major break through in the treatment of multiple myeloma. Bortezomib can be administered in the outpa...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1080/14740338.2018.1513487
更新日期:2018-09-01 00:00:00
abstract:INTRODUCTION:Gastrointestinal bleeding (GIB) is a major problem in patients on oral anticoagulation therapy. This issue has become even more pressing since the introduction of direct oral anticoagulants (DOACs) in 2009. Areas covered: Here we review current evidence related to GIB associated with oral anticoagulants, f...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1080/14740338.2017.1325870
更新日期:2017-06-01 00:00:00
abstract:INTRODUCTION:In the last couple of years, the number of patients with chronic inflammatory rheumatic diseases being treated with TNF α antagonist has increased dramatically. Adalimumab, a fully human monoclonal antibody against TNF α, is one of the most frequently administered TNF α antagonists. Yet, unresolved issues ...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.2011.581661
更新日期:2011-07-01 00:00:00
abstract::Drugs are currently an important cause of liver disease, ranked as the most frequent reason for acute liver failure. Despite recent advances in knowledge of the mechanisms implicated in drug-induced hepatocellular damage and cholestasis, as well as the identification of several risk factors, the diagnosis of hepatotox...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.3.4.329
更新日期:2004-07-01 00:00:00
abstract:INTRODUCTION:Anticonvulsant hypersensitivity syndrome (AHS) is a rare but potentially life-threatening adverse drug reaction, primarily associated with phenytoin, phenobarbital and carbamazepine. It is characterized by a triad of fever, skin eruption and internal organ involvement (usually liver), which occur two to ei...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.2012.705828
更新日期:2012-09-01 00:00:00
abstract:INTRODUCTION:Bone strength determinants such as bone mineral density and bone quality parameters are determined by life-long remodeling of skeletal tissue. Denosumab is a fully human mAb receptor activator of NF-κB ligand, which selectively inhibits osteoclastogenesis, the end product of a cascade interaction among num...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.2010.516249
更新日期:2011-03-01 00:00:00
abstract::Thionamides, selective inhibitors of thyroid peroxidase-mediated iodination by tyrosine residues in thyroglobulin, have been effectively used in the treatment of hyperthyroidism. The choices for initial treatment of patients with Graves' disease differ in various countries, and many physicians around the world prefer ...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.5.1.107
更新日期:2006-01-01 00:00:00
abstract:INTRODUCTION:Conjugated equine estrogens (CEE) are widely used for the treatment of menopausal symptoms, such as vasomotor symptoms and vulvovaginal atrophy, and for the prevention of bone loss, in postmenopausal women. The safety profile of CEE has been extensively published over the past 20 years. AREAS COVERED:Data...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740338.2013.824965
更新日期:2014-01-01 00:00:00
abstract::Introduction: Psoriasis is a chronic inflammatory systemic disease that affects 2% of the population and is associated with an important physical and physiological burden. About 0.5-2% of psoriatic cases onset during the pediatric age range, and often it's not diagnosed until adulthood. Adalimumab is an antitumor necr...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1080/14740338.2020.1752659
更新日期:2020-04-01 00:00:00
abstract::Unlicensed and off-label prescribing is common in children. This is likely to be due to a combination of the difficulty in carrying out reliable clinical trials in children and the lack of financial reward for the industry. The term 'paediatric' encompasses preterm babies to near adult-sized adolescents, and all aspec...
journal_title:Expert opinion on drug safety
pub_type: 社论
doi:10.1517/14740338.2.2.109
更新日期:2003-03-01 00:00:00
abstract:INTRODUCTION:Approximately 40-50% of patients with cutaneous melanoma harbor point mutations in BRAF. BRAF and MEK inhibitors in combination are now a standard therapy for advanced BRAFV600-mutated melanoma. Nevertheless, survival rates with the combination are limited, highlighting the need for further therapeutic imp...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章
doi:10.1080/14740338.2020.1817376
更新日期:2020-10-01 00:00:00
abstract:IMPORTANCE OF THE FIELD:Trastuzumab has become a mainstay in the treatment of women with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer in the metastatic and adjuvant settings. Although trastuzumab is generally well tolerated, cardiac toxicity has emerged as a rare but potentially serious ...
journal_title:Expert opinion on drug safety
pub_type: 杂志文章,评审
doi:10.1517/14740331003627441
更新日期:2010-03-01 00:00:00