Abstract:
:Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors. Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety. It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans. Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes. The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU. This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Blesch KS,Gieschke R,Tsukamoto Y,Reigner BG,Burger HU,Steimer JLdoi
10.1023/a:1023525513696subject
Has Abstractpub_date
2003-05-01 00:00:00pages
195-223issue
2eissn
0167-6997issn
1573-0646journal_volume
21pub_type
杂志文章,评审abstract::We studied the effect of riccardin D, a macrocyclic bisbibenzyl, which was isolated from the Chinese liverwort plant, on human leukemia cells and the underlying molecular mechanism. Riccardin D had a significant antiproliferative effect on human leukemia cell lines HL-60, K562 and its multidrug resistant (MDR) counter...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9554-8
更新日期:2012-02-01 00:00:00
abstract::The protective role of Luteolin (LUT) against Azoxymethane (AOM)-induced mouse colon carcinogenesis has been documented earlier. The aim of this study is to investigate on the mechanism of chemopreventive action exhibited by LUT employing AOM-induced colon carcinogenesis in mice as an experimental model. LUT inhibited...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9359-9
更新日期:2011-04-01 00:00:00
abstract::Tea (Camellia sinensis) is one of the most widely used beverages worldwide and tea consumption has been shown to have an inverse correlation to the incidence of human cancers in epidemiological and experimental studies. In the present study, the protective effects of green tea polyphenols (GTP) and black tea polypheno...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9204-6
更新日期:2009-12-01 00:00:00
abstract::Artemisinin and its derivatives are well known antimalarial drugs, particularly useful after resistance to traditional antimalarial pharmaceuticals has started to occur in Plasmodium falciparum. In recent years, anticancer activity of artemisinin has been reported both in vitro and in vivo. Artemisinin has inhibitory ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9188-2
更新日期:2009-10-01 00:00:00
abstract::Menogaril, a semisynthetic anthracycline antibiotic, was administered to patients with metastatic adenocarcinoma of the prostate. Forty-five patients with measurable disease and 45 patients with evaluable disease received 150-200 mg/m2 over 1 hour every 28 days. There were three partial responses (PR) among 87 patient...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1007/BF00873240
更新日期:1994-01-01 00:00:00
abstract::In a previous study we reported on the synthesis of 1,4-naphthoquinone-sulfides by thiolation of 1,4-naphthohydroquinones with primary aryl and alkyl thiols using laccase as catalyst. These compounds were synthesized as Vitamin K3 analogues. Vitamin K3 (VK3; 2-methyl-1,4-naphthoquinone; menadione) is known to have pot...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-019-00855-8
更新日期:2020-04-01 00:00:00
abstract::TNF-alpha may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the efficacy of NGR-TNF...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-005-4540-2
更新日期:2006-01-01 00:00:00
abstract::PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wildtype lethal factor in the treatment of Colo205 colon adenocarcinoma in vitro and B16-BL6 mouse melanoma in vitro and in vivo. This therapy was also tested in combination with the small molecule paclitaxel, based on pri...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9847-1
更新日期:2013-02-01 00:00:00
abstract::A Phase II study of Didemnin-B, a marine cyclic depsipeptide, was undertaken in patients with progressive epithelial ovarian cancer. The starting dose was 2.6 mg/m2. Fifteen patients received the drug, of whom twelve were evaluable. There were no responses observed in the twelve patients. The two most frequent toxicit...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/BF01275473
更新日期:1992-04-01 00:00:00
abstract::XK-469 is advancing to Phase I clinical trials. Preclinical studies were carried out to assist in clinical applications. DOSE-SCHEDULE ROUTE TESTING: Single dose i.v. treatment with XK-469 produced lethality (LD20 to LD100) above 142 mg/kg. Optimum treatment required total dosages of 350 to 600 mg/kg. Furthermore, hig...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1014469828729
更新日期:2002-02-01 00:00:00
abstract::HDAC inhibitors (HDACI) are now emerging as one of the most promising new classes of drugs for the treatment of select forms of non-Hodgkin's lymphoma (NHL). They are particularly active in T-cell lymphomas, possibly hodgkin's lymphoma and indolent B cell lymphomas. Presently, two of these agents, vorinostat and romid...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9591-3
更新日期:2010-12-01 00:00:00
abstract::Antiproliferative factor (APF) is a potent frizzled protein 8-related sialoglycopeptide inhibitor of bladder epithelial cell proliferation that mediates its activity by binding to cytoskeletal associated protein 4 in the cell membrane. Synthetic asialylated APF (as-APF) (Galβ1-3GalNAcα-O-TVPAAVVVA) was previously show...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9746-x
更新日期:2012-10-01 00:00:00
abstract:PURPOSE:Erlotinib (Tarceva®, OSI-774) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. As high-grade gliomas frequently show amplification, overexpression and/or mutation of EGFR, this drug has been tested in several clinical trials with glioblastoma patients, but unfortunat...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9569-1
更新日期:2012-04-01 00:00:00
abstract::Infantile hemangioma is the most common vascular tumor of childhood. It is characterized by clinical expansion of endothelial cells and promoted by angiogenic factors. Luteolin is a flavonoid compound that carries anti-cancer and anti-angiogenesis properties. The study aimed to investigate the effect of luteolin in tr...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-01052-8
更新日期:2021-01-07 00:00:00
abstract::The combination of anti-cancer drugs with nutritional factors is a potential strategy for improving the efficacy of chemotherapy, particularly for hepatocellular carcinoma because its conventional therapies are mostly ineffective. Using a highly invasive hepatoma SK-Hep-1 cell line, we investigated the possible synerg...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9727-0
更新日期:2012-08-01 00:00:00
abstract::Imidazolium-trans-dimethylsulfoxideimidazoletetrachlororuthenate (NAMI-A) is a ruthenium compound effective on solid tumor metastases. In this study, we evaluated the effects of different routes of administration of NAMI-A on the distribution to primary tumor, lungs and kidneys in BD2F1 hybrids with Lewis lung carcino...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1022916310694
更新日期:2003-02-01 00:00:00
abstract::Mitoxantrone (Novantrone) and prednimustine (Sterecyt) are both active as single agents in the treatment of unfavorable non-Hodgkin lymphoma (UNHL). The efficacy and toxicity of the combination of these agents (NOSTE) was evaluated in 28 patients with advanced histopathologically proven UNHL who were not eligible for ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00195368
更新日期:1988-06-01 00:00:00
abstract:PURPOSE:To compare two different infusion schedules of phenylacetate (PA) in patients with primary brain tumors and to assess the feasibility of the administration in a multi-institutional setting. PATIENTS AND METHODS:Adult patients with recurrent primary brain tumors were treated with PA on two different schedules. ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1026299118067
更新日期:2003-11-01 00:00:00
abstract:BACKGROUND:The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) and recommended phase II dose for Tomudex and Doxorubicin when given in combination to patients with advanced metastatic cancer. The secondary objective was to assess the toxicity profile. PATIENTS AND METHODS:Star...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/B:DRUG.0000047105.38511.2a
更新日期:2005-01-01 00:00:00
abstract::Sunitinib is an oral antityrosine kinase inhibitor that has antiangiogenic and antitumor activities. It has been approved for the treatment of advanced RCC and for imatinib-refractory gastrointestinal stromal tumors (GIST). Tumor lysis syndrom can occur in solid tumors. We report a case of patient with metastatic RCC ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9275-z
更新日期:2010-10-01 00:00:00
abstract::Fluorinated pyrimidines, particularly 5-fluorouracil (FUra), have been the subject of intense and almost continuous basic and clinical study since development in the late 1950's by Dr. Charles Heidelberger. Despite this intensive effort, the most important mechanisms by which FUra influences tumor growth in individual...
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1007/BF00178188
更新日期:1989-04-01 00:00:00
abstract::Aberrant activation of the Wnt/β-catenin signaling pathway promotes osteosarcoma tumorigenesis and metastasis. In this study, we tested the hypothesis that osteosarcoma progression may be delayed by disrupting the Wnt/β-catenin pathway using small molecule inhibitors such as curcumin and PKF118-310. Effective inhibiti...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9311-z
更新日期:2010-12-01 00:00:00
abstract::Mezerein, the most active antitumor compound isolated from the daphne species of plants, has a structural similarity to phorbol myristate acetate (PMA), the major active compound isolated from croton oil. PMA is known to have tumor promoting activity and is a potent inflammatory agent. Mezerein has similarly been repo...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00170855
更新日期:1989-07-01 00:00:00
abstract:BACKGROUND:This phase I, dose-finding study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib plus S-1/cisplatin in Japanese patients with advanced/metastatic gastric cancer. PATIENTS AND METHODS:Patients received oral sunitinib on a continuous daily dosing (CDD)...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-013-9948-5
更新日期:2014-04-01 00:00:00
abstract::Androgen receptors are present in both pancreatic cancer tissue and cell lines. Flutamide is a potent antiandrogen widely used in clinical practice for patients with metastatic prostate cancer. This Phase II trial was undertaken to evaluate the impact of flutamide in patients with advanced pancreatic adenocarcinoma wh...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1005989519350
更新日期:1997-01-01 00:00:00
abstract::Angiogenesis is recognized as an important biological process that allows growth of a tumor beyond an initial small size. PTK787/ZK222584, a potent orally active angiogenesis inhibitor capable of inhibiting all known isoforms of Vascular Endothelial Growth Factor (VEGF) receptor, belongs to the class of aminophthalazi...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9157-9
更新日期:2009-02-01 00:00:00
abstract::Cribrostatin 6 is a quinone-containing natural product that induces the death of cancer cell lines in culture, and its mechanism of action and scope of activity are unknown. Here we show that cribrostatin 6 has broad anticancer activity, potently inducing apoptotic cell death that is not preceded by any defined cell c...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9390-x
更新日期:2011-08-01 00:00:00
abstract::Drug discovery involves various steps and is a long process being even more demanding for complex diseases such as cancer. Tumors are ensembles of subpopulations with different mutations, require very specific and effective strategies. Conventional drug screening technologies may not be adequate and efficient anymore....
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1007/s10637-014-0081-x
更新日期:2014-12-01 00:00:00
abstract::The anti-tumor properties of novel derivatives prepared from Aconitum C(20)-diterpenoid alkaloid, which show the least toxicity among the Aconitum alkaloids, were investigated in the Non-Hodgkin's lymphoma cell line Raji cells. Two novel Aconitum C(20)-diterpenoid alkaloid derivatives, 11-m-Trifluorometylbenzoyl (Mb)-...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9327-4
更新日期:2011-02-01 00:00:00
abstract::A retrospective cohort study was performed to investigate the effectiveness of preemptive postsurgical therapy with cetuximab for patients with a major risk of recurrence or metastasis after clinical complete resection of primary oral squamous cell carcinoma (OSCC). The study period was from 2007 to 2019 for patients ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-021-01062-0
更新日期:2021-01-15 00:00:00