Abstract:
PURPOSE:The aim of this study was to investigate typical population pharmacokinetic (PK) parameters, potential covariates, and interindividual and residual variabilities of PI-88, a heparanase endoglycosidase enzyme inhibitor being developed for the treatment of cancer. METHODS:A population PK model of PI-88 was developed and evaluated using nonlinear mixed effects modeling (NONMEM). Plasma concentration versus time data was obtained from a total of 76 subjects that participated in phase I trials of PI-88 delivered subcutaneously (SC) at doses ranging from 80 to 315 mg. Overall, the PK effects of 12 clinical covariates were evaluated, including weight, age, creatinine clearance, body surface area, body mass index, sex, cancer (vs. healthy subject), docetaxel coadministration, prior chemotherapy, prior investigational therapy, prior radiotherapy and prior surgery. RESULTS:Population PK analysis of the data-set showed that apparent clearance (CL/F) and apparent volume of distribution (V/F) of PI-88 were positively correlated with body surface area and the absorption rate constant (KA) was positively correlated with body mass index. In addition, CL/F was found to be significantly lower in patients with malignancies versus healthy subjects. By incorporating these covariates into the PK parameter equations, the interindividual variability of CL/F was reduced from 30.6 to 20.2% (decrease of 34%), V/F was reduced from 31.4 to 20.7% (decrease of 34.1%) and KA was reduced from 52.6 to 46.2% (decrease of 12.2%). CONCLUSIONS:This population PK model indicates that the PK variability of PI-88 can be significantly reduced by taking BSA into account when dosing this drug SC.
journal_name
Cancer Chemother Pharmacoljournal_title
Cancer chemotherapy and pharmacologyauthors
Hudachek SF,Eckhardt SG,Hicks B,Gustafson DLdoi
10.1007/s00280-009-1080-zsubject
Has Abstractpub_date
2010-03-01 00:00:00pages
743-53issue
4eissn
0344-5704issn
1432-0843journal_volume
65pub_type
杂志文章abstract::DON (6-diazo-5-oxo-L-norleucine), a glutamine antagonist, has been subjected to limited clinical trials since 1957. Use of the drug in adults has been curtailed due to sparse reports of effectiveness as well as its dose-limiting toxicities, i.e., severe nausea, vomiting and mucositis. In earlier studies, children give...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00262746
更新日期:1988-01-01 00:00:00
abstract:PURPOSE:The aromatase inhibitor, letrozole, is being investigated in experimental animal models as a novel treatment for high-grade gliomas (HGGs). To facilitate optimal dosing for such studies, we evaluated the plasma and brain pharmacokinetics (PK) of letrozole in NOD-scid gamma (NSG) mice, which are frequently emplo...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-018-3705-6
更新日期:2019-01-01 00:00:00
abstract:PURPOSE:Afatinib is an irreversible ErbB family blocker currently under evaluation in late-stage clinical trials. This study primarily assessed the cardiac safety, pharmacokinetics and antitumor activity of afatinib in cancer patients. METHODS:In this multicenter, Phase II, open-label, single-arm trial, 60 patients wi...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-013-2286-7
更新日期:2013-12-01 00:00:00
abstract::For years, MDA-MB-435 cells have been widely but erroneously used as breast cancer cells with aggressive behaviour. Recent data show that they are in fact melanoma cells. However, many scientists are still unaware of this "new" identity. ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 评论,信件
doi:10.1007/s00280-008-0776-9
更新日期:2009-02-01 00:00:00
abstract:PURPOSE:The study investigated the effects of pemetrexed, gefitinib, and their combination on human colorectal cancer cells. METHODS:Six human colorectal cancer cells were exposed to pemetrexed, gefitinib, and their combination. Antitumor effects were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium br...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-013-2251-5
更新日期:2013-10-01 00:00:00
abstract:PURPOSE:Because of the recurrence of hepatocellular carcinoma (HCC) at the graft after liver transplantation, circulating HCC cells may be present during the anhepatic period. Intravenous doxorubicin (DOX) is used during the anhepatic period to combat these cells; however, pharmacokinetics data have been poorly analyze...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-013-2311-x
更新日期:2013-12-01 00:00:00
abstract:PURPOSE:One of the major problems of cancer chemotherapy is the development of multidrug resistance (MDR) phenotype. Among the numerous mechanisms of MDR, a prominent one is the increased expression of membrane transporter proteins, the action of which leads to decreased intracellular drug concentration and cytotoxicit...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-010-1385-y
更新日期:2011-04-01 00:00:00
abstract:BACKGROUND:Docetaxel has marked inter-patient PK variability, and metabolic phenotypic probes may enable individualised dosing. This is the first report directly comparing the erythromycin breath test (EBT) (a CYP3A4 probe) with the antipyrine clearance test (ACT), (a general CYP-P450/predominant CYP3A4 probe) for the ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-011-1676-y
更新日期:2012-01-01 00:00:00
abstract::UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s002800051080
更新日期:1998-01-01 00:00:00
abstract:PURPOSE:An intact and fully functional multiprotein DNA replication complex (DNA synthesome) from human as well as from murine mammary carcinoma cells was first isolated and characterized in our laboratory. The human cell synthesome supports the in vitro origin-specific simian virus 40 (SV40) DNA replication reaction i...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800050046
更新日期:2000-01-01 00:00:00
abstract::Paclitaxel is used as a single agent, and in combination with other drugs, as a standard of care in the treatment of squamous cell carcinoma of the head and neck (SCCHN). However, the use of paclitaxel for therapy of SCCHN may be accompanied by serious side effects. Paclitaxel is a known cytotoxic inhibitor of cell pr...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-004-0929-4
更新日期:2005-07-01 00:00:00
abstract:PURPOSE:This phase I study was undertaken to evaluate the safety and tolerability of prolonged infusional etoposide, and to evaluate its pharmacokinetic/pharmacodynamic profile in patients with advanced cancer. METHODS:A group of 17 patients received a 7-day infusion of etoposide (schedule A) every 21 days at doses fr...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s002800050511
更新日期:1996-01-01 00:00:00
abstract:PURPOSE:Angiogenesis plays a crucial role in the development, growth, and metastasis of carcinomas, and studies have reported conflicting evidence regarding the VEGFR expression in anaplastic thyroid cancer. We investigated the expression of VEGFR2 in patients with anaplastic thyroid cancer (ATC) and analyzed the clini...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-018-3657-x
更新日期:2018-10-01 00:00:00
abstract::A total of 2,238 new cancer patients were treated in our institution in 1988; among the 423 (18.9%) who were greater than 70 years old, 51 underwent chemotherapy. The median age was 75.8 years, and the Karnofsky performance status (KPS) was greater than or equal to 70% for 40 patients. Malignancies were hematopoietic ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00687328
更新日期:1991-01-01 00:00:00
abstract::The pharmacokinetics of mitomycin (MMC) was studied in Wistar rats. Up to five half-lives, the plasma concentration-time curve was biphasic. The AUC changed linearly with increasing doses between 0.5 and 7.5 mg/kg, which corresponds to 0.2 and 3 times the LD50 value in rats. Most of the drug was metabolized, and only ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00257305
更新日期:1988-01-01 00:00:00
abstract::Severe, debilitating nausea and vomiting are seen in almost 100% of patients treated with cis-platinum. These side-effects can be so severe and prolonged as to preclude therapy in a large number of patients. Commonly used antiemetics have had only limited success in controlling cis-platinum-induced nausea and vomiting...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00258206
更新日期:1981-01-01 00:00:00
abstract::A total of 26 evaluable patients with previously untreated, non-resectable adenocarcinoma of the lung were given 80 mg/m2 i.v. teniposide daily for 5 days every 3 weeks. Three partial responses (11%) were obtained that lasted for 12, 11 and 32 weeks, respectively. Leucopenia was the dose-limiting side effect, with WBC...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00685166
更新日期:1991-01-01 00:00:00
abstract:PURPOSE:Artemisinins are now established drugs for treatment of malaria. These agents have been shown to possess impressive anti-cancer properties. We have investigated the role of artemisone (ATM), a novel derivative of artemisinin (ART) in a cancer setting both alone and in combination with established chemotherapeut...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-010-1355-4
更新日期:2011-03-01 00:00:00
abstract:PURPOSE:Cancer, a major public health problem, exhibits significant redox alteration. Thioredoxin (Trx) system, including Trx and Trx reductase (TrxR), as well as Trx-interacting protein (TXNIP) play important roles in controlling the cellular redox balance in cancer cells. In most cancers, Trx and TrxR are usually ove...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00280-019-03869-4
更新日期:2019-09-01 00:00:00
abstract:BACKGROUND:Expression of the DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) correlates with resistance to irinotecan in colorectal cancer cell lines. This phase I study evaluated the maximum tolerated dose (MTD) of lomeguatrib, an inactivating pseudosubstrate of MGMT, in combination with irinotecan...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-009-1225-0
更新日期:2010-10-01 00:00:00
abstract:PURPOSE:The chimeric protein BCR-ABL, a constitutively active protein-tyrosine kinase, triggers downstream signalling proteins, such as STAT3, ultimately resulting in the survival of myeloid progenitors in BCR-ABL-positive leukemias. Here, we evaluated the effect of LLL-3, an inhibitor of STAT3 activity, on cell viabil...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-009-1109-3
更新日期:2010-05-01 00:00:00
abstract:PURPOSE:Icotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. A phase II study was conducted to evaluate the efficacy and safety of icotinib in combination with whole-brain radiotherapy (WBRT) in Chinese NSCLC patients with brain metastases (BMs); the cerebrospinal fluid...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-015-2760-5
更新日期:2015-09-01 00:00:00
abstract:BACKGROUND:The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation. METHODS:PK d...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/s00280-015-2836-2
更新日期:2015-10-01 00:00:00
abstract::A series of in vitro cytotoxicity studies were performed to achieve pharmacologic reversal of resistance to the alkylating agent mitomycin (MMC) in L-1210 leukemia cells. A multidrug-resistant (MDR), P-glycoprotein-positive cell line, RL-1210/.1 [11], was exposed to potential MDR modulators in the absence or presence ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00685114
更新日期:1991-01-01 00:00:00
abstract:PURPOSE:The role of the microenvironment during the initiation and progression of carcinogenesis is now realized to be of critical importance, both for enhanced understanding of fundamental cancer biology, as well as exploiting this source of relatively new knowledge for improved molecular diagnostics and therapeutics....
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00280-008-0881-9
更新日期:2009-03-01 00:00:00
abstract::Detailed pharmacokinetic analysis and subsequent evaluation of myelotoxicity were performed in 55 patients who had been randomized to 4 different doses of epirubicin (40, 60, 90 or 135 mg/m2 given i.v. every 3 weeks). A significantly positive correlation was demonstrated between the AUC and the myelotoxicity of epirub...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF00685824
更新日期:1991-01-01 00:00:00
abstract::In the 1981 cooperative soft-tissue sarcoma (CWS-81) study, a clear correlation between the degree of response to initial chemotherapy comprising vincristine, actinomycin D, cyclophosphamide, and Adriamycin (VACA) and the survival of patients with rhabdomyosarcoma was found. In the subsequent CWS-86 study, cyclophosph...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00253241
更新日期:1989-01-01 00:00:00
abstract::Experimental data suggest that multidrug resistance in cancer may be overcome by using an increased dose of anticancer agent(s) in combination with a resistance-modifying agent (RMA). We studied the pharmacokinetics and metabolism of both epirubicin (EPI) and verapamil (VPL) to explore the possible pharmacokinetic int...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00686150
更新日期:1993-01-01 00:00:00
abstract:PURPOSE:It has recently been recognised that anticancer chemotherapy can elicit an immunogenic form of apoptosis characterised by the exposure of calreticulin (CRT) on the surface of dying tumour cells, entailing an immune response that contributes to the therapeutic outcome. CRT exposure has been found to be induced b...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-010-1302-4
更新日期:2010-08-01 00:00:00
abstract::In a pilot study of cyclical chemotherapy in patients with poor-prognosis non-Hodgkin's lymphoma (NHL), high-dose methotrexate (MTX) 1 g/m2 with folinic acid rescue was given as initial treatment and then between cycles of a single-arm CHOP combination administered every 4 weeks. Of 21 patients with previously untreat...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00254195
更新日期:1983-01-01 00:00:00