345 research outputs found
A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours
Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1â14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg mâ2twice a day and of docetaxel from 75 to 100 mg mâ2. The dose-limiting toxicity (DLT) was asthenia grade 2â3 at a dose of 1000 mg mâ2bid of capecitabine combined with docetaxel 100 mg mâ2. Neutropenia grade 3â4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg mâ2twice a day plus docetaxel 100 mg mâ2was tolerable, as was capecitabine 1250 mg mâ2twice a day plus docetaxel 75 mg mâ2. © 2000 Cancer Research Campaig
Matrix metalloproteinase-9 in relation to patients with complications after colorectal surgery: a systematic review
Purpose: Anastomotic leakage (AL) is the most severe complication following colorectal resection and is associated with increased mortality. The main group of enzymes responsible for collagen and protein degradation in the extracellular matrix is matrix metalloproteinases. The literature is conflicting regarding anastomotic leakage and the degradation of extracellular collagen by matrix metalloproteinase-9 (MMP-9). In this systematic review, the
Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors
PURPOSE: To assess the maximum-tolerated dose, toxicity, and
pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase
I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors.
EXPERIMENTAL DESIGN: Patients received DE-310 as a 3-hour infusion once
every 2 weeks (dose, 1.0-2.0 mg/m(2)) or once every 6 weeks (dose, 6.0-9.0
mg/m(2)). Because pharmacokinetics revealed a drug terminal half-life
exceeding the 2 weeks administration interval, the protocol was amended to
a 6-week interval between administrations also based on available
information from a parallel trial using an every 4 weeks schedule.
Conjugated DX-8951 (the carrier-linked molecule), and the metabolites
DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days
post first and second dose. RESULTS: Twenty-seven patients were enrolled
into the study and received a total of 86 administrations. Neutropenia and
grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive
disease, were dose-limiting toxicities. Other hematologic and
nonhematologic toxicities were mild to moderate and reversible. The
apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was
13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951
was 600. No drug concentration was detectable in erythrocytes, skin, and
saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable
in tumor biopsies. One patient with metastatic adenocarcinoma of unknown
primary achieved a histologically proven complete remission. One confirmed
partial remission was observed in a patient with metastatic pancreatic
cancer and disease stabilization was noted in 14 additional patients.
CONCLUSIONS: The recommended phase II dose of DE-310 is 7.5 mg/m(2) given
once every 6 weeks. The active moiety DX-8951 is released slowly from
DE-310 and over an extended period, achieving the desired prolonged
exposure to this topoisomerase I inhibitor
Darolutamide does not interfere with OATP-mediated uptake of docetaxel
The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drugâdrug interaction was identified
Darolutamide does not interfere with OATP-mediated uptake of docetaxel
The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drugâdrug interaction was identified
Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38
We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500âh, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC500âh) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC500âh using only two timed samples: AUC500âh=(6.588ĂC2.5âh)+(146.4ĂC49.5âh)+15.53, where C2.5âh and C49.5âh are plasma concentrations at 2.5 and 49.5âh after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan
Pharmacokinetics and tissue distribution of PGGâpaclitaxel, a novel macromolecular formulation of paclitaxel, in nu/nu mice bearing NCI-460 lung cancer xenografts
PGGâPTX is a water-soluble formulation of paclitaxel (PTX), made by conjugating PTX to poly(l-Îł-glutamylglutamine) acid (PGG) via ester bonds, that spontaneously forms a nanoparticle in aqueous environments. The purpose of this study was to compare the pharmacokinetics and tissue distribution of PTX following injection of either free PTX or PGGâPTX in mice.
Both [3H]PTX and PGGâ[3H]PTX were administered as an IV bolus injection to mice bearing SC NCI-H460 lung cancer xenografts at a dose of 40-mg PTX equivalents/kg. Plasma, tumor, major organs, urine, and feces were collected at intervals out to 340Â h. Total taxanes, taxane extractable into ethyl acetate, and native PTX were quantified by liquid scintillation counting and HPLC.
Conjugation of PTX to the PGG polymer increased plasma and tumor C
max, prolonged plasma half-life and the period of accumulation in tumor, and reduced washout from tumor. In plasma injection of PGGâPTX increased total taxane AUC0â340 by 23-fold above that attained with PTX. In tumors, it increased the total taxane by a factor of 7.7, extractable taxane by 5.7, and native PTX by a factor of 3.5-fold. Conjugation delayed and reduced total urinary and fecal excretion of total taxanes.
Incorporation of PTX into the PGGâPTX polymer significantly prolonged the half-life of total taxanes, extractable taxane, and native PTX in both the plasma and tumor compartments. This resulted in a large increase in the amount of active PTX delivered to the tumor. PGGâPTX is an attractive candidate for further development
Transanal total mesorectal excision: how are we doing so far?
Aim This subgroup analysis of a prospective multicentre
cohort study aims to compare postoperative morbidity
between transanal total mesorectal excision (TaTME)
and laparoscopic total mesorectal excision (LaTME).
Method The study was designed as a subgroup analysis
of a prospective multicentre cohort study. Patients
undergoing TaTME or LaTME for rectal cancer were
selected. All patients were followed up until the first
visit to the outpatient clinic after hospital discharge.
Postoperative complications were classified according to
the ClavienâDindo classification and the comprehensive
complication index (CCI). Propensity score matching
was performed.
Results In total, 220 patients were selected from the
overall prospective multicentre cohort study. After
propensity score matching, 48 patients from each group
were compared. The median tumour height for TaTME
was 10.0 cm (6.0â10.8) and for LaTME was 9.5 cm
(7.0â12.0) (P = 0.459). The duration of surgery and
anaesthesia were both significantly longer for TaTME
(221 vs 180 min, P < 0.001, and 264 vs 217 min,
P < 0.001). TaTME was not converted to laparotomy
whilst surgery in five patients undergoing LaTME was
converted to laparotomy (0.0% vs 10.4%, P = 0.056).
No statistically significant differences were observed for
ClavienâDindo classification, CCI, readmissions, reoperations and mortality.
Conclusion The study showed that TaTME is a safe
and feasible approach for rectal cancer resection. This
new technique obtained similar postoperative morbidity
to LaTME
- âŠ