126 research outputs found
Moving molecular targeted drug therapy towards personalized medicine: Issues related to clinical trial design
With the event of new Molecular targets, clinical trial design requirements to perform these trials are changing. This paper discusses some of the considerations that need to be taken into account when designing a trial, including those trials that assess combinations of targets
Topotecan lacks third space sequestration
The objective of this study was to determine the influence of pleural and
ascitic fluid on the pharmacokinetics of the antitumor camptothecin
derivative topotecan. Four patients with histological proof of malignant
solid tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on several
occasions in both the presence and absence of third space volumes. Serial
plasma and pleural or ascitic fluid samples were collected during each
dosing and analyzed by high-performance liquid chromatography for both the
intact lactone form of topotecan and its ring-opened carboxylate form. The
apparent topotecan clearance demonstrated substantial interpatient
variability but remained unchanged within the same patient in the presence
[110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of
pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven
courses)]. Similarly, terminal half-lives and area under the
concentration-time curve ratios of lactone:total drug in plasma were
similar between courses within each patient. Topotecan penetration into
pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range,
1.37-1.86 h), and ratios with plasma concentration increased with time
after dosing in all patients. The mean ratio of third space topotecan
total drug area under the concentration-time curve to that in plasma was
0.55 (range, 0.26-0.87). These data indicate that topotecan can be safely
administered to patients with pleural effusions or ascites and that there
is substantial penetration of topotecan into these third spaces, which may
prove beneficial for local antitumor effects
Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body-surface area dosage regimens
Anticancer drugs still are dosed based on the body-surface area (BSA) of
the individual patient, although the BSA is not the main predictor of the
clearance for the majority of drugs. The relevance of BSA-based dosing has
not been evaluated for topotecan yet. A retrospective pharmacological
analysis was performed of kinetic data from four clinical Phase I studies
in which topotecan was administered p.o. as a single agent combined with
data from a combination study of topotecan and cisplatin. A strong
correlation (r = 0.91) was found between the area under the plasma
concentration time curve of the lactone and carboxylate forms of topotecan
by plotting 326 data sets obtained from 112 patients receiving oral
topotecan at dose levels ranging from 0.15-2.70 mg/m2. The intrapatient
variability, studied in 47 patients sampled for 3 or more days, for the
apparent lactone clearance, ranged from 7.4-69% (mean, 24 +/- 13%; median,
20%). The interpatient variabilities in the lactone clearance, calculated
with the data of all studied patients, expressed in liter/h/m2 and in
liter/h were 38% and 42%, respectively. In view of the relatively high
inter- and intrapatient variabilities in topotecan clearance, in contrast
to a variability of only 12% in the BSA of the studied patients, no
advantage of BSA-based dosing was found over fixed dose regimens
Factors involved in prolongation of the terminal disposition phase of SN-38: clinical and experimental studies
The active metabolite of irinotecan (CPT-11),
7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through enzymatic
cleavage of CPT-11 by carboxyl esterases (CEs) or through cytochrome P-450
3A-mediated oxidation to 7-ethyl-10-[4-(1-piperidino)-1-amino]
carbonyloxycamptothecin (NPC) and a subsequent conversion by CE. In the
liver, SN-38 is glucuronidated (SN-38G) by UGT1A1, which also conjugates
bilirubin. Fourteen patients were treated with 350 mg/m2 CPT-11, and we
performed pharmacokinetic analysis during a 500-h collection period. The
half-life and area under the plasma concentration-time curve of SN-38 were
47+/-7.9 h and 2.0+/-0.79 microM x h, respectively, both representing a
2-fold increase as compared with earlier reported estimates (A. Sparreboom
et al, Clin. Cancer Res., 4: 2747-2754, 1998). As an explanation for this
phenomenon, we noted substantial formation of SN-38 from CPT-11 and NPC by
plasma CE, consistent with the low circulating levels of NPC observed. In
addition, transport studies in Caco-2 monolayers indicated that
nonglucuronidated SN-38 could cross the membrane from apical to
basolateral, indicating the potential for recirculation processes that can
prolong circulation times. Interestingly, individual levels of fecal
beta-glucuronidase, which is known to mediate SN-38G hydrolysis, were not
related to any of the SN-38 kinetic parameters (r = 0.09; P = 0.26),
suggesting that interindividual variation in this enzyme is unimportant in
explaining SN-38 pharmacokinetic variability. We have also found, in
contrast to earlier data, that SN-38G/SN-38 plasma concentration ratios
decrease over time from approximately 7 (up to 50 h) to approximately 1
(at 500 h). This decrease could be explained by the fact that
glucuronidation of SN-38 and bilirubin is increasingly competitive at
lower drug levels. In addition, no evidence was found for SN-38G transport
through the Caco-2 cells. Our findings indicate that until now the
circulation time of SN-38 has been underestimated. This is of crucial
importance to our understanding of the clinical action of CPT-11 and for
future pharmacokinetic/pharmacodynamic relationships
Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients
This study was designed to evaluate irinotecan (CPT-11) disposition and
pharmacodynamics in the presence and absence of the broad-spectrum
antibiotic neomycin. Seven evaluable cancer patients experiencing diarrhea
graded > or =2 after receiving CPT-11 alone (350 mg/m(2) i.v. once every 3
weeks) received the same dose combined with oral neomycin at 1000 mg three
times per day (days -2 to 5) in the second course. Neomycin had no effect
on the systemic exposure of CPT-11 and its major metabolites (P > or =
0.22). However, it changed fecal beta-glucuronidase activity from 7.03 +/-
1.76 microg/h/mg (phenolphthalein assay) to undetectable levels and
decreased fecal concentrations of the pharmacologically active metabolite
SN-38. Although neomycin had no significant effect on hematological
toxicity (P > 0.05), diarrhea ameliorated in six of seven patients (P =
0.033). Our findings indicate that bacterial beta-glucuronidase plays a
crucial role in CPT-11-induced diarrhea without affecting enterocycling
and systemic SN-38 levels
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
Realizing better doctor-patient dialogue about choices in palliative care and early phase clinical trial participation: towards an online value clarification tool (OnVaCT)
Background: Patients with advanced cancer for whom standard systemic treatment is no longer available may be
offered participation in early phase clinical trials. In the decision making process, both medical-technical information
and patient values and preferences are important. Since patients report decisional conflict after deciding on
participation in these trials, improving the decision making process is essential. We aim to develop and evaluate an
Online Value Clarification Tool (OnVaCT) to assist patients in clarifying their values around this end-of-life decision.
This improved sharing of values is hypothesized to support medical oncologists in tailoring their information to
individual patients’ needs and, consequently, to support patients in taking decisions in line with their values and
reduce decisional conflict.
Methods: In the first part, patients’ values and preferences and medical oncologists’ views hereupon will be
explored in interviews and focus groups to build a first prototype OnVaCT using digital communication (serious
gaming). Next, we will test feasibility during think aloud sessions, to deliver a ready-to-implement OnVaCT. In the
second part, the OnVaCT, with accompanied training module, will be evaluated in a pre-test (12–18 months before
implementation) post-test (12–18 months after implementation) study in three major Dutch cancer centres. We will
include 276 patients (> 18 years) with advanced cancer for whom standard systemic therapy is no longer available,
and who are referred for participation in early phase clinical trials. The first consultation will be recorded to analyse
patient-physician communication regarding the discussion of patients’ values and the decision making process.
Three weeks afterwards, decisional conflict will be measured.
Discussion: This project aims to support the discussion of patient values when considering participation in early
phase clinical trials. By including patients before their first appointment with the medical oncologist and record
Drug-administration sequence does not change pharmacodynamics and kinetics of irinotecan and cisplatin
In this study, 11 patients with solid tumors were randomized to receive
irinotecan (CPT-11; 200 mg/m2) as a 90-min i.v. infusion, immediately
followed by cisplatin (CDDP; 80 mg/m2) as a 3-h i.v. infusion in the first
course and the reversed sequence in the second course or vice versa. No
significant differences in any toxicity were observed between the
treatment schedules (decrease in absolute neutrophil count, 74.7 +/- 18.3
versus 80.3 +/- 18.0%; P = 0.41). CPT-11 lactone clearance was similar to
single agent data and not significantly different between study courses
(60.4 +/- 17.1 versus 65.5 +/- 16.3 liter/h/m2; P = 0.66). The kinetic
profiles of the major CPT-11 metabolites SN-38, SN-38 glucuronide,
7-ethyl-10-[4-N-(5-aminopentanoic
acid)-1-piperidinolcarbonyloxycamptothecine (APC), and
7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecine (NPC) were
also sequence independent (P > or = 0.20). In addition, CPT-11 had no
influence on the clearance of nonprotein-bound CDDP (40.8 +/- 16.7 versus
50.3 +/- 18.6 liter/h/m2; P = 0.08) and the platinum DNA-adduct formation
in peripheral leukocytes in either sequence (1.94 +/- 2.20 versus 2.42 +/-
1.62 pg Pt/microg DNA; P = 0.41). These data indicate that the toxicity of
the combination CPT-11 and CDDP is schedule independent and that there is
no mutual pharmacokinetic interaction
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