82 research outputs found
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
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
Phase I and pharmacokinetic study of brostallicin (PNU-166196), a new DNA minor-groove binder, administered intravenously every 3 weeks to adult patients with metastatic cancer
PURPOSE: Brostallicin (PNU-166196) is a cytotoxic agent that binds to the
minor groove of DNA with significant antitumor activity in preclinical
studies. This trial was designed to determine the maximum tolerated dose,
the toxicity profile, and the pharmacokinetics of Brostallicin in cancer
patients. Experimental Design: Patients were treated with escalating doses
of Brostallicin ranging from 0.85 to 15 mg/m(2) administered as a 10-min
i.v. infusion every 3 weeks. Blood samples for pharmacokinetic analysis
were collected during the first and second course, and analyzed by
liquid-chromatography with tandem-mass spectrometric detection. RESULTS:
Twenty-seven evaluable patients received a total of 73 courses. Grade 4
neutropenia was the only dose-limiting toxicity at 12.5 mg/m(2), whereas
grade 4 thrombocytopenia (1 patient) and grade 4 neutropenia (2 patients)
were the dose-limiting toxicities at 15 mg/m(2). Other side effects,
including thrombocytopenia and nausea, were generally mild. The maximum
tolerated dose was defined at 10 mg/m(2). The clearance and terminal
half-life of Brostallicin were dose-independent, with mean (+/-SD) values
of 9.33 +/- 2.38 liters/h/m(2) and 4.69 +/- 1.88 h, respectively. There
was no significant accumulation of Brostallicin with repeated
administration. Significant relationships were observed between systemic
exposure to Brostallicin and neutrophil counts at nadir. One partial
response was observed in a patient with a gastrointestinal stromal tumor.
CONCLUSION: Brostallicin was found to be well tolerated, with neutropenia
being the principal toxicity. The recommended dose for additional
evaluation in this schedule is 10 mg/m(2)
Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive hairy cell leukemia
BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.</p
A phase 1 study of PARP-inhibitor ABT-767 in advanced solid tumors with BRCA1/2 mutations and high-grade serous ovarian, fallopian tube, or primary peritoneal cancer
Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20mg once daily to 500mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined. Results Ninety-three patients were treated with ABT-767; 80 had a primary diagnosis of ovarian cancer. ABT-767 demonstrated dose-proportional PK up to 500mg BID and half-life of 2h. Food had no effect on ABT-767 bioavailability. Most common grade 3/4 treatment-related adverse events were nausea, fatigue, decreased appetite, and anemia. Anemia showed dose-dependent increase. RP2D was 400mg BID. Objective response rate by RECIST 1.1 was 21% (17/80) in all evaluable patients and 20% (14/71) in evaluable patients with ovarian cancer. Response rate by RECIST 1.1 and/or CA-125 was 30% (24/80) in patients with ovarian cancer. Mutations in BRCA1 or BRCA2, homologous recombination deficiency (HRD), and platinum sensitivity were associated with tumor response. Median progression-free survival was longer for HRD positive (6.7months) versus HRD negative patients (1.8months) with ovarian cancer. Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400mg BID and dose-proportional PK. Patients with BRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767
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