Elucidation of the metabolic and elimination pathways of panobinostat (LBH589) using [14C]-panobinostat

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2549-2549 ◽  
Author(s):  
S. Clive ◽  
M. M. Woo ◽  
M. Stewart ◽  
T. Nydam ◽  
S. Hirawat ◽  
...  
Keyword(s):  
Blood Plasma ◽  
Hydroxamic Acid ◽  
Oral Absorption ◽  
Total Radioactivity ◽  
Side Chain ◽  
Clinical Activity ◽  
Deacetylase Inhibitor ◽  
Radiometric Detection ◽  
Major Route ◽  
Clinically Significant

2549 Background: Panobinostat (PAN), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor, demonstrating anti-tumor activities in a wide variety of preclinical models and showing promising clinical activity. This study elucidates the metabolic and elimination pathways of PAN using [14C]-PAN. Methods: Four patients with advanced cancer received a single oral 20 mg dose of [14C]-PAN (50 μCi). Whole blood, plasma, urine, and feces were collected over 7 days. Total radioactivity was measured in blood, plasma, and excreta by liquid scintillation counting. PAN and its metabolite concentrations in plasma and excreta were measured by LC-MS/MS and HPLC with radiometric detection. Patients were monitored for safety. Results: The single PAN dose was well tolerated with no clinically significant laboratory or ECG abnormalities observed. PAN had a rapid oral absorption [median Tmax 0.8 h (range, 0.5–1 h)] and moderate elimination (median t1/2 31 h). The median t1/2 for blood and plasma radioactivity was 54 and 75 hours, respectively. Mass balance was achieved with ≥87% of the administered radioactivity being recovered in the excreta of all patients after 7 days. 44–77% and 29–51% of the dose was recovered in the feces and urine, respectively. Unchanged PAN accounted for ≤3% of the administered dose in the feces, suggesting good oral absorption. The most prominent metabolic pathways involved modifications of the hydroxamic acid (HA) side chain, to form an amide via reduction, carboxylic acid via either hydrolysis or one- and two-carbon (M1) shortening of the HA side chain. Oxygenation and glucuronidation were also observed. PAN accounted for ≤9% of the total radioactivity AUC. The most abundant circulating metabolites in plasma were the glucuronide of M1 (19%) and carbamoyl glucuronide of PAN (13%). At least 40 metabolites, many at trace levels, were observed circulating in plasma. Conclusions: PAN and its metabolites are equally excreted in the urine and feces. Elimination of PAN is primarily by metabolism via reduction, hydrolysis, oxidation and glucuronidation. The balanced elimination and absence of a single major route of PAN metabolism suggest that clinical drug-drug interactions are unlikely with PAN. [Table: see text]

A Phase 2 Study of Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Relapsed or Refractory Indolent Non Hodgkin Lymphoma. A California Cancer Consortium Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2568-2568 ◽  
Author(s):  
Mark H. Kirschbaum ◽  
Jasmine M. Zain ◽  
Leslie Popplewell ◽  
Vinod Pullarkat ◽  
Auayporn P. Nademanee ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Stable Disease ◽  
Histone Deacetylase Inhibitor ◽  
Interim Analysis ◽  
Hydroxamic Acid ◽  
Marginal Zone ◽  
Study Drug ◽  
Clinical Activity ◽  
Deacetylase Inhibitor ◽  
Mantle Cell

Abstract Background: The indolent (follicular, marginal zone and mantle cell) lymphomas tend to recur with decreasing intervals of remission after standard chemotherapy. New modalities of treatment are necessary. Vorinostat (SAHA), an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deactylases with preclinical and clinical activity against various forms of lymphoma, is being studied in patients with relapsed or refractory indolent lymphoma. We report the results at the first interim analysis, after accrual of the first 17 evaluable patients according to the two-stage trial design. Methods: Patients with relapsed or refractory follicular, marginal zone, or mantle cell lymphoma are eligible. Vorinostat is dosed at 200 mg po twice daily for 14 consecutive days on a 21 day cycle. CT scanning is performed after every three cycles, as is marrow biopsy for those with marrow involvement at time of entry into study. Patients may have received up to four prior chemotherapy regimens including Zevalin or Bexxar; previous transplant is allowed. Results: 17 eligible patients (8 female, 9 male) were accrued prior to interim analysis (1 ineligible patient due to wrong histology is excluded from the analysis). The median age at diagnosis was 61 (34–78) years. All patients had progressed or failed to respond to chemotherapy and/or rituximab. Five patients were taken off study due to progression, two came off study due to toxicities (one for fatigue and diarrhea after 10 cycles and the other for diarrhea and dizziness after 2 cycles). One patient stopped therapy due to intercurrent illness, one came off for alternate therapy, 1 completed the treatment per protocol with a CR, and 7 patients remain on treatment. One patient had grade 4 ANC and thrombocytopenia, and one patient had grade 4 thrombocytopenia. Both patients were able to get subsequent cycles. Grade 3 toxicities attributable to study drug were thrombocytopenia, neutropenia, anemia, and fatigue. By the current Cheson criteria, there were 4 patients who achieved complete remission (CR), and 2 patients who achieved partial remission (PR). The two patients with PR as best response subsequently progressed (one at 189 days, one after 462 days). Four other patients are on therapy with stable disease, one patient with stable disease now for over 420 days. Conclusions: The histone deacetylase inhibitor vorinostat shows promising activity against follicular and marginal zone lymphoma, refractory to chemotherapy and rituximab. The target response for stage 1 (4/17) was met and stage 2 is open for accrual.

Absorption, metabolism, and excretion of 14C gimatecan (LBQ707) after oral administration in patients with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2564-2564 ◽  
Author(s):  
M. M. Woo ◽  
L. Rodriguez ◽  
H. Gu ◽  
K. Crenshaw-Williams ◽  
F. Rocha ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Topoisomerase I ◽  
Oral Absorption ◽  
Total Radioactivity ◽  
Fecal Excretion ◽  
Active Components ◽  
Good Tolerability ◽  
Radiometric Detection ◽  
Pharmacologically Active

2564 Background: Gimatecan (Gim), a new potent oral topoisomerase I inhibitor is a lipophilic 7-oxyiminomethyl derivative of camptothecin. Its in vitro cytoxicity is more sustained than CPT-11 and topotecan, it has excellent anti-tumor activity in mouse xenografts, and shown good tolerability with Ph I activity. The study aim was to profile its disposition in cancer patients. Methods: 4 patients with advanced cancer received a single oral 1.5 mg dose of [14C] Gim (60 μCi) followed by standard Gim treatment on Day 15. Whole blood, plasma, urine, and feces were collected over 7 days with spot fecal collections up to Day 19. Total radioactivity was measured by liquid scintillation counting. Gim and metabolite concentrations in plasma and excreta were measured by LC- MS/MS and HPLC with radiometric detection. Results: Gim showed a rapid first-order absorption and a long elimination phase and was well tolerated. The median (range) Tmax for Gim was 1 h (0.5 to 3 h) and mean t1/2 and oral clearance values were 91 h and 0.6 L/h, respectively. Gim was the major moiety and its active metabolite LCF775 (t-butyl-mono-hydroxy Gim) was the main metabolite (albeit minor, 2–9%) in plasma. Trace glucuronide and sulfate metabolites were also detected in plasma. Mean recovery of radioactivity in urine (0-Day 7) and feces (0-Day 11) was 70.5 % (56.2–80.0%) of the dose. Incomplete recovery is attributed to opiates use in 2 patients and incomplete (sporadic) fecal sampling at later timepoints. Fecal excretion (0-Day 11) was prolonged and major in 3/4 patients (46- 73% of the dose, of which 14–23% is the unchanged Gim suggesting the drug is well absorbed). An additional 1.3–3.5% was recovered in spot collections (Days 14, 15 and 19). Urine excretion (0-Day 7) was 7.2–10.3% of the dose in 3 patients, one patient (cachectic, on opiates) excreted only 21% in feces and 46% in urine. Gim and several Gim metabolites (and glucuronide conjugates thereof) were the major components in excreta. Conclusions: Gim and its minor metabolite, LCF775 were the principal pharmacologically active components in plasma. Fecal excretion is the main elimination pathway in most patients. A long half-life (90hr) of Gim, uncomplicated metabolism, and good oral absorption make Gim an attractive candidate for Ph II development. [Table: see text]

Characterization of the Oral Absorption of Some β-Lactams Effect of the α-Amino Side Chain Group

1993 ◽  
Vol 82 (9) ◽  
pp. 897-900 ◽  
Author(s):  
Doo‐Man oh ◽  
Patrick J. Sinko ◽  
Gordon L. Amidon
Keyword(s):  
Oral Absorption ◽  
Side Chain ◽  
Chain Group

Metabolism of carbaryl and carbofuran by soil-enrichment and bacterial cultures

1984 ◽  
Vol 30 (12) ◽  
pp. 1458-1466 ◽  
Author(s):  
B. S. Rajagopal ◽  
V. R. Rao ◽  
G. Nagendrappa ◽  
N. Sethunathan
Keyword(s):  
Enrichment Culture ◽  
Side Chain ◽  
Bacillus Sp ◽  
Mineral Salts ◽  
Prolonged Incubation ◽  
Soil Enrichment ◽  
Enrichment Cultures ◽  
Hydrolysis Products ◽  
Carbamate Insecticides ◽  
Major Route

Metabolism of side chain and ring 14C-labelled carbaryl and carbofuran in a mineral salts medium by soil-enrichment cultures and a Bacillus sp. was studied. A change in the substrate of the medium from carbaryl to carbofuran led to a marked shift in the dominant bacterium from Bacillus sp. to Arthrobacter sp. although carbaryl-enrichment culture was the primary inoculum in both media. Hydrolysis was the major route of microbial degradation of both carbamate insecticides. During carbaryl degradation by enrichment cultures and Bacillus sp., 1-naphthol and 1,4-naphthoquinone accumulated in the medium. Of the three metabolites formed from carbofuran, 3-hydroxycarbofuran and 3-ketocarbofuran were further metabolized rapidly, while carbofuran phenol was resistant to further degradation. Evolution of 14CO2 and other gaseous 14C-labelled products from both side chain and ring labels was negligible. This and slow degradation of the hydrolysis products led to significant accumulation of 14C in the medium even after prolonged incubation.

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