Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumors

Nemunaitis, John; Mita, Alain C.; Stephenson, Joe; Mita, Monica; Sarantopoulos, John; Iyer, Swaminathan P.; Nanda, Nisha; Gleich, Lyon L.; Benichou, Annie Claude; Craig, Adam

doi:10.1007/s00280-012-1963-2

Cited by 41 publications

(31 citation statements)

References 24 publications

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“…The elimination of omacetaxine, 4′-DMHHT, and cephalotaxine in urine was moderately slow, with the majority excreted within 36 h postdose. The excretion data reported here for omacetaxine, 4′-DMHHT, and cephalotaxine within the first 24 h after administration correspond to results reported previously by Nemunaitis et al, who found urinary excretion of omacetaxine, 4′-DMHHT, and cephalotaxine to be 12 to 15 %, 4 to 5 %, and 0.07 %, respectively [17]. The recovery of TRA in 72 h was slightly higher than the sum of the recoveries of omacetaxine and its two metabolites over this same period (35.2 % versus 30.3 %), suggesting that other 14 C-omacetaxine-derived materials may be present.…”

Section: Discussionsupporting

confidence: 90%

“…After administration, the observed pharmacokinetic profiles of omacetaxine and 4′-DMHHT were consistent with results from a previous study in patients with cancer [17]. The high apparent volume of distribution suggests that omacetaxine is distributed extensively into the tissues; this is consistent with previous reports in which the drug was administered either as a subcutaneous injection or an intravenous infusion [17, 23].…”

Section: Discussionsupporting

confidence: 90%

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Pharmacokinetics and excretion of 14C-omacetaxine in patients with advanced solid tumors

et al. 2016

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SummaryBackground Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of 14C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m214C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4′-desmethylhomoharringtonine (4′-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m2 omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4′ DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other 14C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of 14C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other 14C-omacetaxine-derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Pharmacokinetics and excretion of 14C-omacetaxine in patients with advanced solid tumors

et al. 2016

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“…However, regarding pharmacokinetics only one report is available (18) for the subcutaneous (sc) omacetaxine. Two inactive drug metabolites have been identified, however, for omacetaxine, after sc 1.25 mg/m 2 b.i.d.…”

Section: Pharmacokinetics Of Omacetaxinementioning

confidence: 99%

Omacetaxine: A Protein Translation Inhibitor for Treatment of Chronic Myelogenous Leukemia

Gandhi

Plunkett

Cortés

2014

Clinical Cancer Research

105

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Chronic myelogenous leukemia (CML) is driven by the Bcr-Abl fusion protein which is a result of a (9;22) chromosomal translocation. Imatinib, dasatinib, and nilotinib (tyrosine kinase inhibitors, TKIs) have revolutionized how CML is treated. While the majority of patients respond to these kinase inhibitors, a subset become resistant to these therapeutics. Synribo (omacetaxine mepesuccinate) was recently FDA approved for Philadelphia-positive CML either in chronic or accelerated phase whose disease failed two prior TKIs. With omacetaxine 1.25 mg/m2 twice daily for 14 days during induction and for 7 days during maintenance, a major cytogenetic response occurred in 20% of patients in chronic phase and major hematologic response in 27% of patients in accelerated phase. Laboratory investigations unraveled the mechanism of action and effectiveness of this agent. Bcr-Abl protein is intrinsically programmed to turn over with a short half-life which makes it susceptible to protein translation inhibitors. Omacetaxine (homoharringtonine) inhibits total protein biosynthesis by binding to A-site cleft of ribosomes. As a corollary to this action, there is a diminution of short-lived proteins such as Bcr-Abl followed by cell death. Approval of this first-in-class protein translation inhibitor opens up new avenues for its use in other diseases as well as mechanism-based combinations.

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“…During the treatment of elderly patients with long-term low dose chemotherapy, non-hematological toxicity from HBT has not been found (32,(38)(39)(40)(41). Previous studies have identified cases of grade 4 left bundle branch block during HBT therapy, or grade 2 QT interval prolonged (42), which was not associated with the blood concentration of HBT (43). In the current study, the non-hematological toxicity adverse reactions from HBT treatment were minimal and considered acceptable, and the typical level 3-4 adverse reaction that was detected was hematological toxicity.…”

Section: Discussionmentioning

confidence: 99%

Novel homobarringtonie‑containing therapy for the treatment of patients with primary acute myeloid leukemia that are resistant to conventional therapy

Zhu

et al. 2017

Oncol Lett

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Abstract. The current study investigated the efficacy and safety of a novel treatment regime consisting of homobarringtonie, cytosine arabinoside and etoposide (HCE) for the treatment of primary acute myeloid leukemia (AML). In the present study, 141 patients diagnosed with AML were divided into the HCE (n=47) and the conventional AML therapy, consisting of idamycin combined with cytarabine (IA; n=94), treatment groups. The measured patient outcome parameters were the emission and response rates, as well as medication-induced adverse events, with a median follow-up time of 28 months. There was no significant difference in the 3-year relapse-free survival rate between the HCE and IA treatment groups. The occurrence and severity of hematological or non-hematological toxicity did not differ between the two groups. However, of the 26 patients that demonstrated a poor response to the IA treatment, 19 cases were administered the HCE treatment and 14 of these patients achieved complete remission (CR). Of the 10 patients that demonstrated a poor response to the HCE treatment, 8 patients were administered the IA treatment and 7 of these achieved CR. Therefore, HCE may be an effective treatment regimen for patients with primary AML. As there was no cross-resistance between the HCE and IA regimens, HCE may be an alternative option for patients that respond poorly to IA induction therapy.

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Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumors

Cited by 41 publications

References 24 publications

Pharmacokinetics and excretion of 14C-omacetaxine in patients with advanced solid tumors

Pharmacokinetics and excretion of 14C-omacetaxine in patients with advanced solid tumors

Omacetaxine: A Protein Translation Inhibitor for Treatment of Chronic Myelogenous Leukemia

Novel homobarringtonie‑containing therapy for the treatment of patients with primary acute myeloid leukemia that are resistant to conventional therapy

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