A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and various degrees of hepatic function

Slingerland, Marije; Hess, Dagmar; Clive, Sally; Sharma, Sunil; Sandström, Per; Loman, Niklas; Porro, Maria Grazia; Mu, Song; Waldron, Edward; Valera, Sue Zette; Gelderblom, Hans

doi:10.1007/s00280-014-2594-6

Cited by 39 publications

(30 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We utilized cell viability as well as colony forming assays to demonstrate that PS and SAHA synergized with CNDAC in killing AML cells. Pharmacokinetic evaluations show that the maximum serum plasma concentrations of vorinostat are ~1.4 µM, 1–3 h post dosing in AML (45, 46) and ~19 nM for PS (46) indicating that the concentrations of vorinostat and PS achieved in patients are more than sufficient to inhibit both the proliferative capacity as well as kill AML cells. Correlative studies during therapy would help validate the action of this combination on the proliferative index and survival of circulating AML blasts.…”

Section: Discussionmentioning

confidence: 99%

HDAC Inhibition Induces MicroRNA-182, which Targets RAD51 and Impairs HR Repair to Sensitize Cells to Sapacitabine in Acute Myelogenous Leukemia

Lai

Ewald

Zecevic

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose The double strand breaks elicited by sapacitabine, a clinically active nucleoside analog prodrug are repaired by Rad51 and the homologous recombination repair (HR) pathway which could potentially limit its toxicity. We investigated the mechanism by which HDAC inhibitors targeted Rad51 and HR to sensitize AML cells to sapacitabine. Experimental Design Chromatin immunoprecipitation identified the role of HDACs in silencing microRNA-182 in AML. Immunoblotting, gene expression, overexpression or inhibition of miR-182 and luciferase assays established that miR-182 directly targeted Rad51. HR reporter assays, apoptotic assays and colony forming assays established that the miR-182, as well as the HDAC inhibition-mediated decreases in Rad51 inhibited HR repair and sensitized cells to sapacitabine. Results The gene repressors, HDAC1 and HDAC2, became recruited to the promoter of miR-182 to silence its expression in AML. HDAC inhibition induced miR-182 in AML cell lines and primary AML blasts. miR-182 targeted Rad51 protein both in luciferase assays and in AML cells. Overexpression of miR-182, as well as HDAC inhibition-mediated induction of miR-182 were linked to time- and dose-dependent decreases in the levels of Rad51, an inhibition of HR, increased levels of residual damage and decreased survival after exposure to double strand damage inducing agents. Conclusions Our findings define the mechanism by which HDAC inhibition induces miR-182 to target Rad51 and highlights a novel pharmacological strategy that compromises the ability of AML cells to conduct HR, thereby sensitizing AML cells to DNA damaging agents that activate HR as a repair and potential resistance mechanism.

show abstract

Section: Discussionmentioning

confidence: 99%

HDAC Inhibition Induces MicroRNA-182, which Targets RAD51 and Impairs HR Repair to Sensitize Cells to Sapacitabine in Acute Myelogenous Leukemia

Lai

Ewald

Zecevic

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Mild and moderate hepatic impairment increased the AUC of panobinostat by 43% and 105%, respectively, while the C max increased by 40 and 80% . The terminal half‐life was not modified.…”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 96%

Clinical pharmacokinetics of oral drugs in the treatment of multiple myeloma

Morival

Oumari

Lenglet

et al. 2017

Hematological Oncology

View full text Add to dashboard Cite

Treatment of myeloma is a long-term treatment mainly based on all-oral combinations of drugs. Because oral drugs have a more complex pharmacokinetics compared with IV treatments, an appropriate knowledge of the factors that may alter their systemic exposure is of particular clinical relevance. Both drug-drug interactions, food-effect, and dose-adaptation in renal and hepatic impairment may influence the systemic drug levels with a potential impact on drug efficacy or safety. Moreover, a better control of drug exposure may improve the side effect profiles of these treatments with a favourable impact on patient compliance. Furthermore, as long-term treatments, these drugs may also alter the systemic exposure of coadministered medications in these rather old patients. The aim of this review was to identify the factors modifying the systemic exposure of oral drugs used in myeloma by focusing on the pharmacokinetic drug-drug interactions and the effects of renal and hepatic impairment and of food impact.

show abstract

“…In patients with advanced cancer, those with mild and moderate hepatic impairment had areas under the panobinostat concentration-time curve (AUC) from time zero to infinity (AUC ? ) that were 43 and 105 % higher than those with normal hepatic function [6,21], and dosage modification is recommended in these patients [6]. The effect of severe hepatic impairment on panobinostat pharmacokinetics has not been determined; therefore, panobinostat should not be administered in these patients.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Hepatic impairment is associated with increased panobinostat exposure [6,21]. In patients with advanced cancer, those with mild and moderate hepatic impairment had areas under the panobinostat concentration-time curve (AUC) from time zero to infinity (AUC ? )…”

Section: Pharmacokineticsmentioning

confidence: 99%

Panobinostat: First Global Approval

Garnock-Jones

2015

Drugs

169

109

View full text Add to dashboard Cite

Novartis has developed oral and intravenous formulations of panobinostat (Farydak(®)), a histone deacetylase (HDAC) inhibitor, for the treatment of cancer. HDACs have important roles in maintaining chromatin structure and in regulating gene expression, including that of tumour suppressor genes, and thus represent valid targets in the search for cancer therapeutics. Oral panobinostat is approved in the US, as combination therapy with bortezomib and dexamethasone in patients with recurrent multiple myeloma who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory agent. Regulatory submissions have been made for the use of combination therapy with panobinostat in patients with recurrent multiple myeloma in the EU and Japan. Panobinostat is in various stages of clinical development worldwide for a range of haematological and solid tumours. This article summarizes the milestones in the development of panobinostat leading to this first approval for multiple myeloma.

show abstract

A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and various degrees of hepatic function

Abstract: Despite increased plasma exposure, patients with mild or moderate hepatic dysfunction could be safely treated with the same starting dose of panobinostat as patients with normal hepatic function, with careful monitoring and dose adjustments as required.

Cited by 39 publications

References 31 publications

HDAC Inhibition Induces MicroRNA-182, which Targets RAD51 and Impairs HR Repair to Sensitize Cells to Sapacitabine in Acute Myelogenous Leukemia

HDAC Inhibition Induces MicroRNA-182, which Targets RAD51 and Impairs HR Repair to Sensitize Cells to Sapacitabine in Acute Myelogenous Leukemia

Clinical pharmacokinetics of oral drugs in the treatment of multiple myeloma

Panobinostat: First Global Approval

Contact Info

Product

Resources

About