Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target

Protein methyltransferases are emerging as promising drug targets for therapeutic intervention in human cancers. Pinometostat (EPZ-5676) is a small molecule inhibitor of the DOT1L enzyme, a histone methyltransferase that methylates lysine 79 of histone H3. DOT1L activity is dysregulated in the patho...

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Bibliographic Details
Published in:Journal of controlled release 2015-12, Vol.220 (Pt B), p.758-765
Main Authors: Waters, Nigel J., Daigle, Scott R., Rehlaender, Bruce N., Basavapathruni, Aravind, Campbell, Carly T., Jensen, Tyler B., Truitt, Brett F., Olhava, Edward J., Pollock, Roy M., Stickland, Kim A., Dovletoglou, Angelos
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - blood
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Benzimidazoles - administration & dosage
Benzimidazoles - blood
Benzimidazoles - chemistry
Benzimidazoles - pharmacokinetics
Biological Availability
Chemistry, Pharmaceutical
Continuous IV
Delayed-Action Preparations
DNA Methylation - drug effects
Dogs
DOT1L
Drug Administration Schedule
Drug Carriers
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - blood
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Epigenesis, Genetic - drug effects
EPZ-5676
Gene Expression Regulation, Leukemic - drug effects
Humans
Infusions, Intravenous
Injections, Subcutaneous
Leukemia, Biphenotypic, Acute - drug therapy
Leukemia, Biphenotypic, Acute - enzymology
Leukemia, Biphenotypic, Acute - genetics
Leukemia, Biphenotypic, Acute - pathology
Male
Methyltransferases - antagonists & inhibitors
Methyltransferases - metabolism
Mice
MLL-r
Pinometostat
Rats, Sprague-Dawley
Subcutaneous
Tumor Burden - drug effects
Xenograft Model Antitumor Assays
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Summary:Protein methyltransferases are emerging as promising drug targets for therapeutic intervention in human cancers. Pinometostat (EPZ-5676) is a small molecule inhibitor of the DOT1L enzyme, a histone methyltransferase that methylates lysine 79 of histone H3. DOT1L activity is dysregulated in the pathophysiology of rearranged mixed lineage leukemia (MLL-r). Pinometostat is currently in Phase 1 clinical trials in relapsed refractory acute leukemia patients and is administered as a continuous IV infusion (CIV). The studies herein investigated alternatives to CIV administration of pinometostat to improve patient convenience. Various sustained release technologies were considered, and based on the required dose size as well as practical considerations, subcutaneous (SC) bolus administration of a solution formulation was selected for further evaluation in preclinical studies. SC administration offered improved exposure and complete bioavailability of pinometostat relative to CIV and oral administration. These findings warranted further evaluation in rat xenograft models of MLL-r leukemia. SC dosing in xenograft models demonstrated inhibition of MLL-r tumor growth and inhibition of pharmacodynamic markers of DOT1L activity. However, a dosing frequency of thrice daily (t.i.d) was required in these studies to elicit optimal inhibition of DOT1L target genes and tumor growth inhibition. Development of an extended release formulation may prove useful in the further optimization of the SC delivery of pinometostat, moving towards a more convenient dosing paradigm for patients. [Display omitted]
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2015.09.023