ABSTRACT
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.
Subject(s)
Antineoplastic Agents/administration & dosage , Benzimidazoles/administration & dosage , DNA Methylation/drug effects , Drug Carriers , Enzyme Inhibitors/administration & dosage , Epigenesis, Genetic/drug effects , Leukemia, Biphenotypic, Acute/drug therapy , Methyltransferases/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Benzimidazoles/blood , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Biological Availability , Chemistry, Pharmaceutical , Delayed-Action Preparations , Dogs , Drug Administration Schedule , Enzyme Inhibitors/blood , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Gene Expression Regulation, Leukemic/drug effects , Histone-Lysine N-Methyltransferase , Humans , Infusions, Intravenous , Injections, Subcutaneous , Leukemia, Biphenotypic, Acute/enzymology , Leukemia, Biphenotypic, Acute/genetics , Leukemia, Biphenotypic, Acute/pathology , Male , Methyltransferases/metabolism , Mice , Rats, Sprague-Dawley , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The purpose of this study was to investigate the impact of processing, API loading, and formulation composition on the content uniformity of low-dose tablets made using direct compression (DC) and roller compaction (RC) methods at 1 kg scale. Blends of 1:1 microcrystalline cellulose/lactose or 1:1 microcrystalline cellulose/dicalcium phosphate anhydrous with active pharmaceutical ingredient (API) at loadings of 0.2, 1 and 5% were processed either by DC or RC. A statistical analysis showed that DC produced comparable content uniformity results to RC. Microcrystalline cellulose/lactose formulations had improved average potency compared to microcrystalline cellulose/dicalcium phosphate anhydrous formulations for both DC and RC. The impact of segregation in the DC blends and adhesion to equipment surfaces was assessed to aid in understanding potency trends. DC may be as suitable as RC for low-dose regime (e.g. < 1 mg) when manufacturing clinical supplies at small scale provided the API has a suitable particle size and potency loss to equipment is negligible.
