Phase I Population Pharmacokinetic Assessment of the Oral Bromodomain Inhibitor OTX015 in Patients with Haematologic Malignancies

Clin Pharmacokinet. 2016 Mar;55(3):397-405. doi: 10.1007/s40262-015-0327-6.


Background and objectives: OTX015 (MK-8628) is a novel inhibitor of the bromodomain and extraterminal (BET)-bromodomain (BRD) protein family, binding specifically to bromodomains BRD2/3/4 and impacting the epigenetic regulation of several oncogenes. We characterized the pharmacokinetics of this first-in-class BET-BRD inhibitor administered as a single agent, including population pharmacokinetic modelling.

Methods: A dose-escalation, phase Ib study was performed with oral OTX015 in patients with haematologic malignancies, at doses starting from 10 mg once daily (QD) with continuous or discontinuous schedules. Five or eight blood samples were collected per patient for pharmacokinetic analysis. OTX015 plasma concentrations were determined using validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and analysed using a nonlinear mixed-effects modelling software program. A population pharmacokinetic model was fitted to the data, and patient demographics and clinical chemistry parameters were tested as predictive covariates on the model parameters.

Results: Blood samples were analysed from 81 patients treated with OTX015 at doses ranging from 10 to 160 mg QD or 40 mg twice daily (BID), and 633 time-plasma concentrations were available for analysis. A one-compartment open model with linear elimination adequately described OTX015 pharmacokinetics. The most significant covariate was lean body mass (LBM), which decreased the between-subject variability in apparent total body clearance (CL) and the volume of distribution (V). The estimated pharmacokinetic parameters were the absorption rate constant (k a) = 0.731 h(-1), V = 71.4 L and CL = 8.47 L·h(-1).

Conclusion: The pharmacokinetics of oral OTX015 in patients with haematologic malignancies can be described with a one-compartment model. Population pharmacokinetic modelling of OTX015 plasma concentrations showed that LBM influences V and CL. These findings do not suggest the need for dose adjustment.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / blood
  • Acetanilides / pharmacokinetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Cell Cycle Proteins
  • Female
  • Hematologic Neoplasms / metabolism*
  • Heterocyclic Compounds, 3-Ring / blood
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics*
  • Humans
  • Male
  • Middle Aged
  • Models, Biological*
  • Nuclear Proteins / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • RNA-Binding Proteins / antagonists & inhibitors
  • Transcription Factors / antagonists & inhibitors
  • Young Adult


  • Acetanilides
  • Antineoplastic Agents
  • BRD2 protein, human
  • BRD3 protein, human
  • BRD4 protein, human
  • Cell Cycle Proteins
  • Heterocyclic Compounds, 3-Ring
  • Nuclear Proteins
  • OTX015
  • RNA-Binding Proteins
  • Transcription Factors
  • Protein-Serine-Threonine Kinases