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

Clinical Pharmacokinetics volume 55, pages 397–405 (2016)Cite this article

Abstract

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.

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Financial Support

This study was funded by Oncoethix SA.

Author information

Affiliations

  1. Department of Radio-Pharmacology, Institut Curie-Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint-Cloud, France

    Elodie Odore, François Lokiec & Keyvan Rezaï

  2. Oncology Therapeutic Development, Clichy, France

    Elodie Odore, Esteban Cvitkovic, Mohamed Bekradda, Patrice Herait, Fabrice Bourdel, Carmen Kahatt & Maria E. Riveiro

  3. Oncoethix GmbH, Lucerne, Switzerland

    Esteban Cvitkovic & Patrice Herait

  4. Hôpital Saint Louis, Paris, France

    Emmanuel Raffoux & Catherine Thieblemont

  5. Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    Anastasios Stathis

  6. CHRU Lille, Lille, France

    Bruno Quesnel

  7. The Royal Marsden Hospital, London, UK

    David Cunningham

Authors
  1. Elodie Odore
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  2. François Lokiec
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  3. Esteban Cvitkovic
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  4. Mohamed Bekradda
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  5. Patrice Herait
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  6. Fabrice Bourdel
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  7. Carmen Kahatt
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  8. Emmanuel Raffoux
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  9. Anastasios Stathis
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  10. Catherine Thieblemont
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  11. Bruno Quesnel
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  12. David Cunningham
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  13. Maria E. Riveiro
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  14. Keyvan Rezaï
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Corresponding author

Correspondence to Elodie Odore.

Ethics declarations

EC and PH are founders of Oncoethix. EO, MB, FB, CK and MER are employees of Oncology Therapeutic Development. FL, ER, AS, CT, BQ, DC and KR have no conflicts of interest that are directly relevant to the content of this manuscript.

Additional information

Oncoethix GmbH is a wholly owned subsidiary of Merck Sharp & Dohme Corp. (formerly Oncoethix SA)

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Cite this article

Odore, E., Lokiec, F., Cvitkovic, E. et al. Phase I Population Pharmacokinetic Assessment of the Oral Bromodomain Inhibitor OTX015 in Patients with Haematologic Malignancies. Clin Pharmacokinet 55, 397–405 (2016). https://doi.org/10.1007/s40262-015-0327-6

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  • DOI: https://doi.org/10.1007/s40262-015-0327-6

Keywords

  • Pharmacokinetic Parameter
  • Lean Body Mass
  • Population Pharmacokinetic Model
  • Visual Predictive Check
  • Transit Compartment