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


CONCLUSIONS
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.
Department of Radio-Pharmacology, Institut Curie-Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint-Cloud, France. elodie.odore@curie.fr.|Oncology Therapeutic Development, Clichy, France. elodie.odore@curie.fr.
Elodie
E
Odore
Department of Radio-Pharmacology, Institut Curie-Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint-Cloud, France.
François
F
Lokiec
Oncology Therapeutic Development, Clichy, France.|Oncoethix GmbH, Lucerne, Switzerland.
Esteban
E
Cvitkovic
Oncology Therapeutic Development, Clichy, France.
Mohamed
M
Bekradda
Oncology Therapeutic Development, Clichy, France.|Oncoethix GmbH, Lucerne, Switzerland.
Patrice
P
Herait
Oncology Therapeutic Development, Clichy, France.
Fabrice
F
Bourdel
Oncology Therapeutic Development, Clichy, France.
Carmen
C
Kahatt
Hôpital Saint Louis, Paris, France.
Emmanuel
E
Raffoux
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
Anastasios
A
Stathis
Hôpital Saint Louis, Paris, France.
Catherine
C
Thieblemont
CHRU Lille, Lille, France.
Bruno
B
Quesnel
The Royal Marsden Hospital, London, UK.
David
D
Cunningham
Oncology Therapeutic Development, Clichy, France.
Maria E
ME
Riveiro
Department of Radio-Pharmacology, Institut Curie-Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint-Cloud, France.
Keyvan
K
Rezaï
D000083:Acetanilides / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D018797:Cell Cycle Proteins; D005260:Female; D019337:Hematologic Neoplasms / Q000378:metabolism*; D006575:Heterocyclic Compounds, 3-Ring / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D055815:Young Adult; D000092468:Bromodomain Containing Proteins
D000083:Acetanilides; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D006575:Heterocyclic Compounds, 3-Ring; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C109106:BRD3 protein, human; C441289:BRD4 protein, human; C000605331:OTX015