PMID- 32458089
OWN - NLM
STAT- MEDLINE
DCOM- 20210609
LR  - 20210609
IS  - 1550-7416 (Electronic)
IS  - 1550-7416 (Linking)
VI  - 22
IP  - 4
DP  - 2020 May 26
TI  - Physiologically Based Absorption Modelling to Explore the Impact of Food and 
      Gastric pH Changes on the Pharmacokinetics of Entrectinib.
PG  - 78
LID - 10.1208/s12248-020-00463-y [doi]
AB  - Entrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of 
      TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently 
      received FDA approval for ROS1 fusion-positive non-small cell lung cancer and 
      NTRK fusion-positive solid tumors. This paper describes the application of 
      a physiologically based biophamaceutics modeling (PBBM) during clinical 
      development to understand the impact of food and gastric pH changes on absorption 
      of this lipophilic, basic, molecule with reasonable permeability but strongly 
      pH-dependent solubility. GastroPlus was used to develop a physiologically based 
      pharmacokinetics (PBPK) model integrating in vitro and in silico data and 
      dissolution studies and in silico modelling in DDDPlus were used to understand 
      the role of self-buffering and acidulant on formulation performance. Models were 
      verified by comparison of simulated pharmacokinetics for acidulant and 
      non-acidulant containing formulations to clinical data from a food effect study 
      and relative bioavailability studies with and without the gastric acid-reducing 
      agent lansoprazole. A negligible food effect and minor pH-dependent drug-drug 
      interaction for the market formulation were predicted based on biorelevant in 
      vitro measurements, dissolution studies, and in silico modelling and were 
      confirmed in clinical studies. These outcomes were explained as due to the 
      acidulant counteracting entrectinib self-buffering and greatly reducing the 
      effect of gastric pH changes. Finally, sensitivity analyses with the verified 
      model were applied to support drug product quality. PBBM has great potential to 
      streamline late-stage drug development and may have impact on regulatory 
      questions.
FAU - Parrott, Neil
AU  - Parrott N
AD  - Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 
      Grenzacherstrasse 124, 4070, Basel, Switzerland. neil_john.parrott@roche.com.
FAU - Stillhart, Cordula
AU  - Stillhart C
AD  - Pharmaceutical Research & Development, Formulation & Process Sciences, F. 
      Hoffmann-La Roche Ltd, Basel, Switzerland.
FAU - Lindenberg, Marc
AU  - Lindenberg M
AD  - Pharmaceutical Research & Development, Analytical, F. Hoffmann-La Roche Ltd, 
      Basel, Switzerland.
FAU - Wagner, Bjoern
AU  - Wagner B
AD  - Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 
      Grenzacherstrasse 124, 4070, Basel, Switzerland.
FAU - Kowalski, Karey
AU  - Kowalski K
AD  - Ignyta, San Diego, California, 92121, USA.
FAU - Guerini, Elena
AU  - Guerini E
AD  - Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 
      Grenzacherstrasse 124, 4070, Basel, Switzerland.
FAU - Djebli, Nassim
AU  - Djebli N
AD  - Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 
      Grenzacherstrasse 124, 4070, Basel, Switzerland.
FAU - Meneses-Lorente, Georgina
AU  - Meneses-Lorente G
AD  - Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 
      Grenzacherstrasse 124, 4070, Basel, Switzerland.
LA  - eng
PT  - Journal Article
DEP - 20200526
PL  - United States
TA  - AAPS J
JT  - The AAPS journal
JID - 101223209
RN  - 0 (Benzamides)
RN  - 0 (Indazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - L5ORF0AN1I (entrectinib)
SB  - IM
MH  - Adult
MH  - Benzamides/metabolism/*pharmacokinetics
MH  - Female
MH  - Food
MH  - Food-Drug Interactions/*physiology
MH  - Gastric Absorption/drug effects/*physiology
MH  - Gastric Mucosa/drug effects/*metabolism
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Indazoles/metabolism/*pharmacokinetics
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Protein Kinase Inhibitors/metabolism/*pharmacokinetics
MH  - Young Adult
OTO - NOTNLM
OT  - biopharmaceutics
OT  - food effect
OT  - gastric acid-reducing agents
OT  - physiologically based biopharmaceutics modelling
OT  - physiologically based pharmacokinetics
OT  - proton pump inhibitors
EDAT- 2020/05/28 06:00
MHDA- 2021/06/10 06:00
CRDT- 2020/05/28 06:00
PHST- 2020/02/05 00:00 [received]
PHST- 2020/04/29 00:00 [accepted]
PHST- 2020/05/28 06:00 [entrez]
PHST- 2020/05/28 06:00 [pubmed]
PHST- 2021/06/10 06:00 [medline]
AID - 10.1208/s12248-020-00463-y [pii]
AID - 10.1208/s12248-020-00463-y [doi]
PST - epublish
SO  - AAPS J. 2020 May 26;22(4):78. doi: 10.1208/s12248-020-00463-y.