title: Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib.
abstract: Alectinib, a lipophilic, basic, anaplastic lymphoma kinase (ALK) inhibitor with very low aqueous solubility, has received Food and Drug Administration-accelerated approval for the treatment of patients with ALK+ non-small-cell lung cancer. This paper describes the application of physiologically based absorption modeling during clinical development to predict and understand the impact of food and gastric pH changes on alectinib absorption. The GastroPlus™software was used to develop an absorption model integrating in vitro and in silico data on drug substance properties. Oral pharmacokinetics was simulated by linking the absorption model to a disposition model fit to pharmacokinetic data obtained after an intravenous infusion. Simulations were compared to clinical data from a food effect study and a drug-drug interaction study with esomeprazole, a gastric acid-reducing agent. Prospective predictions of a positive food effect and negligible impact of gastric pH elevation were confirmed with clinical data, although the exact magnitude of the food effect could not be predicted with confidence. After optimization of the absorption model with clinical food effect data, a refined model was further applied to derive recommendations on the timing of dose administration with respect to a meal. The application of biopharmaceutical absorption modeling is an area with great potential to further streamline late stage drug development and with impact on regulatory questions.
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070, Basel, Switzerland. neil_john.parrott@roche.com.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Parrott
authors.affiliation: Roche Innovation Center, New York City, New York, USA.
authors.forename: Li J
authors.initials: LJ
authors.lastname: Yu
authors.affiliation: Pharmaceutical Technology Division, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Takano
authors.affiliation: Translational Clinical Research Division, Chugai Pharmaceutical Co. Ltd., Tokyo, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Roche Innovation Center, New York City, New York, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002227:Carbazoles / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D005260:Female; D005502:Food; D005744:Gastric Acid / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D010880:Piperidines / Q000493:pharmacokinetics*; D010919:Placebos; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D055815:Young Adult
chemical_list: D002227:Carbazoles; D003692:Delayed-Action Preparations; D010880:Piperidines; D010919:Placebos; D047428:Protein Kinase Inhibitors; C582670:alectinib
keywords: biopharmaceutics; food effect; gastric acid-reducing agents; proton pump inhibitors