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.

Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, a Highly Selective ALK Inhibitor, in Healthy Subjects

“…Although the in vitro solubility suggested potentially lower solubility with increasing pH, alectinib solubility was generally low across the pH range. Indeed, PBPK modeling of alectinib absorption predicts a low impact of dissolution in the stomach on oral absorption irrespective of the stomach pH, and no relevant change in exposure is predicted based on a change in gastric pH because of the very low solubility in the stomach at all pH values . Given that alectinib has not shown any perpetrator effects on CYP3A or CYP2C19 enzymes, no confounding influence of potential CYP‐mediated drug–drug interactions with esomeprazole was expected in this assessment.…”

“…In vitro data for alectinib show that its solubility in fed state–simulated intestinal fluid (FeSSIF; 77 μg/mL) was higher than in fasted state–simulated intestinal fluid (FaSSIF; 23 μg/mL), suggesting the potential for a positive food effect . Results from an exploratory food effect assessment using an uncontrolled meal type in the alectinib first‐in‐human study, AF‐001JP, showed an approximate 1.8‐fold effect on alectinib single 300‐mg dose PK .…”

“…Results from an exploratory food effect assessment using an uncontrolled meal type in the alectinib first‐in‐human study, AF‐001JP, showed an approximate 1.8‐fold effect on alectinib single 300‐mg dose PK . Further, although alectinib has low solubility in aqueous buffers, there was some indication for better solubility in acidic pH ranges (solubility of 7.45 μg/mL at pH 1 and 0.013 μg/mL at pH 6 in titrisol buffer) . Thus, to inform appropriate clinical administration of alectinib, a food‐effect study was undertaken with the clinical formulation used in the pivotal studies.…”

Metabolites of alectinib in human: their identification and pharmacological activity

“…For the human ADME study, dosimetry calculation was used to decide the appropriate radiation burden from data on tissue distribution and mass balance obtained in rats [12]. Alectinib, with logD 1.96 at pH 3.575 and pKa 7.05 [21], could bind melanin similarly to many lipophilic basic drugs [22, 23]. The dosimetry calculations limited alectinib to 2.5 MBq (67 μCi)/body and the specific radioactivity of a clinical dose of 600 mg was calculated as 4.17 MBq/g.…”

Clinical Bioavailability of the Novel BACE1 Inhibitor Lanabecestat (AZD3293): Assessment of Tablet Formulations Versus an Oral Solution and the Impact of Gastric pH on Pharmacokinetics

“…To evaluate the potential impact of elevated gastric pH on clinical PK, an absorption model was constructed using the physiochemical properties of lanabecestat with observed clinical PK results. GastroPlus (Simulations Plus, Inc., Lancaster, California) is a mechanistically based simulation software package that simulates absorption and pharmacokinetics in humans and animals and has been used to model the absorption behavior of drugs . A preliminary absorption model was constructed using a combination of in silico and in vitro physiochemical properties.…”