Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib

Abstract

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.

Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors

“…A total of three different clinical capsule formulations (F1, F2A, and F06) have been used in the patient clinical studies. Based on exploratory observations from Study ALKA-372-001 [5,6], performance of the F1 formulation appeared to be sub-optimal during clinical dosing due to the formulation performance being very sensitive to conditions in the gastroenvironmental tract, which is consistent with recently reported GastroPlus data [8]. Subsequently, an alternative gelatin capsule formulation (F2A) was developed.…”

“…Entrectinib is a lipophilic base with high aqueous solubility at low pH but shows a pronounced decrease in solubility as pH increases [8]. In order to improve solubility and reduce the high variability observed with the early formulation (F1) in Study 1, an acidulant was added to the research formulation F2A (and the marketed formulation F06).…”

“…Entrectinib is a lipophilic, basic, moderately permeable molecule with strongly pH-dependent solubility [8]. A total of three different clinical capsule formulations (F1, F2A, and F06) have been used in the patient clinical studies.…”

“…This formulation contained an acidulant (betaine hydrochloride) in order to reduce the sensitivity and variability of entrectinib bioavailability to gastric pH conditions. Further formulation development resulted in the marketed formulation F06 which also included an acidulant (tartaric acid) as a functional excipient [8]. The preclinical pharmacokinetics (PK) of entrectinib have been evaluated in mice, rats and dogs to support the preclinical safety and PK assessments of entrectinib [7].…”

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

“…The precise impact of the observed fluid volume changes, in combination with the PPI-induced drop in gastric pH, on the absorption of ritonavir will be further evaluated using in vitro dissolution testing in combination with physiologically-based pharmacokinetic (PBPK) modelling. PBPK modelling has previously been utilized to predict in vivo drug-drug interactions between weakly basic compounds and PPIs or other acid-reducing agents [ 31 , 32 , 33 ]. From a broader perspective, the results of this study should be taken into consideration when developing and testing new drug candidates especially for populations in which PPI use is most frequent, including elderly [ 12 ].…”