Effect of Food and a Proton-Pump Inhibitor on the Absorption of Encorafenib: An In Vivo–In Vitro–In Silico Approach

Abstract

Encorafenib is a kinase inhibitor indicated for the treatment of patients with BRAF mutant melanoma and BRAF mutant metastatic colorectal cancer. To understand the effect of food and coadministration with a proton-pump inhibitor (PPI), in vitro, in vivo, and in silico data were generated to optimize the clinical dose, evaluate safety, and better understand the oral absorption process under these conditions. Study 1 evaluated the effect of food on the plasma pharmacokinetics, safety, and tolerability after a single oral dose of encorafenib 100 mg. Study 2 evaluated the same end points with coadministration of encorafenib and rabeprazole (PPI perpetrator). The in vitro gastrointestinal TIM-1 model was used to investigate the release of encorafenib and the amount available for absorption under different testing conditions (fasted, fed, and with the use of a PPI). The fasted, fed, and PPI states were predicted for the encorafenib commercial capsule in GastroPlus 9.8. In study 1, both AUC inf and AUC last decreased by 4% with the administration of a high-fat meal. The C max was 36% lower than with fasted conditions. All 3 exposure parameters in study 2 (AUC inf , AUC last , and C max ) had mean changes of <10% when encorafenib was coadministered with a PPI. Using the in vitro gastrointestinal simulator TIM-1, the model demonstrated a similar release of drug, as the bioaccessible fraction, in the 3 conditions was equal (≥80%), predicting no PPI or food effect for this drug formulation. The modeling in GastroPlus 9.8 demonstrated complete absorption of encorafenib when formulated as an amorphous solid dispersion. To obtain these results, it was crucial to integrate the amorphous solubility of the drug that shows a 20-fold higher solubility at pH 6.8 compared with crystalline solubility. The increased amorphous solubility is likely the reason no PPI effect was observed compared with fasted state conditions. The prolongation in gastric emptying in the fed state resulted in delayed plasma T max for encorafenib. No dose adjustment is necessary when encorafenib is administered in the fed state or when coadministered with a PPI. Both the TIM-1 and physiologically based pharmacokinetic model results were consistent with the observed clinical data, suggesting that these will be valuable tools for future work.

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

“…After that, the male animals were selected for subsequent studies. In addition, all the pharmacokinetic studies were executed in the overnight fasted condition (∼10 h) to avoid any variation due to the fed state, as it is reported that there might be a lower exposure in the presence of food . To investigate the pharmacokinetics of EIDD-1931 under any disease state, we first induced the particular disease state and confirmed by disease-specific marker(s) supported by histopathological findings wherever required.…”

Dose-sparing effect of lapatinib co-administered with a high-fat enteral nutrition emulsion: preclinical pharmacokinetic study

“…This was likely attributed to the limited efficacy of a liquid diet in delaying gastric emptying and reducing small intestinal motility. Meanwhile, food may alter lapatinib bioavailability by changing the gastrointestinal pH, increasing splanchnic blood flow, affecting metabolism, and many other factors ( Huh et al, 2023 ; Piscitelli et al, 2023 ; Vertzoni et al, 2019 ). In the rat model, TPF-T had minimal influence on the lapatinib pharmacokinetics probably because rats had higher bile flow.…”

Introducing the Molecular Pharmaceutics Special Issue on Industrial Drug Delivery─In Silico to Bedside

“…It also shows the expanded space of oral small molecule drug delivery including modeling and artificial intelligence. In the industrial setting these computational approaches are used both in the discovery space to select the right candidates but also as part of formulation development to model absorption, formulation processes, and degradation pathways or as part of process development.…”