Objectives: Omaveloxolone is a nuclear factor (erythroid-derived 2)-like 2 activator approved in the US and EU for the treatment of Friedreich ataxia in patients aged ≥16 years. It is approved at a dosage of 150 mg administered orally once daily on an empty stomach. Food-drug interactions can potentially alter the pharmacokinetic (PK) parameters of an oral drug, which may affect its efficacy and/or safety profile. Physiologically based biopharmaceutics modeling (PBBM) enables prediction of the PK profiles of oral drugs by integrating drug physicochemical properties and formulation factors with system physiological parameters. A PBBM was developed to predict and explain the effect of the US Food and Drug Administration high-fat meal on the PK of omaveloxolone.
Methods: The PBBM was developed using physicochemical, dissolution, bile salt solubilization, precipitation, permeability, and in vitro and in vivo metabolism data. It was then validated across 9 distinct clinical scenarios that evaluated the impact of food, dose proportionality, and drug-drug interactions. Sensitivity analyses were performed to identify the parameters that could impact the absorption and metabolism of omaveloxolone in the fasted state.
Results: The model’s predictive ability was evaluated based on the model’s performance indicators of maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC), which met predefined acceptance criteria across all analyzed clinical scenarios. Key parameters influencing the PK of omaveloxolone included bile salt solubilization, maximum rate of reaction of CYP3A4, particle size distribution, and permeability. The PBBM predicted a 350% increase in Cmax, with only a 15% increase in the AUC; this is consistent with clinical study findings. The effect of a high-fat meal on the PK of omaveloxolone is unique, as it differs from the linear correlation between Cmax and AUC ratios reported for other compounds from 323 food effect studies.[1-6] The PBBM showed that in vivo omaveloxolone absorption is solubility and dissolution rate limited. In the fed state, bile salt solubilization resulted in more rapid dissolution, leading to enhanced drug absorption in the upper gastrointestinal tract compared with the fasted state. Consequently, there was an increase in first-pass gut extraction, which explains a large transient elevation in Cmax without a corresponding increase in AUC.
Conclusions: By mechanically integrating solubility and dissolution into PBBM, the unique impact of a high-fat meal on the PK profile of omaveloxolone was accurately anticipated. These findings reinforce the drug label recommendations on administration of omaveloxolone on an empty stomach. PBBM has the potential to predict the impact of food on drug PK and possibly eliminates the need for a clinical study.
Citations: [1] Singh BN, Malhotra BK. Clin Pharmacokinet. 2004;43(15):1127-1156. [2] Qin H, et al. Basic Clin Pharmacol Toxicol. 2022;130(2):268-276. [3] Riedmaier AE, et al. AAPS J. 2020;22(6):123. [4] Omachi F, et al. J Pharm Health Care Sci. 2019;5:26. [5] Kesisoglou F, et al. AAPS J. 2023;25(4):60. [6] Li M, et al. CPT Pharmacometrics Syst Pharmacol. 2018;7(2):82-89.
