088: Development, Verification & Application of Physiologically-based Pharmacokinetic Model to Evaluate the CYP3A4-mediated Drug-Drug Interactions Potential of Omaveloxolone

Statement of Purpose: A physiologically based pharmacokinetic model (PBPK) model for omaveloxolone was constructed to evaluate the potential drug-drug interactions (DDIs) when co-administered with cytochrome P450 (CYP)3A4 modulators and substrates of CYP3A4.

Description of Methods & Materials: The PBPK model was developed using a combination of in vitro and clinical pharmacokinetic (PK) data obtained following the administration of single and multiple oral doses (150 mg) of omaveloxolone in healthy subjects. The model included a first-order absorption model in conjunction with a minimal PBPK plus single adjusting compartment distribution model. The base model incorporated the relative contribution (fm) CYP3A4 (99%) and CYP2C8 (1%) to drug clearance based on in vitro phenotyping data. The model was verified against the data from single ascending dose study. The model was subsequently refined by adjusting fm for CYP3A4 to 90%, based on the recovery of itraconazole clinical DDI data. The model was further modified by adjusting the absorption constant to 6 h-1 to match the higher maximum observed concentration (C_max) observed in patients and applied to simulate steady-state drug exposures in patients with Friedreich’s ataxia (FA). For perpetrator DDI assessment, in vitro CYP3A4 induction (IndMax and IndC50) data were incorporated. The optimized IndMax and IndC50 for CYP3A4 were 5.2-fold and 0.166 μM, respectively, based on the recovery of midazolam DDI.

Data & Results: The predicted geometric mean C_max and area under the concentration time curve from time zero to infinity (AUC_0-∞) using the developed PBPK model for omaveloxolone were within 0.62– 1.31-fold of the observed values (single-dose of 50 to 150 mg). The predicted mean C_max and AUC values for omaveloxolone for the dose cohort of 80 mg, 150 mg, 160 mg and 300 mg, QD in FA subjects were within 0.63 to 1.01-fold of the observed values. The simulated C_max and AUC_0-∞ geometric least square mean ratios (GLSMRs) following coadministration of itraconazole or gemfibrozil with a single oral dose of 150 mg omaveloxolone were within 0.9 to 1.2-fold of the observed GLSMR values of omaveloxolone. The simulated midazolam C_max and AUC_0-∞ GLSMRs following co-administration of a single oral dose of 2 mg midazolam with omaveloxolone were within 1.05 to 1.21-fold of the observed values. The simulated plasma profiles of omaveloxolone were comparable to the observed PK profile in FA patients. The verified model was applied to simulate DDI with the moderate and weak CYP3A4 inhibitors fluconazole and cimetidine respectively, as well as with moderate (efavirenz) and strong (rifampin) CYP3A4 inducers after 150 mg single and multiple doses of omaveloxolone (Table 1).

Interpretation, Conclusion or Significance: The results from this study were utilized to provide guidance when strong and moderate CYP3A4 inhibitors and inducers and CYP3A4 substrates are to be co-administered with omaveloxolone. Concomitant use of strong and moderate CYP3A4 inhibitors or inducers with omaveloxolone is recommended to be avoided. If concomitant use of strong and moderate CYP3A4 inhibitors cannot be avoided, omaveloxolone dosage reduction with monitoring is recommended. No dose adjustments are recommended for CYP3A4 substrates when co-administered with omaveloxolone.

Disclosures: Aparna Shinde, Scott Hynes, and Hamim Zahir are employees of Reata Pharmaceuticals. Hannah Jones, Alice Ke Zamek, and Nikunjkumar Patel are employees of Certara. Sarabjit Gahir is a former employee of Reata Pharmaceutical and a current employee of Bellus Health.